Yutaka Nakaya : 認定病態栄養専門師のための病態栄養ガイドブック, Medical Review Co.,Ltd, Tokyo, Apr. 2005.
37.
Masahiro Nomura, Yutaka Nakaya, A Nishikado, K Koshiba, K Yamaguchi, Tomohito Kawano and Susumu Ito : Autonomic nervous activity and QT dispersion at common bile duct treatment during endoscopic retrograde cholangiopancreticography: Correlation with cardiac accident, Jan. 2005.
38.
Masahiro Nomura, Yutaka Nakaya, Susumu Ito and H Itozaki : Visualization of cardiac electrical current using 32-channel high temperature superconducting quantum interference device, Massachusetts, Aug. 2004.
39.
Masahiro Nomura, Yutaka Nakaya, Akiyoshi Nishikado, K Koshiba, Kouji Yamaguchi, Tomohito Kawano and Susumu Ito : AUTONOMIC NERVOUS ACTIVITY AND QT DISPERSION AT COMMON BILE DUCT TREATMENT DURING ENDOSCOPYIC RETROGRAE CHOLANGIOANCREATOICOGRAPHY:CORRELAATION WITH CARDIAC ACCIDENTS., Course of Preventive Medicine, Tokushima, Jul. 2004.
40.
Yutaka Nakaya, 鈴木 和枝, Kazuaki Mawatari, Masashi Kuwahata, Yutaka Taketani, Nagakatsu Harada and Hironori Yamamoto : 臨床栄養学(第4版), 医学出版社, Tokyo, Mar. 2004.
Yutaka Nakaya, M Yukinaka, Masahiro Nomura, F Kishi and Ken Saito : Analysis of elevtromotive force by magnetocardiogram Is the origin of initial QRS force (septal vector) of electrocardiogram intraventricular septum?, Springer-Verlag, 2000.
47.
Tetsuya Saijyo, Masahiro Nomura, Y Haruta, H Itozaki, H Toyoda, Yutaka Nakaya, Susumu Ito and H Kado : Magnetogastrograms using 64-channel SQUID system: Study on clinical usefulness., Springer-Verlag, New York, 2000.
Yutaka Nakaya and Masahiro Nomura : Magnetocardiography - an useful tool for the study of electromotive forces, Tohoku University Press, Sendai, 1999.
50.
Y Kondo, Masahiro Nomura, Yutaka Nakaya, T Nada, M Yukinaka, Susumu Ito, H Isozaki and R Nagaishi : Magnetocardiographic measurement using a high-temperature SQUID in healthy subjects: comparison with conventional low-temperature SQUID system, Tohoku University press., Sendai, 1999.
51.
M Yukinaka, Masahiro Nomura, T Nada, Y Kondo, Ken Saito, Susumu Ito and Yutaka Nakaya : QTc dispersion using magnetocardiogram: analysis in patients with myocardial infarction, Tohoku University press., 1999.
52.
Masahiro Nomura, Y Kondo, T Nada, M Yukinaka, Ken Saito, Susumu Ito and Yutaka Nakaya : Biomagnetic measurement of small intestinal electrical activity by 64-channel magnetographic imaging, Tohoku University press., 1999.
Yutaka Nakaya : 5. 循環器疾患, 株式会社 講談社サイエンティフィク, Tokyo, Oct. 1998.
55.
Masahiro Nomura, Yutaka Nakaya, Fumiko Kishi, Michiko Yukinaka, Ken Saito, Hiroshi Shibata and Susumu Ito : Heart rate variability during painful medical procedures (percutaneous ethanol injection therapy), World Scientific Publishing, 1997.
56.
Masahiro Nomura, Ken Saito, Yutaka Nakaya and Susumu Ito : 循環器症候群·領域別症候群シリーズ No.12 複数短形性心室頻拍, NIPPONRINSHOSHA Co.,Ltd., Osaka, 1996.
57.
岸 史子, Masahiro Nomura, Ken Saito, Yutaka Nakaya and Susumu Ito : 循環器症候群·領域別症候群シリーズ No.12 倒錯型心室頻拍, NIPPONRINSHOSHA Co.,Ltd., Osaka, 1996.
58.
岸 史子, Masahiro Nomura, Ken Saito, Yutaka Nakaya and Susumu Ito : 循環器症候群·領域別症候群シリーズ No.12 単形性心室頻拍, NIPPONRINSHOSHA Co.,Ltd., Osaka, 1996.
59.
Ken Saito, 岸 史子, Masahiro Nomura and Yutaka Nakaya : 循環器症候群·領域別症候群シリーズ No.12 多形性心室頻拍, NIPPONRINSHOSHA Co.,Ltd., Osaka, 1996.
60.
Ken Saito, 岸 史子, Masahiro Nomura and Yutaka Nakaya : 循環器症候群·領域別症候群シリーズ No.12 特発性心室細動, NIPPONRINSHOSHA Co.,Ltd., Osaka, 1996.
61.
Masahiro Nomura, Susumu Ito and Yutaka Nakaya : 現代臨床機能検査-その実際と選択-, NIPPONRINSHOSHA Co.,Ltd., 1996.
62.
Susumu Ito, Yutaka Nakaya and 福田 信夫 : 肝臓と多臓器病変, 日本医学館, Tokyo, Jul. 1995.
63.
Masahiro Nomura and Yutaka Nakaya : Fundamentals of cardiac arrhythmia, IOS Press, 1995.
64.
Yutaka Nakaya, Masahiro Nomura, Ken Saito, F Kishi, Hirokazu Miyoshi and Akiyoshi Nishikado : Comparative studies of magnetocardiographic and electrocardiographic mappings for the localization of accessory pathway in WPW syndrome, IOS Press, 1995.
65.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, Fumiko Kishi, Hirokazu Miyoshi, Susumu Ito, Masao Wada, Satoshi Fujita, Tsutomu Takae and Itsuro Tamura : Atrial excitation onto the MRI using magnetocardiogram., IOS Press, 1995.
66.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, F Kishi, H Miyoshi, Susumu Ito, M Wada, S Fujita, T Takae and I Tamura : Localization of the focus in ventricular tachycardia by magnetocardiogram, IOS Press, 1995.
67.
森 博愛, 白神 皞, 近藤 一正, Yutaka Nakaya, Ken Saito and Ichiro Shimizu : コメディカルのための内科学, 医学出版社, Tokyo, May 1994.
68.
Yutaka Nakaya and Masahiro Nomura : 心磁図法の虚血性心疾患への応用, NIPPONRINSHOSHA Co.,Ltd., 1994.
69.
Yutaka Nakaya, Kazuhiro Mori, H Miyoshi, F Kishi, Ken Saito and Masahiro Nomura : Cyclic AMP-mediated nitric oxide production by vasoactive substances, Yubunsha Publishing, 1994.
70.
森 博愛, 小塚 隆弘, 松尾 裕英 and Yutaka Nakaya : 心臓病のイメージ診断, Medical-Aoi Publications,Inc, Tokyo, Nov. 1992.
71.
Ken Saito, 森 博愛, Yutaka Nakaya, 日浅 芳一 and 坂東 重信 : 心電図の基礎と臨床, IGAKU-SHOIN Ltd.Tokyo,Japan, Tokyo, Oct. 1990.
72.
Masahiro Nomura, Yutaka Nakaya, K Watanabe, Mariko Katayama, Akemi Takeuchi, Kazuya Fujino and H Mori : Detection of accessory pathway in patients with WPW syndrome by means of the isomagnetic map and MRI, Plenum Press, 1989.
73.
Yutaka Nakaya, H Mori and Masahiro Nomura : Clinical value of magnetocardiographic mapping, Plenum Press, 1989.
74.
Masahiro Nomura, K Watanabe, Mariko Katayama, Akemi Takeuchi, Kazuya Fujino, Yutaka Nakaya and H Mori : Detection of the abnormal repolarization vector in diabetes mellitus by means of the isomagnetic map, Plenum Press, 1989.
75.
Mariko Katayama, Masahiro Nomura, K Watanabe, Akemi Takeuchi, Kazuya Fujino, Yutaka Nakaya and H Mori : The magnetocardiogram in patients with systolic and diastolic overload of the right ventricle, Plenum Press, 1989.
76.
K Watanabe, Akemi Takeuchi, Mariko Katayama, Yoshiharu Fukuda, Masahiro Nomura, M Sumi, M Murakami, Yutaka Nakaya and H Mori : Analysis of activation sequence by isomegnetic and vector arrow maps, Tokyo Denki University Press, Tokyo, 1987.
77.
M Sumi, K Watanabe, Akemi Takeuchi, Shuichiro Nakaya, Yoshiharu Fukuda, Masahiro Nomura, Kazuya Fujino, M Murakami, Yutaka Nakaya and H Mori : Isomagnetic map in right ventricular overloading, Tokyo Denki University Press, Tokyo, 1987.
78.
M Murakami, K Watanabe, Akemi Takeuchi, Mariko Katayama, Masahiro Nomura, Yoshiharu Fukuda, M Sumi, Yutaka Nakaya and H Mori : The QRS wave of the magnetocardiogram in myocardial infarction, Tokyo Denki University Press, Tokyo, 1987.
79.
Hiroyoshi Mori, Toshiharu Niki, Yoshiyuki Tamura, Yutaka Nakaya, Ken Saito and 他25名 : 最新循環器病学, KANEHARA & CO., LTD., Tokyo, Oct. 1983.
80.
Ken Saito, Yutaka Nakaya, Hiroyoshi Mori, Yoshiyuki Tamura and 他10名 : 虚血症心疾患, 医学出版社, Tokyo, Jul. 1982.
Academic Paper (Judged Full Paper):
1.
Nagakatsu Harada, Yuka Gotoda, Adzumi Hatakeyama, Tadahiko Nakagawa, Yumiko Miyatake, Masashi Kuroda, Saeko Masumoto, Rie Tsutsumi, Yutaka Nakaya and Hiroshi Sakaue : Differential regulation of Actn2 and Actn3 expression during unfolded protein response in C2C12 myotubes., Journal of Muscle Research and Cell Motility, 2020.
(Summary)
ACTN2 and ACTN3 encode sarcomeric α-actinin-2 and α-actinin-3 proteins, respectively, that constitute the Z-line in mammalian skeletal muscle fibers. In human ACTN3, a nonsense mutation at codon 577 that encodes arginine (R) produces the R577X polymorphism. Individuals having a homozygous 577XX genotype do not produce α-actinin-3 protein. The 577XX genotype reportedly occurs in sprint and power athletes in frequency lower than in the normal population, suggesting that α-actinin-3 deficiency diminishes fast-type muscle function. Among humans who carry 577R alleles, varying ACTN3 expression levels under certain conditions can have diverse effects on atheletic and muscle performance. However, the factors that regulate ACTN3 expression are unclear. Here we investigated whether the unfolded protein response (UPR) under endoplasmic reticulum (ER) stress regulates expression of Actn3 and its isoform Actn2 in mouse C2C12 myotubes. Among UPR-related transcription factors, XBP1 upregulated Actn2, whereas XBP1, ATF4 and ATF6 downregulated Actn3 promoter activity. Chemical induction of ER stress increased Actn2 mRNA levels, but decreased those for Actn3. ER stress also decreased α-actinin-3 protein levels, whereas levels of α-actinin-2 were unchanged. The intracellular composition of muscle contraction-related proteins was altered under ER stress, in that expression of parvalbumin (a fast-twitch muscle-specific protein) and troponin I type 1 (skeletal, slow) was suppressed. siRNA-induced suppression of Actn3 mimicked the inhibitory effect of ER stress on parvalbumin levels. Thus, endogenous expression levels of α-actinin-3 can be altered by ER stress, which may modulate muscle performance and athletic aptitudes, particularly in humans who carry ACTN3 577R alleles.
expression and thereby induced production of full-length α-actinin-3 protein in the presence of aminoglycoside. Together these results indicate that the ACTN3 R577X polymorphism could be a novel target for readthrough therapy, which may affect athletic and muscle performance in humans.
Shusuke Yagi, Ken-ichi Aihara, Takeshi Kondo, Kiyoe Kurahashi, Sumiko Yoshida, Itsuro Endo, Daiju Fukuda, Yutaka Nakaya, Kin-Ichiro Suwaki, Takashi Takeji, Toshihiro Wada, Masdan Hotimah Salim, Saori Hama, Tomomi Matsuura, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Takeshi Tobiume, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Munehide Matsuhisa, Michio Shimabukuro, Masashi Akaike and Masataka Sata : Predictors for the Treatment Effect of Sodium Glucose Co-transporter 2 Inhibitors in Patients with Type 2 Diabetes Mellitus., Advances in Therapy, Vol.35, No.1, 124-134, 2017.
(Summary)
Predictors for the effect of sodium glucose co-transporter 2 (SGLT2) inhibitors at lowering hemoglobin A1c (HbA1c) levels in type 2 diabetes mellitus patients remain unclear. We therefore aimed to elucidate these predictors in type 2 diabetes patients after 3 months of SGLT2 treatment. A total of 302 consecutive type 2 diabetes patients who had been treated with SGLT2 inhibitors as monotherapy or add-on therapy to existing antidiabetic treatments were enrolled retrospectively. After excluding 27 patients whose HbA1c levels could not be evaluated 3 months after treatment, the glucose-lowering effects of SGLT2 inhibitors were assessed in 275 patients by measuring HbA1c levels before and 3 months after treatment. The predictors for changes in HbA1c levels after 3 months of treatment were evaluated. SGLT2 inhibitor treatment for 3 months decreased HbA1c levels from 7.8 ± 1.2% to 7.4 ± 1.0% (p < 0.0001). A multiple regression analysis showed that the independent determinants for SGLT2 inhibitor treatment effect included decreased HbA1c levels after 1 month of treatment, high baseline HbA1c levels, and a high estimated glomerular filtration rate (eGFR). We show that type 2 diabetes patients who received the greatest glucose-lowering effect with SGLT2 inhibitor treatment were those with preserved renal function (high baseline eGFR) and high baseline HbA1c levels. Moreover, SGLT2 inhibitor treatment efficacy could be predicted by the patients' initial response to treatment.
Yutaka Nakaya, Daiju Fukuda, Takashi Oyamada, Kazuo Ogawa, Nagakatsu Harada, Hironori Nakagami, Ryuichi Morishita, Masataka Sata and Hiroshi Sakaue : A novel lipoprotein (a) lowering drug, D-47, decreases neointima thickening after vascular injury., The Journal of Medical Investigation : JMI, Vol.64, No.1, 2, 64-67, 2017.
(Summary)
Although Lp(a) have been thought to be a cardiovascular risk factor, it is unclear whether lowering Lp(a) levels reduces the risk of cardiovascular diseases. No pharmacological agents which selectively reduce serum Lp(a) levels, and Lp(a) is present in primate but absent in common laboratory animals such as mice and pigs. In the present study we used transgenic mice of human Lp(a) and tested effect a novel Lp(a) lowering drug D-47 on neointima formation after vascular injury. D-47 successfully decreased plasma levels of Lp(a) and possibly inhibited neointima formation in Lp(a) transgenic mice. The results indicate that we can modulate plasma Lp(a) levels by pharmacologic agents and inhibit atherogenic properties of Lp(a) by reducing plasma levels of Lp(a). J. Med. Invest. 64: 64-67, February, 2017.
(Keyword)
lipoprotein a / atherosclerosis / cardiovascular events / low density lipoprotein
There is an increasing interest in elucidating the molecular mechanisms by which voluntary exercise is regulated. In this study, we examined how the central nervous system regulates exercise. We used SPORTS rats, which were established in our laboratory as a highly voluntary murine exercise model. SPORTS rats showed lower levels of serum ghrelin compared with those of the parental line of Wistar rats. Intracerebroventricular and intraperitoneal injection of ghrelin decreased wheel-running activity in SPORTS rats. In addition, daily injection of the ghrelin inhibitor JMV3002 into the lateral ventricles of Wistar rats increased wheel-running activity. Co-administration of obestatin inhibited ghrelin-induced increases in food intake but did not inhibit ghrelin-induced suppression of voluntary exercise in rats. Growth hormone secretagogue receptor (GHSR) in the hypothalamus and hippocampus of SPORTS rats was not difference that in control rats. We created an arcuate nucleus destruction model by administering monosodium glutamate (MSG) to neonatal SPORTS rats. Injection of ghrelin into MSG-treated rats decreased voluntary exercise but did not increase food intake, suggesting that wheel-running activity is not controlled by the arcuate nucleus neurons that regulate feeding. These results provide new insights into the mechanism by which ghrelin regulates voluntary activity independent of arcuate nucleus neurons.
Otsuka Ryo, Nagakatsu Harada, Aoki Shouhei, Shirai Kanna, Kazuchika Nishitsuji, Nozaki Ayane, Hatakeyama Adzumi, Masayuki Shono, Noriko Mizusawa, Katsuhiko Yoshimoto, Yutaka Nakaya, Hiroshi Kitahata and Hiroshi Sakaue : C-terminal region of GADD34 regulates eIF2alpha dephosphorylation and cell proliferation in CHO-K1 cells., Cell Stress & Chaperones, Vol.21, No.1, 29-40, 2016.
(Summary)
GADD34 is a member of a growth arrest and DNA damage (GADD)-inducible gene family. Here, we established a novel Chinese hamster ovary (CHO)-K1-derived cell line, CHO-K1-G34M, which carries a nonsense mutation (termed the Q525X mutation) in the GADD34 gene. The Q525X mutant protein lacks the C-terminal 66 amino acids required for GADD34 to bind to and activate protein phosphatase 1 (PP1). We investigated the effects of GADD34 with or without the Q525X mutation on the phosphorylation status of PP1 target proteins, including the subunit of eukaryotic initiation factor 2 (eIF2) and glycogen synthase kinase 3 (GSK3). CHO-K1-G34M cells had higher levels of eIF2 phosphorylation compared to the control CHO-K1-normal cells both in the presence and absence of endoplasmic reticulum stress. Overexpression of the wild-type GADD34 protein in CHO-K1-normal cells largely reduced eIF2 phosphorylation, while overexpression of the Q525X mutant did not produce similar reductions. Meanwhile, neither wild type nor Q525X mutation of GADD34 affected the GSK3 phosphorylation status. GADD34 also did not affect the canonical Wnt signaling pathway downstream of GSK3. Cell proliferation rates were higher, while expression levels of the cyclin-dependent kinase inhibitor p21 were lower in CHO-K1-G34M cells compared to the CHO-K1-normal cells. The GADD34 Q525X mutant had a reduced ability to inhibit cell proliferation and enhance p21 expression of the CHO-K1-normal cells compared to the wild-type GADD34 protein. These results suggest that the GADD34 protein C-terminal plays important roles in regulating not only eIF2 dephosphorylation but also cell proliferation in CHO-K1 cells.
Masakazu Goda, Osamu Jinnouchi, Tsukasa Takaoka, Koji Abe, Koichi Tamura, Yutaka Nakaya, Yoshihito Furukita, Hirokazu Takechi, Akira Tangoku and Noriaki Takeda : Efficacy of percutaneous endoscopic gastrostomy on unplanned treatment interruption and nutritional status in patients undergoing chemoradiotherapy for advanced head and neck cancer., The Journal of Medical Investigation : JMI, Vol.62, No.3-4, 173-176, 2015.
(Summary)
It is suggested that therapeutic PEG placement is useful for preventing unplanned interruption of CRT in patients with advanced head and neck cancer. After severe mucositis and inadequate oral intake have developed during CRT, PEG placement should be considered before the radiation therapy dose of 30 Gy.
Soushi Ishida, Ichiro Hashimoto, Takuya Seike, Yoshiro Abe, Yutaka Nakaya and Hideki Nakanishi : Serum albumin levels correlate with inflammation rather than nutrition supply in burns patients : a retrospective study, The Journal of Medical Investigation : JMI, Vol.61, No.3.4, 361-368, 2014.
(Summary)
The aim of this retrospective study was to examine whether serum albumin levels offer a good marker of nutritional status in patients with burns. Serum albumin levels have been used to evaluate nutritional status in burns patients, even though these levels are affected by various factors and are not specific to malnutrition. To clarify whether provision of nutrition or presence of inflammation affects serum albumin levels, we studied serum albumin levels, C-reactive protein (CRP) levels and caloric intake over time in 30 patients with burns. Serum albumin levels did not respond to provision of nutrition, but correlated negatively with CRP levels, suggesting that serum albumin levels are more closely associated with inflammation than nutrition. This study also suggests that hypoalbuminemia is a good indicator of the severity of burns or associated complications. We conclude that serum albumin levels do not offer a good nutritional marker in burns patients.
Yoko Sakai, Shinji Kawahito, Kazumi Takaishi, Naoji Mita, Hiroyuki Kinoshita, Noboru Hatakeyama, Toshiharu Azma, Yutaka Nakaya and Hiroshi Kitahata : Propofol-induced relaxation of rat aorta is altered by aging., The Journal of Medical Investigation : JMI, Vol.61, No.3-4, 278-284, 2014.
(Summary)
Propofol causes vasodilation via endothelium-dependent and -independent mechanisms. Because endothelial function is impaired with aging, the effects of propofol on endothelium-dependent vasodilation might be altered by aging. The aim of this study was thus to determine the effects of aging on vascular responses to propofol. Young (4-6 weeks old) or adult (16-25 weeks old) rats were anesthetized with sevoflurane. The thoracic aorta was dissected and cut into pieces 3-4 mm in length. In some rings, the endothelium was deliberately removed. The ring segment of the aorta was mounted for isometric force recording at a resting tension of 0.5-1.0 g in a 2 ml organ bath, containing Krebs-Ringer bicarbonate buffer. Arteries were precontracted with phenylephrine, and the function of endothelium was confirmed with acetylcholine. Then, we studied the concentration-dependent effects of propofol in endothelium-intact (control group) and -denuded aortic rings (denuded group), as well as those treated with N()-nitro-L-arginine methylester (L-NAME group). Relaxation due to propofol was observed in the control groups of both young and adult rats in a concentration-dependent manner, but the magnitude of relaxation was significantly greater in young rats. In addition, in young rats, relaxation due to propofol was significantly and equally reduced in both L-NAME and denuded groups at all propofol concentrations that we studied (10(-6)-10(-3) M). In adult rats, relaxation due to propofol was quite similar between control and L-NAME groups at all propofol concentrations, whereas it was significantly reduced in the denuded group. These results suggest that endothelium-derived nitric oxide plays an important role in propofol-induced vasodilation in young rats, but not in adult rats. J. Med. Invest. 61: 278-284, August, 2014.
Kazuaki Mawatari, Emiko Yoshioka, Satomi Toda, Sonoko Yasui, Hiroko Furukawa, Takaaki Shimohata, Takamasa Ohnishi, Masaki Morishima, Nagakatsu Harada, Akira Takahashi, Hiroshi Sakaue and Yutaka Nakaya : Enhancement of endothelial function inhibits left atrial thrombi development in an animal model of spontaneous left atrial thrombosis., Circulation Journal, Vol.78, No.8, 1980-1988, 2014.
(Summary)
Left atrial (LA) thrombosis is an important cause of systemic embolization. The SPORTS rat model of LA thrombi (Spontaneously-Running Tokushima-Shikoku), which have a unique characteristic of high voluntary wheel running, was previously established. The aim of the present study was to investigate how SPORTS rats develop LA thrombi.Methods and Results:Nitric oxide (NO) produced from cardiovascular endothelial cells plays an important protective role in the local regulation of blood flow, vascular tone, and platelet aggregation. No evidence of atrial fibrillation or hypercoagulability in SPORTS rats regardless of age was found; however, SPORTS rats demonstrated endothelial dysfunction and a decrease of NO production from a young age. In addition, endothelial NO synthase activity was significantly decreased in the LA and thoracic aorta endothelia of SPORTS rats. While voluntary wheel running was able to intermittently increase NO levels, running did not statistically decrease the incidence of LA thrombi at autopsy. However, L-arginine treatment significantly increased NO production and provided protection from the development of LA thrombi in SPORTS rats. They present study results indicate that NO has an important role in the development of LA thrombus, and endothelia pathways could provide new targets of therapy to prevent LA thrombosis. (Circ J 2014; 78: 1980-1988).
Rie Tsutsumi, 平田 容子, Emiko Nakataki, Jun Oto, Yasuo Tsutsumi, Yutaka Nakaya, Hideaki Imanaka and Masaji Nishimura : The nutritional needs of critically ill patients do not change according to their stage, Journal of the Japanese Society of Intensive Care Medicine, Vol.21, 173-174, 2014.
(Keyword)
energy expenditure / respiratory quotient (RQ) / mechanical ventilation
Jörns Anne, Arndt Tanja, Vilsendorf Meyer zu Andreas, Klempnauer Jürgen, Wedekind Dirk, Hedrich Hans-Jürgen, Marselli Lorella, Marchetti Piero, Nagakatsu Harada, Yutaka Nakaya, Wang Gen-Sheng, Scott W. Fraser, Gysemans Conny, Mathieu Chantal and Lenzen Sigurd : Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes, Diabetologia, Vol.57, No.3, 512-521, 2014.
(Summary)
Research on the pathogenesis of type 1 diabetes relies heavily on good animal models. The aim of this work was to study the translational value of animal models of type 1 diabetes to the human situation. We compared the four major animal models of spontaneous type 1 diabetes, namely the NOD mouse, BioBreeding (BB) rat, Komeda rat and LEW.1AR1-iddm rat, by examining the immunohistochemistry and in situ RT-PCR of immune cell infiltrate and cytokine pattern in pancreatic islets, and by comparing findings with human data. After type 1 diabetes manifestation CD8(+) T cells, CD68(+) macrophages and CD4(+) T cells were observed as the main immune cell types with declining frequency, in infiltrated islets of all diabetic pancreases. IL-1β and TNF-α were the main proinflammatory cytokines in the immune cell infiltrate in NOD mice, BB rats and LEW.1AR1-iddm rats, as well as in humans. The Komeda rat was the exception, with IFN-γ and TNF-α being the main cytokines. In addition, IL-17 and IL-6 and the anti-inflammatory cytokines IL-4, IL-10 and IL-13 were found in some infiltrating immune cells. Apoptotic as well as proliferating beta cells were observed in infiltrated islets. In healthy pancreases no proinflammatory cytokine expression was observed. With the exception of the Komeda rat, the animal models mirror very well the situation in humans with type 1 diabetes. Thus animal models of type 1 diabetes can provide meaningful information on the disease processes in the pancreas of patients with type 1 diabetes.
Hirokazu Takechi, Kazuaki Mawatari, Nagakatsu Harada, Yutaka Nakaya, Megumi Asakura, Mutsumi Aihara, Hiromitsu Takizawa, Masakazu Goto, Takeshi Nishino, Takuya Minato, Yoshihito Furukita, Yota Yamamoto, Yasuhiro Yuasa, Hiromichi Yamai, Takahiro Yoshida, Jun-ichi Seike and Akira Tangoku : Glutamine protects the small intestinal mucosa in anticancer drug-induced rat enteritis model., The Journal of Medical Investigation : JMI, Vol.61, No.1-2, 59-64, 2014.
(Summary)
Supportive therapy during chemotherapy has become essential, but effective preventive therapies to gastrointestinal mucosal injury are few. We investigated the efficacy of glutamine in rat anticancer drug-induced enteritis model. In this study, we used twenty male SD rats. They were divided into control, 5-fluorouracil (5-FU) (orally administered at 20 mg/kg day), 5-FU+glutamine (1000 mg/kg/day) and 5-FU+glutamine+fiber and oligosaccharide (GFO(®)) (1000 mg/kg/day) groups. All groups were sacrificed on day 6 and upper jejunums were excised. The jejunal villous height was measured in specimens. IgA level in jejunal washing solution, and serum diamine oxidase activity were also measured. The jejunal villous height was recognized as shorter in the specimen from 5-FU treated rats compared with 5-FU+glutamine treated rats (p<0.001). Serum diamine oxidase activity in 5-FU+glutamine group were significantly superior to that in 5-FU group (p=0.028). IgA level in jejunal washing solution tended to be higher in 5-FU+glutamine group than that in 5-FU group (p=0.076). On the other hand, serum diamine oxidase activity and IgA level in jejunal washing solution showed no significant difference between 5-FU+GFO and 5-FU treatment group. Our results suggest that glutamine showed protective effects on mucosal injury of small intestine in rat anticancer drug-induced enteritis model.
(Keyword)
glutamine / gastrointestinal toxity / anticancer drug / diamine oxidase / IgA
Hirata Yoichiro, Hirotsugu Kurobe, Nishio Chika, Tanaka Kimie, Daiju Fukuda, Uematsu Etsuko, Nishimoto Sachiko, Takeshi Soeki, Nagakatsu Harada, Hiroshi Sakaue, Tetsuya Kitagawa, Michio Shimabukuro, Yutaka Nakaya and Masataka Sata : Exendin-4, a glucagon-like peptide-1 receptor agonist, attenuates neointimal hyperplasia after vascular injury., European Journal of Pharmacology, Vol.699, No.1-3, 106-111, 2013.
(Summary)
Exendin-4 is a glucagon-like peptide-1 receptor agonist that has been used as a drug for treatment of type 2 diabetes. To investigate the effect of exendin-4 on the cardiovascular system, we investigated the impact of exendin-4 on neointimal hyperplasia of the femoral artery after vascular injury. We performed wire-mediated endovascular injury in C57BL/6 mice, followed by administration of exendin-4 24 nmol/kg/day via infusion pump. Four weeks after the injury, exendin-4 treatment significantly attenuated neointimal hyperplasia of the injured artery, although it did not affect glucose metabolism and lipid profile in wild-type mice. Immunofluorescence study revealed abundant expression of GLP-1 receptor on α-smooth muscle actin-positive cells in the injured vessel. Cell proliferation assay using rat aortic smooth muscle cells showed that exendin-4 reduced PDGF-BB induced smooth muscle cell proliferation through the cAMP/PKA pathway. Exendin-4 also inhibited TNFα production by peritoneal macrophages in response to inflammatory stimulus. Our findings indicate that a GLP-1 receptor agonist attenuated neointimal formation after vascular injury. GLP-1 receptor agonists or drugs that raise endogenous GLP-1 level might be effective in the treatment of vascular diseases.
Qinkai Li, Toshio Hosaka, Nagakatsu Harada, Yutaka Nakaya and Makoto Funaki : Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes, Molecular and Cellular Endocrinology, Vol.365, No.1, 25-35, 2013.
(Summary)
Serotonin (5-hydroxytryptamine, 5-HT) was found to be elevated in the serum of diabetic patients. In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3β in LDM, leading to drastic ubiquitination. Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM.
Asuka Shiota, Michio Shimabukuro, Daiju Fukuda, Takeshi Soeki, Hiromi Sato, Etsuko Uematsu, Yoichiro Hirata, Hirotsugu Kurobe, Hiroshi Sakaue, Yutaka Nakaya, Hiroaki Masuzaki and Masataka Sata : Activation of AMPK-Sirt1 pathway by telmisartan in white adipose tissue: A possible link to anti-metabolic effects., European Journal of Pharmacology, Vol.692, No.1-3, 84-90, 2012.
(Summary)
Telmisartan exerts anti-metabolic effects beyond its angiotensin receptor blockade activities, but the mechanisms have hitherto remained elusive. We sought to elucidate the peroxisome proliferator-activated receptor-γ (PPAR-γ)-dependent and PPAR-γ-independent mechanisms underlying the anti-metabolic effects of telmisartan in white adipose tissue. Nine-week-old male C57BL/6 mice were fed with a 60% high-fat diet for 6 weeks, with 1mg/kg telmisartan or vehicle administrated orally during the last 3 weeks. 3T3-L1 adipocytes were cultured with telmisartan either with 2-chloro-5-nitro-N-phenylbenzamide (GW9662), a selective irreversible antagonist of PPAR-γ, or compound C, an ATP-competitive inhibitor of AMPK. Western blotting and semiquantitative RT-PCR analysis were used to assess adiponectin, Sirt1, and AMPK levels. Lipid accumulation was assessed by Oil red O staining. The activation of transcription factor PPAR-γ2 was evaluated by using a luciferase reporter assay for mPPAR-γ2 expression plasmid vector. Treatment with telmisartan increased serum adiponectin levels in high-fat diet-fed mice concomitantly with an upregulation of adiponectin mRNA in visceral adipose tissue. In vitro telmisartan treatment dose-dependently increased adiponectin mRNA in 3T3-L1 cells; the increase was inhibited by compound C, but not by GW9662. Telmisartan increased expression of Sirt1 mRNA and Sirt1 protein as well as the phosphorylation of AMPK in 3T3-L1 cells. Telmisartan can increase adiponectin production in white adipose tissue partly via a PPAR-γ2-independent mechanism. Precise understanding of this molecular mechanism will require further investigation.
Nagakatsu Harada, Fujimoto Erika, Okuyama Maiko, Hiroshi Sakaue and Yutaka Nakaya : Identification and functional characterization of human glycerol-3-phosphate acyltransferase 1 gene promoters., Biochemical and Biophysical Research Communications, Vol.423, No.1, 128-133, 2012.
(Summary)
Glycerol-3-phosphate acyltransferase 1 (GPAT1) acts as a rate limiting enzyme in triacylglycerol and phospholipid synthesis in mammals. GPAT1 regulates hepatic lipid accumulation associated with metabolic disorders. Here we have identified two transcriptional initiation sites and two promoters (promoter I and II) required for expression of the human GPAT1 (hGPAT1) gene. Promoter I regulates transcription of three alternative hGPAT1 mRNA variants, hGPAT1-V1, V2, and V3, while promoter II induces expression of a fourth variant, hGPAT1-V4. RT-PCR analysis and luciferase reporter assays revealed that promoter II acts in lipogenic tissues like the liver (and liver-derived HepG2 cells), whereas promoter I is differentially regulated and also acts in non-liver HeLa cells. Among liver-enriched transcription factors, HNF4α and C/EBPα slightly activated hGPAT1 promoter I, while factors including HNF1α altered promoter II activity. The lipogenic transcription factor SREBP1c greatly increased promoter II activity in HepG2 cells. The use of various truncated or mutated fragments of promoter II revealed that one sterol regulatory element-like motif and one inverted CCAAT box on promoter II contributed to the SREBP1c response. These cis-acting elements and trans-acting factors can be potential targets for manipulation of hepatic GPAT1 levels in humans.
Nakagawa Tadahiko, Nagakatsu Harada, Miyamoto Aiko, Kawanishi Yukiko, Yoshida Masaki, Masayuki Shono, Kazuaki Mawatari, Akira Takahashi, Hiroshi Sakaue and Yutaka Nakaya : Membrane topology of murine glycerol-3-phosphate acyltransferase 2., Biochemical and Biophysical Research Communications, Vol.418, No.3, 506-511, 2012.
(Summary)
Glycerol-3-phosphate acyltransferase (GPAT) is a rate-limiting enzyme in mammalian triacylglycerol biosynthesis. GPAT is a target for the treatment of metabolic disorders associated with high lipid accumulation. Although the molecular basis for GPAT1 activation has been investigated extensively, the activation of other isoforms, such as GPAT2, is less well understood. Here the membrane topology of the GPAT2 protein was examined using an epitope-tag-based method. Exogenously expressed GPAT2 protein was present in the membrane fraction of transformed HEK293 cells even in the presence of Na(2)CO(3) (100 mM), indicating that GPAT2 is a membrane-bound protein. Trypsin treatment of the membrane fraction degraded the N-terminal (FLAG) and C-terminal (myc-epitope) protein tags of the GPAT2 protein. Bioinformatic analysis of the GPAT2 protein sequence indicated four hydrophobic sequences as potential membrane-spanning regions (TM1-TM4). Immunoblotting of the myc-epitope tag, which was inserted between each TM region of the GPAT2 protein, showed that the amino acid sequence between TM3 and TM4 was protected from trypsin digestion. These results suggest that the GPAT2 protein has two transmembrane segments and that the N-terminal and C-terminal regions of this protein face the cytoplasm. These results also suggest that the enzymatically active motifs I-III of the GPAT2 protein face the cytosol, while motif IV is within the membrane. It is expected that the use of this topological model of GPAT2 will be essential in efforts to elucidate the molecular mechanisms of GPAT2 activity in mammalian cells.
Tomoko Inubushi, Norio Kamemura, Masataka Oda, Jun Sakurai, Yutaka Nakaya, Nagakatsu Harada, Midori Suenaga, Yoichi Matsunaga, Kazumi Ishidoh and Nobuhiko Katunuma : L-tryptophan suppresses rise in blood glucose and preserves insulin secretion in type-2 diabetes mellitus rats., Journal of Nutritional Science and Vitaminology, Vol.58, No.6, 415-422, 2012.
(Summary)
Ample evidence indicates that a high-protein/low-carbohydrate diet increases glucose energy expenditure and is beneficial in patients with type-2 diabetes mellitus (T2DM). The present study was designed to investigate the effects of L-tryptophan in T2DM. Blood glucose was measured by the glucose dehydrogenase assay and serum insulin was measured with ELISA in both normal and hereditary T2DM rats after oral glucose administration with or without L-D-tryptophan and tryptamine. The effect of tryptophan on glucose absorption was examined in the small intestine of rats using the everted-sac method. Glucose incorporation in adipocytes was assayed with [(3)H]-2-deoxy-D-glucose using a liquid scintillation counter. Indirect computer-regulated respiratory gas-assay calorimetry was applied to assay energy expenditure in rats. L-Tryptophan suppressed both serum glucose and insulin levels after oral glucose administration and inhibited glucose absorption from the intestine. Tryptamine, but not L-tryptophan, enhanced insulin-stimulated [(3)H]-glucose incorporation into differentiated adipocytes. L-Tryptophan increased glucose-associated energy expenditure in rats in vivo. L-Tryptophan-rich chow consumed from a young age preserved the secretion of insulin and delayed the progression of T2DM in hereditary diabetic rats. The results suggested that L-tryptophan suppresses the elevation of blood glucose and lessens the burden associated with insulin secretion from β-cells.
(Keyword)
Adipocytes / Administration, Oral / Animals / Blood Glucose / Diabetes Mellitus, Experimental / Diabetes Mellitus, Type 2 / Energy Metabolism / Glucose Tolerance Test / Insulin / Insulin-Secreting Cells / Male / Rats / Rats, Sprague-Dawley / Tryptophan
Sonoko Yasui, Kazuaki Mawatari, Ran Morizumi, Hiroko Furukawa, Takaaki Shimohata, Nagakatsu Harada, Akira Takahashi and Yutaka Nakaya : Hydrogen peroxide inhibits insulin-induced ATP-sensitive potassium channel activation independent of insulin signaling pathway in cultured vascular smooth muscle cells., The Journal of Medical Investigation : JMI, Vol.59, No.1-2, 36-44, 2012.
(Summary)
Both reactive oxygen species (ROS) and insulin resistance have been reported to play essential pathophysiological roles in cardiovascular diseases, such as hypertension and atherosclerosis. However, the mechanistic link between ROS and insulin resistance in the vasculature remains unclear. Recently we have shown that insulin causes membrane hyperpolarization via ATP-sensitive potassium (K(ATP)) channel activation, which is mediated by phosphatidylinositol 3-kinase (PI3-K) in cultured vascular smooth muscle cells (VSMCs). K(ATP) channel in the vasculature is critical in the regulation of vascular tonus. Here we examined the effects of ROS induced by hydrogen peroxide (H(2)O(2)) on insulin-induced K(ATP) channel activities in cultured VSMCs, A10 cells. H(2)O(2) (10 µM) increased significantly intercellular ROS in A10 cells. By using a cell-attached patch clamp experiment, 10 µM H(2)O(2) suppressed significantly insulin-induced K(ATP) channel activation without inhibition of insulin receptor signal transduction component including IRS and Akt in A10 cells. Furthermore 10 µM H(2)O(2) suppressed significantly pinacidil-induced K(ATP) channel activation in A10 cells. These data suggest that H(2)O(2) might inhibit directly K(ATP) channel independent of insulin signaling pathway. This study may contribute to our understanding of mechanisms of insulin resistance-associated cardiovascular disease.
Although an inverse correlation between insulin sensitivity and the level of Gq/11-coupled receptor agonists, such as endothelin-1, thrombin, and 5-hydroxytryptamine (5-HT), has been reported, its precise mechanism remains unclear. In this report, we provide evidence that 5-HT induced production of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and caused insulin resistance in 3T3-L1 adipocytes, primary adipocytes, and C2C12 myotubes. In 3T3-L1 adipocytes, 5-HT stimulated HB-EGF production by promoting metalloproteinase-dependent shedding of transmembrane protein pro-HB-EGF. HB-EGF then bound and tyrosine-phosphorylated EGF receptors, which activated the mammalian target of rapamycin pathway through ERK1/2 phosphorylation. Mammalian target of rapamycin activation caused serine phosphorylation of insulin receptor substrate-1, which attenuated insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and glucose uptake. Pharmacological inhibition of either Gq/11-coupled receptors or metalloproteinases, as well as either inhibition or knockdown of HB-EGF or Gq/11, restored insulin signal transduction impaired by 5-HT. Inhibition of metalloproteinase activity also abolished HB-EGF production and subsequent EGF receptor activation by other Gq/11-coupled receptor agonists known to cause insulin resistance, such as endothelin-1 and thrombin. These results suggest that transactivation of the EGF receptor through HB-EGF processing plays a pivotal role in 5-HT-induced insulin resistance.
Shinji Kawahito, Takashi Kawano, Hiroshi Kitahata, Jun Oto, Akira Takahashi, Kazumi Takaishi, Nagakatsu Harada, Tadahiko Nakagawa, Hiroyuki Kinoshita, Toshiharu Azma, Yutaka Nakaya and Shuzo Oshita : Molecular mechanisms of the inhibitory effects of clonidine on vascular adenosine triphosphate-sensitive potassium channels., Anesthesia & Analgesia, Vol.113, No.6, 1374-1380, 2011.
(Summary)
We investigated the effects of the imidazoline-derived α2-adrenoceptor agonist clonidine on vascular adenosine triphosphate-sensitive potassium (K(ATP)) channel activity in rat vascular smooth muscle cells and recombinant vascular K(ATP) channels transiently expressed in COS-7 cells. Using the patch-clamp method, we investigated the effects of clonidine on the following: (1) native vascular K(ATP) channels; (2) recombinant K(ATP) channels with different combinations of various types of inwardly rectifying potassium channel (Kir6.0 family: Kir6.1, 6.2) and sulfonylurea receptor (SUR1, 2A, 2B) subunits; (3) SUR-deficient channels derived from a truncated isoform of the Kir6.2 subunit (Kir6.2ΔC36 channels); and (4) mutant Kir6.2ΔC36 channels with diminished sensitivity to ATP (Kir6.2ΔC36-K185Q channels). Clonidine (≥3 × 10(-8) M) inhibited native K(ATP) channel activity in cell-attached configurations with a half-maximal inhibitory concentration value of 1.21 × 10(-6) M and in inside-out configurations with a half-maximal inhibitory concentration value of 0.89 × 10(-6) M. With similar potency, clonidine (10(-6) or 10(-3) M) also inhibited the activities of various recombinant SUR/Kir6.0 K(ATP) channels, the Kir6.2ΔC36 channel, and the Kir6.2ΔC36-K185Q channel. Clinically relevant concentrations of clonidine inhibit K(ATP) channel activity in vascular smooth muscle cells. This inhibition seems to be the result of its effect on the Kir6.0 subunit and not on the SUR subunit.
Masataka Kusunoki, Kazuhiko Tsutsumi, Daisuke Sato, Aki Nakamura, Satoshi Habu, Yuichi Mori, Munehiko Morishita, Takayuki Yonemoto, Tetsuro Miyata, Yutaka Nakaya and Takao Nakamura : Pioglitazone-induced body weight gain is prevented by combined administration with the lipoprotein lipase activator NO-1886., European Journal of Pharmacology, Vol.668, No.3, 486-491, 2011.
(Summary)
Pioglitazone improves insulin resistance in diabetics but often causes body weight gain. The lipoprotein lipase activator NO-1886 has been shown to exert both anti-obesity and anti-insulin-resistance effects. In this study, we investigated the effect of the combined administration of pioglitazone with NO-1886 (pioglitazone+NO-1886) in preventing body weight gain in insulin-resistant, high-fat fed rats. The rats were fed a standard or high-fat diet for 16 weeks. The high-fat fed rats were randomized at week 9 into 4 groups (i.e., control, pioglitazone (30 mg/kg/day), NO-1886 (100mg/kg/day), and pioglitazone+NO-1886 (30 and 100mg/kg/day, respectively)). The high-fat fed control rats developed obesity and insulin resistance. After 7 weeks of drug treatment, pioglitazone+NO-1886 was found to prevent the body weight gain caused by pioglitazone alone (pioglitazone+NO-1886: 76.0 ± 16.8 g vs. pioglitazone: 127.8 ± 39.5 g, P<0.05) and to increase glucose infusion rate during insulin clamp, compared with the results in the high-fat fed control group. No differences in plasma nonesterified fatty acid, leptin, adiponectin, glucose, or insulin levels were observed between the pioglitazone+NO-1886 and the pioglitazone-alone groups. However, plasma total cholesterol and HDL-cholesterol levels were significantly increased and plasma triglyceride levels were slightly decreased in the pioglitazone+NO-1886 group, compared with the values in the pioglitazone-alone group. In summary, the combined administration of pioglitazone and NO-1886 prevented the pioglitazone-induced body weight gains and ameliorated insulin resistance observed in high-fat fed rats. These results indicate that combined therapy with pioglitazone and NO-1886 may be beneficial for the treatment of type 2 diabetes.
Yoichiro Hirata, Minoru Tabata, Hirotsugu Kurobe, Tatsuo Motoki, Masashi Akaike, Chika Nishio, Mayuko Higashida, Hiroaki Mikasa, Yutaka Nakaya, Shuichiro Takanashi, Takashi Igarashi, Tetsuya Kitagawa and Masataka Sata : Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue., Journal of the American College of Cardiology, Vol.58, No.3, 248-255, 2011.
(Summary)
The purpose of this report was to assess the link between macrophage polarization in epicardial adipose tissue and atherosclerosis in patients with coronary artery disease (CAD).
Masataka Kusunoki, Kazuhiko Tsutsumi, Daisuke Sato, Aki Nakamura, Satoshi Habu, Yuichi Mori, Munehiko Morishita, Takayuki Yonemoto, Tetsuro Miyata, Yutaka Nakaya and Takao Nakamura : Activation of lipoprotein lipase increases serum high density lipoprotein 2 cholesterol and enlarges high density lipoprotein 2 particles in rats., European Journal of Pharmacology, Vol.668, No.1-2, 337-339, 2011.
(Summary)
It is known that postheparin plasma lipoprotein lipase (LPL) activity correlates with serum high density lipoprotein cholesterol (HDL-C) levels in humans and animals. Furthermore, LPL has been reported to cause enlargement of HDL particle size in vitro. However, these effects have not yet been experimentally proven. The aim of this study was to determine whether LPL has a role in increase in HDL-C and enlargement of HDL particle by activating the LPL function with NO-1886, the LPL promoting agent. NO-1886 administration increased postheparin plasma LPL activity without influencing hepatic triglyceride lipase activity. NO-1886 increased serum HDL(2)-cholesterol (HDL(2)-C) concentration and enlarged HDL(2) particle size, but did not increase serum HDL(3)-cholesterol concentration or enlarge HDL(3) particle size. Also, serum HDL(2)-C concentrations were positively correlated with HDL(2) particle size (r=0.910). Our study demonstrates that the LPL activation induced with NO-1886 may cause production of HDL(2)-C by catabolism of triglyceride-rich lipoproteins and enlarges HDL(2) particle size in rats.
Hiroko Furukawa, Kazuaki Mawatari, Kei Koyama, Sonoko Yasui, Ran Morizumi, Takaaki Shimohata, Nagakatsu Harada, Akira Takahashi and Yutaka Nakaya : Telmisartan increases localization of glucose transporter 4 to the plasma membrane and increases glucose uptake via peroxisome proliferator-activated receptor γ in 3T3-L1 adipocytes., European Journal of Pharmacology, Vol.660, No.2-3, 485-491, 2011.
(Summary)
Angiotensin II is a peptide hormone with strong vasoconstrictive action, and recent reports have shown that Angiotensin II receptor type 1 antagonists (angiotensin II receptor blockers) also improve glucose metabolism. The angiotensin II receptor blocker telmisartan acts as an agonistic ligand of the peroxisome proliferator-activated receptor gamma (PPARγ). In this study, we investigated the effects of telmisartan on glucose uptake and insulin sensitivity in 3T3-L1 adipocytes and compared it with the action of other angiotensin II receptor blockers. Telmisartan treatment dose-dependently increased (from 1 μM) protein expression of PPARγ-regulated molecules such as fatty acid binding protein 4 (FABP4), insulin receptor, and glucose transporter 4 (GLUT4). Telmisartan increased glucose uptake both with and without insulin stimulation in 3T3-L1 adipocytes. Telmisartan increased the up-regulation of phosphorylated insulin receptor, insulin receptor substrate-1 (IRS-1) and Akt by insulin, suggesting that telmisartan increases insulin sensitivity. Furthermore, in the absence of insulin, telmisartan, but not candesartan, increased GLUT4 levels at the plasma membrane. These effects by 10 μM telmisartan were similar potency to those of 1 μM troglitazone, an activator of PPARγ. In addition, up-regulation of glucose uptake by telmisartan was inhibited by a PPARγ antagonist, T0070907 (2-chloro-5-nitro-N-4-pyridinyl-benzamide). These results indicate that telmisartan acts via PPARγ activation in adipose tissue and may be an effective therapy for the metabolic syndrome.
(Keyword)
3T3-L1 Cells / Adipocytes / Angiotensin II Type 1 Receptor Blockers / Animals / Benzimidazoles / Benzoates / Cell Membrane / Fatty Acid-Binding Proteins / Glucose / Glucose Transporter Type 4 / Insulin / Mice / PPAR gamma / Protein Transport / Receptor, Insulin / Signal Transduction
Yukie Moriyama, Rieko Eriguchi, Yuzuru Sato and Yutaka Nakaya : Chronic hemodialysis patients with visceral obesity have a higher risk for cardiovascular events., Asia Pacific Journal of Clinical Nutrition, Vol.20, No.1, 109-117, 2011.
(Summary)
The risk of cardiovascular disease is substantially high in hemodialysis patients. The risk factors for cardiovascular disease in dialysis patients include age, malnutrition, duration of dialysis, diabetes mellitus and hyperphosphatemia. However, it is not clear whether cardiovascular disease is associated with abdominal obesity in dialysis patients. The aim of the present study was to clarify the relationship among visceral fat area and cardiovascular complications in chronic dialysis patients. Area of visceral fat was measured using computed tomography scan in 94 patients. The abdominal aortic calcification index (ACI), blood lipid profile and complication of cardiovascular disease were evaluated in these patients. Compared to patients with smaller visceral fat area (<100 cm2), those with larger visceral fat area (100 cm2) showed significantly higher cardiovascular complication and higher serum levels of triglyceride and significantly lower serum levels of HDL-cholesterol. Patients with larger visceral fat area and longer duration of dialysis showed severer calcification by ACI analysis, and showed higher incidences of ischemic heart disease. This study suggested that chronic dialysis patients with higher visceral fat area have a higher risk for vascular events, especially ischemic heart disease.
Yutaka Nakaya, Takaaki Shimohata, Sayaka Haraguchi, Toshiyuki Nakao, Jun Minaguchi, Haruo Sumitani, Nagakatsu Harada and Hiroshi Sakaue : Severe catabolic state after an overnight fast in patients with chronic renal failure., Nutrition, Vol.27, No.3, 329-332, 2011.
(Summary)
Starvation causes more rapid development of a catabolic state in patients with liver cirrhosis than in normal subjects. Because the kidneys have a gluconeogenic activity similar to that of the liver, we tested whether patients with chronic renal failure develop a catabolic state after an overnight fast. The effect of an overnight fast on diurnal changes in respiratory quotient (RQ) was studied in 12 normal subjects and 12 patients with stable chronic renal failure. Changes in RQ in the early morning after an overnight fast were also studied in 27 patients with chronic renal failure not on dialysis. We also examined the effect on RQ of consuming a light snack in the evening before the measurements. The RQ before breakfast, but not at other times, was significantly lower in patients with renal failure than in normal subjects (0.824 ± 0.051 versus 0.868 ± 0.038, P < 0.05). This indicated that patients with renal failure had higher fat use and developed a catabolic state early in the morning. The RQ before breakfast showed significant inverse correlations with creatinine levels (r = -0.604, P < 0.001). Supplementation with a carbohydrate-rich snack in the evening resulted in a significant increase of 0.07 ± 0.04 (P < 0.05) in mean RQ in the early morning. This suggested that a late evening snack is useful for improving the catabolic state of patients with renal failure. Starvation involving an overnight fast facilitates catabolism of visceral and muscle proteins in renal failure. This suggests that nutritional management of renal failure should focus not only on the contents of a meal, but also on the timing of the meal.
Yasuo M. Tsutsumi, Rie Tsutsumi, Kazuaki Mawatari, Yutaka Nakaya, Michiko Kinoshita, Katsuya Tanaka and Shuzo Oshita : Compound K, a metabolite of ginsenosides, induces cardiac protection mediated nitric oxide via Akt/PI3K pathway., Life Sciences, Vol.88, No.15-16, 725-729, 2011.
(Summary)
Compound K (C-K; 20-O-D-glucopyranosyl-20(S)-protopanaxadiol) is a novel ginsenoside metabolite formed by intestinal bacteria and does not occur naturally in ginseng. In this study, we investigated whether administration of C-K has protective effects on myocardial ischemia-reperfusion injury and its potential mechanisms.
Takaaki Shimohata, Masayuki Nakano, Xin Lian, Tomomi Shigeyama, Hitomi Iba, Akiko Hamamoto, Masaki Yoshida, Nagakatsu Harada, Hironori Yamamoto, Masayuki Yamato, Kazuaki Mawatari, Toshiaki Tamaki, Yutaka Nakaya and Akira Takahashi : Vibrio parahaemolyticus infection induces modulation of IL-8 secretion through dual pathway via VP1680 in Caco-2 cells., The Journal of Infectious Diseases, Vol.203, No.4, 537-544, 2011.
(Summary)
Vibrio parahaemolyticus causes acute gastroenteritis and inflammations in humans. A variety of pathogenic bacteria can stimulate mitogen-activated protein kinases (MAPKs) in host cells. Phosphorylation of MAPKs leads to production of interleukin (IL)- 8 and subsequently causes inflammations. Thus, MAPK cascades were strong candidates for the main signaling pathway of V. parahaemolyticus-induced acute inflammation.
Yohko Hirata, Toshio Hosaka, Takeo Iwata, Le Thi Kim Chung, Bayasgalan Jambaldorj, Kiyoshi Teshigawara, Nagakatsu Harada, Hiroshi Sakaue, Tohru Sakai, Katsuhiko Yoshimoto and Yutaka Nakaya : Vimentin binds IRAP and is involved in GLUT4 vesicle trafficking., Biochemical and Biophysical Research Communications, Vol.405, No.1, 96-101, 2011.
(Summary)
Insulin-responsive aminopeptidase (IRAP) and GLUT4 are two major cargo proteins of GLUT4 storage vesicles (GSVs) that are translocated from a postendosomal storage compartment to the plasma membrane (PM) in response to insulin. The cytoplasmic region of IRAP is reportedly involved in retention of GSVs. In this study, vimentin was identified using the cytoplasmic domain of IRAP as bait. The validity of this interaction was confirmed by pull-down assays and immunoprecipitation in 3T3-L1 adipocytes. In addition, it was shown that GLUT4 translocation to the PM by insulin was decreased in vimentin-depleted adipocytes, presumably due to dispersing GSVs away from the cytoskeleton. These findings suggest that the IRAP binding protein, vimentin, plays an important role in retention of GSVs.
(Keyword)
3T3-L1 Cells / Animals / Cystinyl Aminopeptidase / Cytoplasmic Vesicles / Gene Knockdown Techniques / Glucose Transporter Type 4 / Mice / Protein Transport / Vimentin
The aim of this study is to determine the signal transduction of membrane stretch on intermediate-conductance Ca(2+)-activated K(+) (IKca) channels in rat aorta smooth muscle cells using the patch-clamp technique. To stretch the cell membrane, both suction to the rear end of patch pipette and hypotonic shock were used. In cell-attached and inside-out patch configurations, the open probability of IKca channels increased when 20- to 45-mmHg suction was applied. Hyposmotic swelling efficiently increased IKca channel current. When the Ca(2+)-free solution was superfused, the activation of IKca current by the hyposmotic swelling was reduced. Furthermore, gadolinium (Gd(3+)) attenuated the activation of IKca channels induced by hyposmotic swelling, whereas nicardipine did not. In the experiments with Ca(2+)-free bath solution, pretreatment with GF109203X, a protein kinase C (PKC) inhibitor, completely abolished the stretch-induced activation of IKca currents. The stretch-induced activation of IKca channels was strongly inhibited by cytochalasin D, indicating a role for the F-actin in modulation of IKca channels by changes in cell stretching. These data suggest that cell membrane stretch activates IKca channels. In addition, the activation is associated with extracellular Ca(2+) influx through stretch-activated nonselective cation channels, and is also modulated by the F-actin cytoskeleton and the activation of PKC.
Mio Nakamura, Masahide Yazaki, Yumiko Kobayashi, Kazuhiro Fukushima, Shu-ichi Ikeda, Keiko Kobayashi, Takeyori Saheki and Yutaka Nakaya : The characteristics of food intake in patients with type II citrullinemia., Journal of Nutritional Science and Vitaminology, Vol.57, No.3, 239-245, 2011.
(Summary)
Some patients with citrin deficiency caused by SLC25A13 gene mutations develop adult-onset type II citrullinemia (CTLN2) with hepatic encephalopathy. A recent nutritional survey of 18 citrin-deficient subjects (age 1-33 y) confirmed a marked decrease in carbohydrate intake compared to an age-matched general Japanese population. However, a quantitative understanding of food intake in CTLN2 patients remains unclear, although qualitative dietary information has been reported. In order to elucidate the characteristics of daily nutrition of CTLN2 patients, the food intake of 5 male patients (age 39-52 y) was investigated in detail by the Food Frequency Questionnaire. In the present survey, the mean energy ratio of protein : fat : carbohydrate (PFC ratio) of the 5 patients was 19±3% : 44±5% : 37±4%, which was almost identical to previously reported data in younger citrin-deficient subjects (19±2% : 44±5% : 37±7%). Cereal intake was especially low in all CTLN2 patients at 309±33 g/d (56% of control), compared to that in an age-matched general Japanese population (553±197 g/d). Additionally, CTLN2 patients preferred high fat and protein foods. Commonly, fat intake declines with age in the general Japanese population, but this tendency was not observed in the 5 CTLN2 patients. The present results suggest that intakes of low-carbohydrate, high-protein and high-fat food was characteristic the 5 CTLN2 patients surveyed, as has been previously reported in younger citrin-deficient subjects, and that the PFC ratio may not be influenced by age or CTLN2-onset.
Yoichiro Hirata, Hirotsugu Kurobe, Masashi Akaike, Fumio Chikugo, Takaki Hori, Yoshimi Bando, Chika Nishio, Mayuko Higashida, Yutaka Nakaya, Tetsuya Kitagawa and Masataka Sata : Enhanced inflammation in epicardial fat in patients with coronary artery disease., International Heart Journal, Vol.52, No.3, 139-142, 2011.
(Summary)
It has been hypothesized that epicardial fat, a local visceral fat depot with close proximity to coronary arteries, may serve as a source of inflammatory cytokines and cells in coronary atherosclerotic lesions. Here, we characterized infiltration of inflammatory cells and expression of adipocytokines in epicardial adipose tissue in patients with and without coronary artery disease (CAD). Pare samples were obtained from epicardial and subcutaneous adipose tissue during elective cardiac surgery (CAD, n = 8; non-CAD, n = 9). Inflammatory cell infiltration was investigated by immunohistochemical staining using antibodies against CD3, CD4, CD8 and CD68. Expression of adipocytokines was evaluated by real-time quantitative reverse transcription-polymerase chain reaction. Infiltration of macrophages and CD8-positive T cells in the epicardial adipose tissue in the CAD group was greater than that in the non-CAD group. In contrast, there was no significant difference between the two groups in the number of inflammatory cells in subcutaneous adipose tissue. No statistical difference could be found between the CAD group and the non-CAD group in the expression levels of adiponectin and inflammatory cytokines in epicardial adipose tissue. Our findings suggest that inflammatory cell infiltration is enhanced in epicardial adipose tissue, but not in subcutaneous fat, in patients with coronary artery disease. Chronic inflammation in epicardial fat may influence the pathogenesis of coronary atherosclerosis.
A Hamamoto, M Bandou, K Nakano, Kazuaki Mawatari, Nagakatsu Harada, Masatake Akutagawa, Yohsuke Kinouchi, Yutaka Nakaya and Akira Takahashi : Differences in stress response after UVC or UVA irradiation in Vibrio parahaemolyticus., Environmental Microbiology Reports, Vol.2, No.5, 660-666, 2010.
Kiyoshi Teshigawara, Toshio Hosaka, Miwa Yamaguchi, Eri Terada, Yuka Kisyuku, Keiko Fukunaga, Yohko Hirata, Bayasgalan Jambaldorj, Nagakatsu Harada, Tohru Sakai and Yutaka Nakaya : Long-term treatment with hyperbaric air improves hyperlipidemia of db/db mice., The Journal of Medical Investigation : JMI, Vol.57, No.3-4, 224-231, 2010.
(Summary)
Hyperbaric air (HBA) is used to improve healing of wounds including diabetic ulcer. The aim of this study was to clarify the effects of HBA exposure on lipid and glucose metabolism in db/db mice. HBA did not influence the weight of db/db mice. Serum levels of free fatty acid and triglyceride, but not glucose and insulin, were significantly decreased after 6 weeks of treatment with HBA. The mRNA expressions of CPT-1, PPAR and PGC-1 genes, which are related to lipid metabolism, were significantly up-regulated in the muscle and liver. Increases in TNF and MCP1 mRNA, which impaired lipid metabolism, were also attenuated by HBA treatment. These results suggest that exposure of HBA could have beneficial effects on lipid metabolism in patients with type 2 diabetes mellitus.
Takashi Kawano, Katsuya Tanaka, hua Yin, Satoru Eguchi, Hiroaki Kawano, Akira Takahashi, Yutaka Nakaya and Shuzo Oshita : Effects of ketamine on nicorandil induced ATP-sensitive potassium channel activity in cell line derived from rat aortic smooth muscle., The Journal of Medical Investigation : JMI, Vol.57, No.3-4, 237-244, 2010.
(Summary)
Nicorandil opens adenosine triphosphate-sensitive potassium (K(ATP)) channels in the cardiovascular system and is being increasingly used for the treatment of angina pectoris. In the present study, we tested whether intravenous anesthetic agent ketamine affected nicorandil-induced native vascular K(ATP) channel activation.
Ali Khaleghian, Gholam Hossein Riazi, Mahmoud Ghafari, Marzieh Rezaie, Akira Takahashi, Yutaka Nakaya and Hossain Nazari : Effect of inganen anticancer properties on microtobule organization., Pakistan Journal of Pharmaceutical Sciences, Vol.23, No.3, 273-278, 2010.
(Summary)
Euphorbia tirucalli (Euphorbiaceae family) an environmental risk factor for Burkitt's lymphoma also has pharmacological activities. In the northeast of region in Brazil its latex is used as an antimicrobial, antiparasitic in the treatment of coughs, rheumatism, cancer and other disease as folk treatment. The prevalent constituents of this plant latex are diterpenes from the Inganen types (ingenol esters) as well as the tigliane (phorbol esters). Scientifically, there is not any data till now about anticancer effects of the Euphorbia tirucalli Linn., since the Ingenol esters have already presented tumor-promoting ability. Microtubules (MTs), and cytoskeletal proteins are essential in eukaryotic cells for a variety of functions, such as cellular transport, cell motility and mitosis. Single Inganen in cytoplasm can interact with these proteins and affect on their crucial functions. In this study, we showed the effects of Inganen on MT organization using ultraviolet spectrophotometer and fluorometry. The fluorescent spectroscopy showed a significant tubulin conformational change at the presence of Inganen which decrease polymerization of tubulin as well as the ultraviolet spectroscopy results. The aim of this study is to find the potential function of Inganen for treatment of cancer in cells and human organs.
Zehong Su, Masayuki Nakano, Tetsuro Koga, Xin Lian, Akiko Hamamoto, Takaaki Shimohata, Yumi Harada, Kazuaki Mawatari, Nagakatsu Harada, Masatake Akutagawa, Yutaka Nakaya and Akira Takahashi : Hfq regulates anti-oxidative ability in Vibrio parahaemolyticus., The Journal of General and Applied Microbiology, Vol.56, No.3, 181-186, 2010.
(Summary)
Hfq plays a fundamental role in bacterial cell physiology. It can stimulate or repress the expression of certain target genes, and there is a possibility that Hfq regulates the oxidative stress response. However, how Hfq functions that in Vibrio parahaemolyticus remains speculative. In this paper, we explain the functions Hfq plays in V. parahaemolyticus in the gene expression of superoxide dismutase gene and catalase gene, comparing the hfq deletion mutant strain to the parental strain. The results show that the hfq deletion mutant V. parahaemolyticus has a stronger ability to resist H(2)O(2). Superoxide dismutase (SOD) and catalase (CAT) activities in the hfq deletion mutant were remarkably higher than in the parental strain. Genetic experiments indicated that the gene expression of sod and kat was up-regulated in the mutant strain. These results indicate that Hfq down-regulates CAT and SOD activity, and Hfq is associated with the oxidative stress response.
Xin Lian, Kayo Tetsutani, Akiko Hamamoto, Masayuki Nakano, Kazuaki Mawatari, Nagakatsu Harada, Masayuki Yamato, Masatake Akutagawa, Yohsuke Kinouchi, Yutaka Nakaya and Akira Takahashi : A new colored beverage disinfection system using UV-A light-emitting diodes, Biocontrol Science, Vol.15, No.1, 33-37, 2010.
(Summary)
In this study we evaluated the ability of the UV-A-LED to eliminate bacteria in a colored beverage. Ten edible pigments were used to make a colored solution at concentrations of 1.0%, 0.1%, 0.01% and 0.001%. We used a colony-forming assay to monitor the bactericidal action against the bacteria. The bactericidal effect of UV-A-LED against Escherichia coli DH5 a decreased with the increasing concentration of almost all of the edible pigments. Although less effective in colored solutions and commercially available orange juice than in the positive control PBS, it holds potential for further development and use to ensure food and water safety.
Masaki Yoshida, Nagakatsu Harada, Keiko Yoshida, Tadahiko Nakagawa, Takaaki Shimohata, Kazuaki Mawatari, Akira Takahashi, Hiroshi Sakaue and Yutaka Nakaya : High density lipoprotein inhibits the activation of sterol regulatory element-binding protein-1 in cultured cells., FEBS Letters, Vol.584, No.6, 1217-1222, 2010.
(Summary)
A link between cellular uptake of high density lipoprotein (HDL) and regulation of sterol regulatory element-binding protein-1 (SREBP-1) was investigated in vitro. HDL decreased nuclear SREBP-1 levels as well as SREBP-1 target gene expression in HepG2 and HEK293 cells. However, HDL did not repress an exogenously expressed, constitutively active form of SREBP-1. HDL increased cellular cholesterol levels, and cellular cholesterol depletion by methyl-beta-cyclodextrin abolished the effects of HDL. These results suggest that HDL inhibits the activation of SREBP-1 through a cholesterol-dependent mechanism, which may play an important role in regulating lipid synthetic pathways mediated by SREBP-1.
Hattori Atsushi, Kazuaki Mawatari, Tuzuki Satomi, Yoshioka Emiko, Toda Satomi, Yoshida Masaki, Yasui Sonoko, Furukawa Hiroko, Morishima Masaki, Ono Katsushige, Takamasa Ohnishi, Nakano Masayuki, Nagakatsu Harada, Akira Takahashi and Yutaka Nakaya : β-Adrenergic-AMPK Pathway Phosphorylates Acetyl-CoA Carboxylase in a High-epinephrine Rat Model, SPORTS, Obesity, Vol.18, No.1, 48-54, 2010.
(Summary)
We established a new animal model called SPORTS (Spontaneously-Running Tokushima-Shikoku) rats, which show high-epinephrine (Epi) levels. Recent reports show that Epi activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) in adipocytes. Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in fatty acid synthesis, and the enzymatic activity is suppressed when its Ser-79 is phosphorylated by AMPK. The aim of this study was to investigate the in vivo effect of Epi on ACC and abdominal visceral fat accumulation. We divided both 6-week male control and SPORTS rats into two groups, which were fed either normal diet or high fat and sucrose (HFS) diet for 16 weeks. At the end of diet treatment, retroperitoneal fat was collected for western blotting and histological analysis. Food intake was not different among the groups, but SPORTS rats showed significantly lower weight gain than control rats in both diet groups. After 10 weeks of diet treatment, glucose tolerance tests (GTTs) revealed that SPORTS rats had increased insulin sensitivity. Furthermore, SPORTS rats had lower quantities of both abdominal fat and plasma triglyceride (TG). In abdominal fat, elevated ACC Ser-79 phosphorylation was observed in SPORTS rats and suppressed by an antagonist of beta-adrenergic receptor (AR), propranolol, or an inhibitor of AMPK, Compound C. From these results, high level of Epi induced ACC phosphorylation mediated through beta-AR and AMPK signaling pathways in abdominal visceral fat of SPORTS rats, which may contribute to reduce abdominal visceral fat accumulation and increase insulin sensitivity. Our results suggest that beta-AR-regulated ACC activity would be a target for treating lifestyle-related diseases, such as obesity.
Qinkai Li, Weidong Yin, Manbo Cai, Yi Liu, Hongjie Hou, Qingyun Shen, Chi Zhang, Junxia Xiao, Xiaobo Hu, Qishisan Wu, Makoto Funaki and Yutaka Nakaya : NO-1886 suppresses diet-induced insulin resistance and cholesterol accumulation through STAT5-dependent upregulation of IGF1 and CYP7A1., The Journal of Endocrinology, Vol.204, No.1, 47-56, 2010.
(Summary)
Insulin resistance and dyslipidemia are both considered to be risk factors for metabolic syndrome. Low levels of IGF1 are associated with insulin resistance. Elevation of low-density lipoprotein cholesterol (LDL-C) concomitant with depression of high-density lipoprotein cholesterol (HDL-C) increase the risk of obesity and type 2 diabetes mellitus (T2DM). Liver secretes IGF1 and catabolizes cholesterol regulated by the rate-limiting enzyme of bile acid synthesis from cholesterol 7alpha-hydroxylase (CYP7A1). NO-1886, a chemically synthesized lipoprotein lipase activator, suppresses diet-induced insulin resistance with the improvement of HDL-C. The goal of the present study is to evaluate whether NO-1886 upregulates IGF1 and CYP7A1 to benefit glucose and cholesterol metabolism. By using human hepatoma cell lines (HepG2 cells) as an in vitro model, we found that NO-1886 promoted IGF1 secretion and CYP7A1 expression through the activation of signal transducer and activator of transcription 5 (STAT5). Pretreatment of cells with AG 490, the inhibitor of STAT pathway, completely abolished NO-1886-induced IGF1 secretion and CYP7A1 expression. Studies performed in Chinese Bama minipigs pointed out an augmentation of plasma IGF1 elicited by a single dose administration of NO-1886. Long-term supplementation with NO-1886 recovered hyperinsulinemia and low plasma levels of IGF1 suppressed LDL-C and facilitated reverse cholesterol transport by decreasing hepatic cholesterol accumulation through increasing CYP7A1 expression in high-fat/high-sucrose/high-cholesterol diet minipigs. These findings indicate that NO-1886 upregulates IGF1 secretion and CYP7A1 expression to improve insulin resistance and hepatic cholesterol accumulation, which may represent an alternative therapeutic avenue of NO-1886 for T2DM and metabolic syndrome.
Le Thi Kim Chung, Toshio Hosaka, Nagakatsu Harada, Bayasgalan Jambaldorj, Keiko Fukunaga, Yuka Nishiwaki, Kiyoshi Teshigawara, Tohru Sakai, Yutaka Nakaya and Makoto Funaki : Myosin IIA participates in docking of Glut4 storage vesicles with the plasma membrane in 3T3-L1 adipocytes., Biochemical and Biophysical Research Communications, Vol.391, No.1, 995-999, 2009.
(Summary)
In adipocytes and myocytes, insulin stimulation translocates glucose transporter 4 (Glut4) storage vesicles (GSVs) from their intracellular storage sites to the plasma membrane (PM) where they dock with the PM. Then, Glut4 is inserted into the PM and initiates glucose uptake into these cells. Previous studies using chemical inhibitors demonstrated that myosin II participates in fusion of GSVs and the PM and increase in the intrinsic activity of Glut4. In this study, the effect of myosin IIA on GSV trafficking was examined by knocking down myosin IIA expression. Myosin IIA knockdown decreased both glucose uptake and exposures of myc-tagged Glut4 to the cell surface in insulin-stimulated cells, but did not affect insulin signal transduction. Interestingly, myosin IIA knockdown failed to decrease insulin-dependent trafficking of Glut4 to the PM. Moreover, in myosin IIA knockdown cells, insulin-stimulated binding of GSV SNARE protein, vesicle-associated membrane protein 2 (VAMP2) to PM SNARE protein, syntaxin 4 was inhibited. These data suggest that myosin IIA plays a role in insulin-stimulated docking of GSVs to the PM in 3T3-L1 adipocytes through SNARE complex formation.
(Keyword)
3T3-L1 Cells / Adipocytes / Animals / Cell Membrane / Cytoplasmic Vesicles / Gene Knockdown Techniques / Glucose / Glucose Transporter Type 4 / Insulin / Mice / Nonmuscle Myosin Type IIA / Protein Transport / SNARE Proteins / signal transduction / Vesicle-Associated Membrane Protein 2
Chung Thi Kim Le, Toshio Hosaka, Yoshida Masaki, Nagakatsu Harada, Hiroshi Sakaue, Tohru Sakai and Yutaka Nakaya : Exendin-4, a GLP-1 receptor agonist, directly induces adiponectin expression through protein kinase A pathway and prevents inflammatory adipokine expression., Biochemical and Biophysical Research Communications, Vol.390, No.3, 613-618, 2009.
(Summary)
Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist that has been used as a drug injected subcutaneously for treatment of type 2 diabetes. Many studies have revealed molecular targets of Ex-4, but its influence on adipokines has not been determined. Our study showed that Ex-4 induced secretion of adiponectin into the culture medium of 3T3-L1 adipocytes. This effect of Ex-4 is due to increased adiponectin mRNA level through the GLP-1R. Both forskolin and 3-isobutyl-1-methylxanthine (IBMX), which may finally elevate cyclic adenosine monophosphate (cAMP) concentration, prevented the induction of adiponectin expression by Ex-4. Moreover, H89, a protein kinase A inhibitor, blocked the effect of Ex-4 on adiponectin. On the other hand, Ex-4 decreased the mRNA levels of inflammatory adipokines. The results indicate that Ex-4 directly promotes adiponectin secretion via the protein kinase A pathway in 3T3-L1 adipocytes and may ameliorate insulin resistance.
Gadelmoula Mostafa, Lian Xin, Maeda Miku, Aihara Mutsumi, Kazuaki Mawatari, Hamamoto Akiko, Harada Yumi, Masayuki Yamato, Masatake Akutagawa, Yutaka Nakaya, Yohsuke Kinouchi and Akira Takahashi : Suitability of ultraviolet(A)-light emitting diode for air stream disinfection, The Journal of Medical Investigation : JMI, Vol.56, No.3-4, 150-156, 2009.
(Summary)
We previously developed a high powered light-emitting diode device capable of discharging germicidal ultraviolet irradiation (UVA-LED) at an approximate wavelength of 365 nm. This study examined the bactericidal activity of UVA-LED in moving air streams. Aerosols of Escherichia coli DH5alpha were exposed to UVA-LED irradiation using a stable current (0.5 A and 1.2 mW/cm(2)) or pulse current (1.0 A and 0.2 mW/cm(2)). Settle plate analysis was used for bioaerosol sampling, where results were expressed as Colony Forming Units. A -3 Log inactivation of the E. coli population occurred after 75 minutes of constant exposure to stable current. The pulse current produced inactivation within a similar timeframe. Our results might be significant as a basic study for further investigations about the effect of UVA-LED on airborne bacteria and its suitability for air disinfection applications.
(Keyword)
Aerosols / Air Microbiology / Air Pollution, Indoor / Disinfection / Escherichia coli / Humans / Sick Building Syndrome / Ultraviolet Rays
Li Qinkai, Toshio Hosaka, Jambaldorj Bayasglan, Yutaka Nakaya and Makoto Funaki : Extracellular Matrix with the Rigidity of Adipose Tissues Helps 3T3-L1 Adipocytes Maintain Insulin Responsiveness, The Journal of Medical Investigation : JMI, Vol.56, No.3,4, 142-149, 2009.
(Summary)
Despite the popularity of 3T3-L1 adipocytes as a model system of adipocytes in vivo, they do not carry all of the cellular functions of adipocytes in vivo. In this study, we investigated the effect of extracellular matrix (ECM) rigidity on insulin signal transduction in 3T3-L1 adipocytes. On 250 Pa polyacrylamide gel (soft gel) laminated with a mixture of collagen type 1 and fibronectin, whose rigidity matches that of adipose tissue, expression of the insulin receptor, IRS-1 and AKT was upregulated and their insulin-stimulated phosphorylation was enhanced. Furthermore, the expression of GLUT1 was downregulated, whereas the expression of GLUT4 was unaffected as ECM rigidity decreased. Insulin-stimulated GLUT4 recruitment to the plasma membrane was significantly enhanced in cells seeded on soft gel. These results suggest that adjusting the ECM rigidity to that of adipose tissue augments insulin signaling in 3T3-L1 adipocytes and enhances insulin-stimulated GLUT4 recruitment to the plasma membrane.
hua Yin, Nagakatsu Harada, Kazuaki Mawatari, Yasui Sonoko, Hiroko Segawa, Akira Takahashi, Shuzo Oshita and Yutaka Nakaya : L-DOPA inhibits nitric oxide-dependent vasorelaxation via production of reactive ozygen species in rat aorta, The Journal of Medical Investigation : JMI, Vol.56, No.3,4, 120-129, 2009.
(Summary)
To clarify the underlying mechanisms of L-DOPA induced vasoconstriction in rat aorta. Methods: The effect of L-DOPA on phenylephrine-induced contractile force of blood vessels was examined in vitro using rat aortic ring preparations by isometric tension experiment. Involvement of nitric oxide (NO) in the effect of L-DOPA on vascular smooth muscle was studied by using N(omega)-Nitro-L-arginine (L-NNA), Sodium nitroprusside (SNP) in endothelium-intact and endothelium-denuded aortic rings. L-DOPA potentiated alpha-adrenergic receptor- and depolarization-induced vascular contraction and inhibited acetylcholine-induced vasorelaxation. This effect was diminished by pretreatment of the aortic rings with L-NNA, an inhibitor of NO synthesis, or by removing the endothelium from the ring preparations. In endothelium-denuded rings, L-DOPA inhibited exogenous NO-dependent but not cGMP-mediated vasorelaxation. Increases in cGMP levels in response to an NO donor were attenuated by L-DOPA in cultured rat aortic smooth muscle cells. L-DOPA could not contract rings (without endothelium) pretreated with 3-(5'-hydroxymethyl- 2'-furyl)-1-benzyl indazole (YC-1), an activator of guanylyl cyclase, but SOD (150 U/ml) pretreatment of rings with endothelium inhibited contraction by L-DOPA. These results suggest that L-DOPA inhibits nitric-dependent vasorelaxation on vascular smooth muscle cells via production of reactive oxygen species.
Emi Shuto, Yutaka Taketani, Tanaka Rieko, Nagakatsu Harada, Isshiki Masashi, Sato Minato, Nashiki Kunitaka, Amo Kikuko, Hironori Yamamoto, Higashi Yukihito, Yutaka Nakaya and Eiji Takeda : Dietary Phosphorus Acutely Impairs Endothelial Function., Journal of the American Society of Nephrology, Vol.20, No.7, 1504-1512, 2009.
(Summary)
Excessive dietary phosphorus may increase cardiovascular risk in healthy individuals as well as in patients with chronic kidney disease, but the mechanisms underlying this risk are not completely understood. To determine whether postprandial hyperphosphatemia may promote endothelial dysfunction, we investigated the acute effect of phosphorus loading on endothelial function in vitro and in vivo. Exposing bovine aortic endothelial cells to a phosphorus load increased production of reactive oxygen species, which depended on phosphorus influx via sodium-dependent phosphate transporters, and decreased nitric oxide production via inhibitory phosphorylation of endothelial nitric oxide synthase. Phosphorus loading inhibited endothelium-dependent vasodilation of rat aortic rings. In 11 healthy men, we alternately served meals containing 400 mg or 1200 mg of phosphorus in a double-blind crossover study and measured flow-mediated dilation of the brachial artery before and 2 h after the meals. The high dietary phosphorus load increased serum phosphorus at 2 h and significantly decreased flow-mediated dilation. Flow-mediated dilation correlated inversely with serum phosphorus. Taken together, these findings suggest that endothelial dysfunction mediated by acute postprandial hyperphosphatemia may contribute to the relationship between serum phosphorus level and the risk for cardiovascular morbidity and mortality.
Ibrahim Dalia Ismaeil Hemdan, Katsuya Hirasaka, Reiko Nakao, Shohei Kohno, Sachiko Kagawa, Tomoki Abe, Akiko Harada, Yuushi Okumura, Yutaka Nakaya, Junji Terao and Takeshi Nikawa : Polyphenols prevent clinorotation-induced expression of atrogenes in mouse C2C12 skeletal myotubes., The Journal of Medical Investigation : JMI, Vol.56, No.1-2, 26-32, 2009.
(Summary)
Oxidative stress is a key factor in stimulating the expression of atrogenes, which are muscle atrophy-related ubiquitin ligases, in skeletal muscle, and it induces muscle atrophy during unloading. However, the effects of antioxidative nutrients on atrogene expression have not been demonstrated. We report on the inhibitory effects of polyphenols, such as epicatechin (EC), epicatechin gallate (ECg) and epigallocatechin gallate (EGCg) and quercetin, on atrogene expression up-regulated by three dimensional (3D)-clinorotation or glucocorticoid. These treatments markedly elevated the expression of atrogenes, including atrogin-1 and MuRF-1, in mouse C2C12 myoblasts and myotubes. Interestingly, EC, ECg, EGCg and quercetin significantly decreased the expression of atrogin-1 and MuRF-1 up-regulated by 3D-clinorotation, whereas they hardly affected atrogene expression induced by dexamethasone. ERK signaling is a well known MAPK pathway to mediate oxidative stress. Therefore, we also investigated the effect of these polyphenols on phosphorylation of ERK in C2C12 myotubes. As expected, EC, ECg, EGCg, and quercetin significantly suppressed phosphorylation of ERK, corresponding to the up-regulation of atrogenes induced by 3D-clinorotation. These results suggest that antioxidative nutrients, such as catechins and quercetin, suppress atrogene expression in skeletal muscle cells, possibly through the inhibition of ERK signaling. Thus, catechins and quercetin may prevent unloading-mediated muscle atrophy.
Masaki Yoshida, Nagakatsu Harada, Hironori Yamamoto, Yutaka Taketani, Nagakatsu Harada, Yunjie Yin, Atsushi Hattori, Tomoe Zenitani, Sayuri Hara, Haruka Yonemoto, Aki Nakamura, Masayuki Nakano, Kazuaki Mawatari, Kiyoshi Teshigawara, Hidekazu Arai, Toshio Hosaka, Akira Takahashi, Katsuhiko Yoshimoto and Yutaka Nakaya : Identification of cis-acting promoter sequences required for expression of the glycerol-3-phosphate acyltransferase 1 gene in mice., Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Vol.1791, No.1, 39-52, 2009.
(Summary)
Glycerol-3-phosphate acyltransferase 1 (GPAT1) is a rate limiting enzyme in de novo glycerophospholipid synthesis. The murine GPAT1 promoter sequence (the "classical" sequence) was reported previously. However, the organization of this DNA sequence does not fully match the mouse genome sequences on NCBI/GenBank. Here we have identified net cis-acting promoter sequences for the mouse GPAT1 gene: promoter 1a which includes part of the classical sequence and the downstream promoter 1b. Promoter 1a facilitates transcription of two alternative GPAT1 transcript variants, GPAT1-V1 and V2, while promoter 1b produces a third transcript variant, GPAT1-V3. Upstream stimulating factor-1 (USF-1) controlled both promoters whereas sterol regulatory element-binding protein-1 (SREBP-1) exclusively regulated promoter 1a activity in vitro. Feeding increased GPAT1-V1 and V2, but not V3 mRNA levels in mouse liver. The obese condition of db/db mice did not alter the hepatic expression levels of any of the three GPAT1 variants. Feeding enhanced hepatic mRNA levels, intranuclear protein levels and promoter 1a-binding levels of SREBP-1, but not of USF-1. Thus, promoter 1a was exclusively activated by routine feeding in vivo. Our results indicate differential roles of the two promoters in the regulation of hepatic GPAT1 gene expression in mice.
Y Ono, Yutaka Nakaya, S Bando, Takeshi Soeki, Susumu Ito and Masataka Sata : Telmisartan Decreases Plasma Levels of Asymmetrical Dimethyl-L-Arginine and Improves Lipid and Glucose Metabolism and Vascular Function, International Heart Journal, Vol.50, No.1, 73-83, 2009.
(Summary)
Telmisartan is an angiotensin II receptor blocker (ARB) and also an activator of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). We investigated whether telmisartan improves vascular endothelial function in patients with essential hypertension with the production of endothelial nitric oxide synthase (eNOS) through PPAR-gamma.Telmisartan was administered to 15 patients with essential hypertension. To assess vascular function, asymmetric dimethylarginine (ADMA), an eNOS inhibitor synthesized by endothelial cells, and the pulse-wave velocity (PWV) were measured. The serum levels of lipid, glucose, and glycohemoglobin (HbA1c) were also evaluated before and after treatment. Telmisartan therapy significantly decreased the blood pressure and total- and LDL-cholesterol levels. HbA1c was also significantly improved but not in fasting plasma glucose. The serum levels of ADMA were significantly decreased (0.48 +/- 0.08 to 0.42 +/- 0.05 nmol/mL; P = 0.01). PWV values were significantly decreased by telmisartan from 1,822.5 +/- 352.3 to 1,661.5 +/- 299.8 cm/second (P = 0.04*). Telmisartan decreased PWV presumably via the activation of PPAR-gamma, suggesting that this agent improves vascular endothelial function via its pleiotropic effects, a mechanism that is different from its hypotensive effects.
(Keyword)
Administration, Oral / Aged / Angiotensin II Type 1 Receptor Blockers / Arginine / Benzimidazoles / Benzoates / Blood Glucose / Blood Pressure / Cholesterol, LDL / Dose-Response Relationship, Drug / Endothelium, Vascular / Female / Humans / Hypertension / Male / Nitric Oxide Synthase Type III / PPAR gamma / Treatment Outcome
Nguyen Van Nhien, Tomoki Yabutani, Nguyen Cong Khan, Le Bao Nguyen Khanh, Nguyen Xuan Ninh, Chung Thi Kim Le, Junko Motonaka and Yutaka Nakaya : Association of Low Serum Selenium with Anemia among Adolescent Girls Living in Rural Vietnam, Nutrition, Vol.25, No.1, 6-10, 2009.
(Summary)
We investigated the prevalence of anemia and deficiency in trace elements in adolescent girls living in rural Vietnam. Two hundred forty-five adolescent girls 11-17 y of age from three schools in rural province of Ha Nam, Vietnam, were assessed. The prevalence of anemia was 20.4%. The incidences of low serum selenium (Se), zinc, and copper in subjects were 15.9%, 26.5%, and 4.1%, respectively. The parameter significantly associated with anemia was the low serum levels of Se and vice versa (odds ratio [OR] 5.36, 95% confidence interval [CI] 2.57-11.18, P < 0.0001). Other risk factors for anemia were a body mass index <17.00 kg/m(2) (OR 2.72, 95% CI 1.37-5.37, P = 0.004) and years of age (OR 1.35, 95% CI 1.14-1.59, P < 0.001). A body mass index <17.00 kg/m(2) (OR 2.65, 95% CI 1.25-5.61, P = 0.011) was also found to be a risk factor for low serum Se. The findings of the present study demonstrate that low serum Se is independently associated with anemia in adolescent girls living in rural Vietnam. Interventions are required to gain insight into the potential role of Se on prevention and control of anemia.
(Keyword)
Adolescent / Anemia, Iron-Deficiency / Body Mass Index / children / Confidence Intervals / Copper / Cross-Sectional Studies / Female / Humans / Nutrition Assessment / Nutritional Status / Odds Ratio / Prevalence / Risk Factors / Rural Health / Selenium / Vietnam / zinc
Nhien Van Nguyen, Khan Cong Nguyen, Tomoki Yabutani, Chung Thi Kim Le, Khanh Nguyen Bao Le, Junko Motonaka and Yutaka Nakaya : Relationship of low serum selenium to anemia among primary school children living in rural Vietnam., Journal of Nutritional Science and Vitaminology, Vol.54, No.6, 454-459, 2008.
(Summary)
A cross-sectional study of 292 primary school children was conducted in rural Vietnam to investigate the relationship among micronutrient deficiencies, and other risk factors for anemia. Serum levels of iron, copper, zinc, selenium and magnesium were determined by inductively coupled plasma mass spectrometry and that of retinol by high performance liquid chromatography. Hemoglobin concentration in whole blood was measured by the cyanmethemoglobin method. The incidence of low serum zinc, selenium, magnesium, and copper in the children was 91.4, 75.6, 59.5, and 8.6%, respectively. Forty-five percent of the children were anemic and 11.3% suffered from vitamin A deficiency. A parameter significant associated with anemia was low serum selenium and vice versa (OR 1.85, 95% CI 1.06-3.24, p<0.05). Other factors associated with anemia were serum retinol <1.05 micromol/L (OR 2.05, 95% CI 1.25-3.36, p<0.01), and age in years (OR 1.59, 95% CI 1.16-2.18, p<0.01). The study showed that low selenium is associated with anemia among school children in Vietnam. Interventions are required to gain insight into the potential role of selenium on prevention and control of anemia.
Masayuki Shono, Ichiro Shimizu, Eriko Aoyagi, Tatsuya Taniguchi, Hidetaka Takenaka, Momoko Ishikawa, Mari Urata, Katsutaka Sannomiya, Katsuyoshi Tamaki, Nagakatsu Harada, Yutaka Nakaya and Tetsuji Takayama : Reducing Effect of Feeding Powdered Nacre of Pinctada maxima on the Visceral Fat of Rats, Bioscience, Biotechnology, and Biochemistry, Vol.72, No.10, 2761-2763, 2008.
(Summary)
An abdominal fat accumulation complicated by high blood triglycerides is regarded as a risk factor of metabolic syndrome. Feeding powdered nacre, mother of pearl, from Pinctada maxima, resulted in reduced body weight, visceral fat amount, and blood triglyceride level without influencing the food intake, body length, or amount of muscular tissue, suggesting that nacre powder specifically could decrease visceral fat.
Sorayya Kheirvari, Kayoko Uezu, Shigeru Yamamoto and Yutaka Nakaya : High-dose dietary supplementation of vitamin A induces brain-derived neurotrophic factor and nerve growth factor production in mice with simultaneous deficiency of vitamin A and zinc., Nutritional Neuroscience, Vol.11, No.5, 228-234, 2008.
(Summary)
Marginal vitamin A and zinc (Zn) deficiency often co-exist in many populations. Vitamin A plays a trophic role in brain and is important for its development. We investigated effects of dietary supplementation of vitamin A on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) production in mice depleted for vitamin A and Zn. After 3 months' feeding with a low vitamin A and Zn (LVA-LZ) diet, mice were divided into two groups and replenished with either normal or high vitamin A with low Zn diet for an additional 2 months. Levels of BDNF and NGF were measured from extracts of hippocampus, cortex and cerebellum at the end of the third and fifth months. The LVA-LZ group tended to show decreased amounts of the BDNF and NGF, while animals supplemented with high vitamin A along with Zn deficiency had high BDNF and NGF concentrations. From these results, we conclude that vitamin A may increase BDNF and NGF levels.
(Keyword)
Animals / Brain-Derived Neurotrophic Factor / cerebellum / Cerebral Cortex / Diet / Dietary Supplements / Hippocampus / Male / Mice / Nerve Growth Factor / Specific Pathogen-Free Organisms / vitamin A / Vitamin A Deficiency / zinc
M Nakano, Akira Takahashi, Z Su, Nagakatsu Harada, Kazuaki Mawatari and Yutaka Nakaya : Hfq regulates the expression of the thermostable direct hemolysin gene in Vibrio parahaemolyticus, BMC Microbiology, Vol.8, 155, 2008.
(Summary)
The hfq gene is conserved in a wide variety of bacteria and Hfq is involved in many cellular functions such as stress responses and the regulation of gene expression. It has also been reported that Hfq is involved in bacterial pathogenicity. However, it is not clear whether Hfq regulates virulence in Vibrio parahaemolyticus. To evaluate this, we investigated the effect of Hfq on the expression of virulence-associated genes including thermostable direct hemolysin (TDH), which is considered to be an important virulence factor in V. parahaemolyticus, using an hfq deletion mutant. The production of TDH in the hfq deletion mutant was much higher than in the parental strain. Quantification of tdh promoter activity and mRNA demonstrated that transcription of the tdh gene was up-regulated in the mutant strain. The hfq-complemented strain had a normal (parental) amount of tdh expression. The transcriptional activity of tdhA was particularly increased in the mutant strain. These results indicate that Hfq is closely associated with the expression level of the tdh gene. Interestingly, other genes involved in the pathogenicity of V. parahaemolyticus, such as VP1680, vopC, and vopT, were also up-regulated in the mutant strain. Hfq regulates the expression of virulence-associated factors such as TDH and may be involved in the pathogenicity of V. parahaemolyticus.
Masahiro Nomura, Tomohito Kawano, Kimiko Nakayasu and Yutaka Nakaya : The effects of losartan on signal-averaged P wave in patients with atrial fibrillation, International Journal of Cardiology, Vol.126, No.1, 21-27, 2008.
(Summary)
Losartan has recently been reported to suppress atrial structural remodeling. However, few reports exist on signal-averaged electrocardiography (ECG) for preventing atrial electrical remodeling. We examined the effect of losartan on atrial electricity by using signal-averaged ECG of P waves. The subjects comprised 40 patients with essential hypertension complicated with symptomatic paroxysmal atrial fibrillation. The patients received pilsicainide for the complication; they were defibrillated and divided into two subgroups for antihypertensive therapy: calcium antagonist-administrated (CB) and losartan-administrated (LOS) groups. We recorded the signal-averaged electrocardiography of P waves and calculated (1) filtered P wave duration (PD), (2) the voltage integral for the entire P wave (integral-p), and (3) the root mean square voltages of the terminal 40, 30, and 20 ms (RMS-40, RMS-30, and RMS-20). Procollagen C propeptide type I (PIP) and A- and B-type natriuretic peptide (ANP and BNP, respectively) levels in the groups were measured before and after antihypertensive agent administration. RMS-20 increased significantly and PD decreased significantly in the LOS group 24 weeks after antihypertensive drug administration; however, they remained unchanged in the CB group. Integral-p decreased significantly in both groups, and the decrease rate was significantly higher in the LOS group. Serum BNP levels decreased significantly only in the LOS group. Losartan inhibits atrial remodeling by inhibiting left atrial fibrosis as indicated by the procollagen C propeptide type I, ANP, and BNP levels. Signal-averaged ECG demonstrated that losartan suppresses atrial fibrillation recurrence by improving atrial conduction disturbance.
Isoflurane activates vascular adenosine triphosphate sensitive potassium (K(ATP)) channels, and may induce vasodilation. In the present study, we investigated whether hyperglycemia modifies isoflurane activation of vascular K(ATP) channel. We used a cell-attached patch-clamp configuration to test the effects of isoflurane on K(ATP) channel activity in vascular smooth muscle cells (VSMCs) after incubation for 24 h in medium containing normal glucose (NG, 5.5 mM D-glucose), L-glucose (LG, 5.5 mM D-glucose plus 17.5 mM L-glucose), or high glucose (HG, 23 mM D-glucose). Superoxide levels in aortas were measured by the lucigenin-enhanced chemiluminescence technique. Isoflurane-induced open probabilities were significantly reduced in VSMCs from arteries incubated in HG (0.06 +/- 0.01) compared with NG (0.17 +/- 0.02; P < 0.05) and LG (0.15 +/- 0.02; P < 0.05). Pretreatment of VSMCs with protein kinase C (PKC) inhibitors, calphostin C and PKC inhibitor 20-28, greatly reduced HG inhibition of isoflurane-induced K(ATP) channel activity. In addition, a PKC activator, PMA, mimicked the effects of HG. Superoxide release was significantly increased in arteries incubated in HG (18.3 +/- 11.5 relative light units (RLU) x s(-1) x mg(-1); P < 0.05 versus NG). Coincubated with polyethylene glycol-superoxide dismutase (250 U/mL), a cell-permeable superoxide scavenger, greatly reduced the HG-induced increase of superoxide, but failed to reduce HG inhibition of isoflurane-induced K(ATP) channel activity. Our results suggest that the metabolic stress of hyperglycemia can impair isoflurane-induced vascular K(ATP) channel activity mediated by excessive activation of PKC. This could impede the coronary vasodilation response to isoflurane, causing ischemia or hypoxia in patients with perioperative hyperglycemia.
岩城 正輝, 石丸 勝雄 and Yutaka Nakaya : Long-term Efficacy of Unloading Therapy for β cells after Short-term Intensive Insulin Therapy in Poorly Controlled Type 2 Diabetes, Journal of the The Japan Diabetes Society, Vol.51, No.4, 309-317, 2008.
(Summary)
We tested the long-term effectiveness of combining short-term intensive insulin therapy (SIIT) and unloading therapy for βcells (UTB) in patients with poorly controlled (HbA<sub>1</sub>c≥8%) type 2 diabetes. After glucose toxicity was improved by SIIT, patients were treated using UTB, which included (1) combined α-glucosidase inhibitor and metformin, (2) a small dose of short-acting sulfonylurea, gliclazide, (3) control of hypertension and hyperlipidemia by angiotensin II receptor blockers and statins, and (4) lifestyle modification. Patients numbered 41 with diabetetes (60±13 years old) treated using UTB and followed up as outpatients. Only 4 had SIIT reinstituted due to poor control -3 who were severey obese (BMI≥34) and one using glibenclamide for 13 years. The remaining 37 maintained control fairly well (HbA<sub>1</sub>c<7.0%) with UTB over a mean follow-up of 35±22 months. Those who had no history of sulfonylurea use showed significantly higher success in discontinuing of gliclazide (83%) compared to those previously using sulfonylurea (37%). These results suggest that combining SIIT and UTB may improve glucose toxicity and overloading of β cells, e.g., postprandial hyperglycemia, insulin resistance, and oxidative stress and, in turn, preserve β cell function, suggesting the usefulness of this therapy in poorly controlled type 2 diabetes.
Nhien Van Nguyen, Nguyen Cong Khan, Nguyen Xuan Ninh, Phan Van Huan, Le Thi Hop, Nguyen Thi Lam, Fusao Ota, Tomoki Yabutani, Vu Quynh Hoa, Junko Motonaka, Yutaka Nakaya and Takeshi Nishikawa : Micronutrient deficiencies and anemia among preschool children in rural Vietnam, Asia Pacific Journal of Clinical Nutrition, Vol.17, No.1, 48-55, 2008.
(Summary)
The prevalence of trace elements deficiencies, vitamin A deficiency, anemia, and their relationships were investigated in a cross sectional study involving 243 children aged from 12 to 72 months in rural Vietnam. Serum levels of copper, zinc, selenium and magnesium were determined by inductively coupled plasma mass spectrometer and that of retinol by high performance liquid chromatography. Hemoglobin concentration in whole blood was measured by the cyanmethemoglobin method. The prevalence of deficiencies in zinc, selenium, magnesium, and copper was 86.9%, 62.3%, 51.9%, and 1.7%, respectively. On the other hand, 55.6% were anemic and 11.3% had vitamin A deficiency. Deficiency in two or more micronutrient was found in 79.4% of the children. Parameters associated significantly with anemia were selenium deficiency (OR 2.80 95% CI 1.63-4.80, p=0.0002) and serum retinol<1.05 micromol/L (OR 1.83, 95% CI 1.10-3.05, p=0.021). Magnesium deficiency (OR 3.09 95% CI 1.36-7.03) was found to be a risk factor for zinc deficiency and vice versa. The results indicate that micronutrient deficiencies are prevalent among preschool children in Vietnam. In addition, the results also demonstrate a strong relationship between selenium deficiency and anemia. Clearly, sustainable strategies are urgently required to overcome the problems in the country.
(Keyword)
Anemia, Iron-Deficiency / Child, Preschool / Chromatography, High Pressure Liquid / Confidence Intervals / Cross-Sectional Studies / Female / Hemoglobins / Humans / infant / Magnesium / Magnesium Deficiency / Male / Micronutrients / Nutritional Status / Odds Ratio / Prevalence / Risk Factors / Rural Population / Selenium / Vietnam / Vitamin A Deficiency / zinc
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● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18364326
Nagakatsu Harada, Haruka Yonemoto, Masaki Yoshida, Hironori Yamamoto, Yunjie Yin, Aiko Miyamoto, Atsushi Hattori, Qishisan Wu, Tadahiko Nakagawa, Masayuki Nakano, Kiyoshi Teshigawara, Kazuaki Mawatari, Toshio Hosaka, Akira Takahashi and Yutaka Nakaya : Alternative splicing produces a constitutively active form of human SREBP-1., Biochemical and Biophysical Research Communications, Vol.368, No.3, 820-826, 2008.
(Summary)
We identified a novel alternative splicing event that constitutively produces a truncated active form of human sterol regulatory element-binding protein 1 (SREBP-1). A cDNA of this splicing variant (named SREBP-1Delta) contains a translational stop codon-encoding exon sequence between exons 7 and 8. It produces SREBP-1aDelta (470 a.a.) and SREBP-1cDelta (446 a.a.) proteins that lack transmembrane and C-terminal regulatory sequences necessary for localization of SREBP-1 to the endoplasmic reticulum. A luciferase reporter assay showed that SREBP-1aDelta and SREBP-1cDelta transactivated lipogenic gene promoters to the same extent as that induced by N-terminal active fragments of SREBP-1a and SREBP-1c, respectively. SREBP-1Delta mRNA is expressed in human cell lines as well as adipose and liver tissues. Expression levels ranged from 5% to 16% of total SREBP-1 expression. The ratio of SREBP-1Delta expression to total SREBP-1 expression in HepG2 cells was not affected by either insulin or high glucose treatment.
(Keyword)
Adipose Tissue / Alternative Splicing / Cell Line / Humans / Liver / Organ Specificity / Protein Isoforms / RNA Splice Sites / Sterol Regulatory Element Binding Protein 1 / Tissue Distribution
Takashi Kawano, Tomohito Kawano, Katsuya Tanaka, Satoru Eguchi, Akira Takahashi, Yutaka Nakaya and Shuzo Oshita : Effects of dopamine on ATP-sensitive potassium channels in porcine coronary artery smooth-muscle cells, Journal of Cardiovascular Pharmacology, Vol.51, No.2, 196-201, 2008.
(Summary)
Dopamine is reported to be a coronary vasodilator; however, the exact mechanism of dopamine action in the coronary circulation remains unclear. In this study, we hypothesized that dopamine-induced activation of coronary ATP-sensitive potassium (KATP) channels may be associated with coronary vasodilation. We therefore investigated the direct effects of dopamine on coronary KATP-channel activity. We used patch-clamp configurations to investigate the effects of dopamine on coronary KATP-channel activity. Application of dopamine (10 to 10 M) to the bath solution during cell-attached recordings induced a concentration-dependent increase in KATP-channel activity. In contrast, dopamine failed to activate KATP channels in inside-out patches. Dopamine-induced coronary KATP-channel currents in cell-attached patches were inhibited by pretreatment with the selective D1-like antagonist, Sch-23390, but they were not influenced by the selective D2-like antagonist, domperidone, or the beta-adrenergic receptor antagonist, propranolol. The selective D1-like agonist, SKF-38393, and the adenylyl cyclase activator, forskolin, mimicked the dopamine effects on coronary KATP channels. Furthermore, pretreatment with an inhibitor of protein kinase A, Rp-cAMPS, abolished the dopamine-induced KATP-channel activation. This study demonstrates that dopamine activates coronary KATP channels via signal transduction involving the D1-like dopaminergic receptor-protein kinase A-signaling pathway.
Qishisan Wu, Nagakatsu Harada, Aki Nakamura, Masaki Yoshida, Kazuaki Mawatari, Atsushi Hattori, Qinkai Li, Takaaki Shimohata, (名) Yinhua, Xin Lian, Masayuki Nakano, Toshio Hosaka, Akira Takahashi and Yutaka Nakaya : NO-1886, a lipoprotein lipase activator, attenuates contraction of rat intestinal ring preparations, The Journal of Medical Investigation : JMI, Vol.55, No.1,2, 61-70, 2008.
(Summary)
Various intestinal symptoms or diseases are closely associated with intestinal motility, which may be altered by metabolic disturbances associated with diabetes and obesity. It is therefore important that drugs used in the treatment of metabolic disorders should not have any adverse effects on the intestine. In the present study, we examined whether [4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester (NO-1886), a lipoprotein lipase activator with anti-diabetic and/or anti-obese activity, affects stimulant-induced intestinal contractility. Administration of NO-1886 to intestinal ring preparations of ileum, rectum and colon isolated from Wistar rats attenuated or relaxed contraction induced by a high K+ environment or acetylcholine (ACh). This effect of NO-1886 was dependent on extracellular Ca(2+) and intracellular myosin light chain kinase activity. Our results also showed that ACh-induced colonic contraction was significantly higher in the obese Otsuka Long-Evans Tokushima Fatty (OLETF) than in the non-obese Long-Evans Tokushima Otsuka (LETO) rats. The hypercontractility observed in the colons of OLETF rats occurred concomitantly with an elevation in muscarinic M3 ACh receptor protein levels. Administration of NO-1886 attenuated the obesity-induced hypercontractility of the colonic rings of OLETF rats. Thus, intestinal contractile system would be a novel pharmacological target of the lipoprotein lipase activator NO-1886.
Satoru Eguchi, Takashi Kawano, hua Yin, Katsuya Tanaka, Sonoko Yasui, Kazuaki Mawatari, Akira Takahashi, Yutaka Nakaya, Shuzo Oshita and Nobuyoshi Nakajo : Effects of prostaglandin E1 on vascular ATP-sensitive potassium channels., Journal of Cardiovascular Pharmacology, Vol.50, No.6, 686-691, 2007.
(Summary)
BACKGROUND: Prostaglandin E1 (PGE1) has been reported to activate ATP-sensitive potassium (KATP) channels, which induces vasorelaxation. However, direct evidence of PGE1 interactions with vascular KATP channels is limited. METHODS: The present study investigated the effects and mechanisms of PGE1 on vascular KATP channels in both isometric tension and patch clamp experiments.Isometric tension experiments were performed in rat thoracic aortic rings without an endothelium. Electrophysiologic experiments were performed using patch-clamp techniques to monitor KATP channels in rat vascular smooth muscle cells. RESULTS: PGE1 significantly decreased the isometric tension in a concentration-dependent manner, which was partially inhibited by pretreating with a KATP channel inhibitor, glibenclamide (1 microM), or an inhibitor of protein kinase A (PKA), Rp-cAMPS (100 microM). Application of PGE1 to the bath solution during cell-attached recordings induced a significant increase in KATP channel activity, whereas PGE1 failed to activate KATP channels in the inside-out patches. The PGE1-induced KATP channel currents in cell-attached patches were abolished by pretreating with Rp-cAMPS (100 microM). CONCLUSIONS: The results indicate that the activation of vascular KATP channels played an important role in the PKA-dependent PGE1-induced vasorelaxation. Furthermore, an electrophysiological experiment demonstrated that PGE1 activated vascular KATP channels via PKA activation.
Mirei Mori, Hamamoto Akiko, Akira Takahashi, Nakano Masayuki, Wakikawa Noriko, Tachibana Satoko, Toshitaka Ikehara, Yutaka Nakaya, Masatake Akutagawa and Yohsuke Kinouchi : Development of a new water sterilization device with a 365 nm UV-LED, Medical and Biological Engineering and Computing, Vol.45, No.12, 1237-1241, 2007.
(Summary)
Suitability of an ultraviolet light-emitting diode at an output wavelength of 365 nm (UVA-LED) as a sterilization device was examined in comparison with the other wavelength irradiation such as 254 nm (a low-pressure mercury lam) and 405 nm (LED). The proposed system using the UVA-LED was able to inactivate bacteria, such as Escherichia coli DH5 alpha, Enteropathogenic E. coli, Vibrio parahaemolyticus, Staphylococcus aureus, and Salmonella enterica serovar Enteritidis. The inactivations of the bacteria were dependent on the accumulation of UVA irradiation. Taking advantage of the safety and compact size of LED devices, we expect that the UVA-LED sterilization device can be developed as a new type of water sterilization device.
Akiko Hamamoto, Mirei Mori, Akira Takahashi, Masayuki Nakano, Noriko Wakikawa, Masatake Akutagawa, Toshitaka Ikehara, Yutaka Nakaya and Yohsuke Kinouchi : New water disinfection system using UVA-light emitting diodes., Journal of Applied Microbiology, Vol.103, No.6, 2291-2298, 2007.
(Summary)
To evaluate the ability of high-energy ultraviolet A (UVA) light-emitting diode (LED) to inactivate bacteria in water and investigate the inactivating mechanism of UVA irradiation. We developed a new disinfection device equipped with high-energy UVA-LED. Inactivation of bacteria was determined by colony-forming assay. Vibrio parahaemolyticus, enteropathogenic Escherichia coli, Staphylococcus aureus and Escherichia coli DH5alpha were reduced by greater than 5-log(10) stages within 75 min at 315 J cm(-2) of UVA. Salmonella enteritidis was reduced greater than 4-log(10) stages within 160 min at 672 J cm(-2) of UVA. The formation of 8-hydroxy-2'-deoxyguanosine in UVA-LED irradiated bacteria was 2.6-fold higher than that of UVC-irradiated bacteria at the same inactivation level. Addition of mannitol, a scavenger of hydroxyl radicals (OH(*)), or catalase, an enzyme scavenging hydrogen peroxide (H(2)O(2)) to bacterial suspensions significantly suppressed disinfection effect of UVA-LED. This disinfection system has enough ability to inactivate bacteria and OH(*) and H(2)O(2) participates in the disinfection mechanism of UVA irradiation. We newly developed UVA irradiation system and found that UVA alone was able to disinfect the water efficiently. This will become a useful disinfection system.
Hirohide Yamada, Takashi Kawano, Katsuya Tanaka, Sonoko Yasui, Kazuaki Mawatari, Akira Takahashi, Yutaka Nakaya and Shuzo Oshita : Effects of intracellular MgADP and acidification on the inhibition of cardiac sarcolemmal ATP-sensitive potassium channels by propofol, Journal of Anesthesia, Vol.21, No.4, 472-479, 2007.
(Summary)
Propofol inhibits adenosine triphosphate-sensitive potassium (K(ATP)) channels, which may result in the blocking of ischemic preconditioning in the heart. During cardiac ischemia, sarcolemmal K(ATP) channel activity is regulated by the increased levels of cytosolic metabolites, such as adenosine diphosphate (ADP) and protons. However, it remains unclear whether these cytosolic metabolites modulate the inhibitory action of propofol. The aim of this study was to investigate the effects of intracellular MgADP and acidification on K(ATP) channel inhibition by propofol. We used inside-out patch-clamp configurations to investigate the effects of propofol on the activities of recombinant cardiac sarcolemmal K(ATP) channels, which are reassociated by expressed subunits, sulfonylurea receptor (SUR) 2A, and inwardly rectifying potassium channels (Kir6.2). In the absence of MgADP, propofol inhibited the SUR2A/Kir6.2 channel currents in a concentration-dependent manner, and an IC(50) of 78 microM. Increasing the intracellular MgADP concentrations to 0.1 and 0.3 mM markedly attenuated the inhibitory potency of propofol, and shifted the IC(50) to 183 and 265 microM, respectively. Moreover, decreasing the intracellular pH from 7.4 to 6.5 attenuated the inhibitory potency of propofol, and shifted the IC(50) to 277 microM. In addition, propofol-induced inhibition of truncated Kir6.2DeltaC36 currents, which form a functional channel without SUR2A, was not affected by an increase in intracellular MgADP. However, intracellular acidification (pH 6.5) significantly reduced the propofol sensitivity of Kir6.2DeltaC36 channels. Our results demonstrated that the existence of intracellular MgADP and protons attenuated the direct inhibitory potency of propofol on recombinant cardiac sarcolemmal K(ATP) channels, via SUR2A and Kir6.2 subunits, respectively.
Katsuya Hirasaka, S Kohno, J Goto, H Furochi, Kazuaki Mawatari, Nagakatsu Harada, Toshio Hosaka, Yutaka Nakaya, K Ishidoh, Toshiyuki Obata, Yousuke Ebina, H Gu, S Takeda, Kyoichi Kishi and Takeshi Nikawa : Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice., Diabetes, Vol.56, No.10, 2511-2522, 2007.
(Summary)
c-Cbl plays an important role in whole-body fuel homeostasis by regulating insulin action. In the present study, we examined the role of Cbl-b, another member of the Cbl family, in insulin action. C57BL/6 (Cbl-b(+/+)) or Cbl-b-deficient (Cbl-b(-/-)) mice were subjected to insulin and glucose tolerance tests and a hyperinsulinemic-euglycemic clamp test. Infiltration of macrophages into white adipose tissue (WAT) was assessed by immunohistochemistry and flow cytometry. We examined macrophage activation using co-cultures of 3T3-L1 adipocytes and peritoneal macrophages. Elderly Cbl-b(-/-) mice developed glucose intolerance and peripheral insulin resistance; serum insulin concentrations after a glucose challenge were always higher in elderly Cbl-b(-/-) mice than age-matched Cbl-b(+/+) mice. Deficiency of the Cbl-b gene significantly decreased the uptake of 2-deoxyglucose into WAT and glucose infusion rate, whereas fatty liver was apparent in elderly Cbl-b(-/-) mice. Cbl-b deficiency was associated with infiltration of macrophages into the WAT and expression of cytokines, such as tumor necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein (MCP)-1. Co-culture of Cbl-b(-/-) macrophages with 3T3-L1 adipocytes induced leptin expression and dephosphorylation of insulin receptor substrate 1, leading to impaired glucose uptake in adipocytes. Furthermore, Vav1, a key factor in macrophage activation, was highly phosphorylated in peritoneal Cbl-b(-/-) macrophages compared with Cbl-b(+/+) macrophages. Treatment with a neutralizing anti-MCP-1 antibody improved peripheral insulin resistance and macrophage infiltration into WAT in elderly Cbl-b(-/-) mice. Cbl-b is a negative regulator of macrophage infiltration and activation, and macrophage activation by Cbl-b deficiency contributes to the peripheral insulin resistance and glucose intolerance via cytokines secreted from macrophages.
Lian Xin, Akira Takahashi, Nakano Masayuki, Hori Emiko, Kazuaki Mawatari, Nagakatsu Harada, Toshio Hosaka and Yutaka Nakaya : Vibrio parahaemolytics elevates interferon aloha production in intestinal-like epithelial Caco-2 cells, Canadian Journal of Microbiology, Vol.53, No.9, 1084-1090, 2007.
(Summary)
Vibrio parahaemolyticus is the leading cause of gastroenteritis from seafood consumption. We tried to determine how the gene expression levels of intestinal-like epithelial cells (Caco-2 cells) and mouse intestinal loop mucosal cells change upon infection with this bacterium. Since we found the robust production of interferon alpha (IFN-alpha) by the V. parahaemolyticus infection, we also assessed the upregulation of a number of IFN-stimulated genes (ISGs). The expressions of IFN protein were determined by Western blotting, and the gene expressions of Caco-2 cells after V. parahaemolyticus infection were determined by quantitative real-time reverse-transcription polymerase chain reaction. Three ISGs (i.e., IFN-alpha-inducible protein 15, IFN-alpha-inducible protein 6-16, and IFN-induced protein with tetratricopeptide repeats 1) were upregulated by V. parahaemolyticus infection. Infection induced the production of IFN-alpha, but not IFN-beta or IFN-gamma. The upregulation of the 3 ISGs was suppressed by treatment with a neutralizing IFN-alpha antibody. Moreover, the production of infection-induced IFN-alpha was found in the mouse intestinal loop mucosal cells. V. parahaemolyticus infection of Caco-2 cells results in IFN-alpha production and the expression of IFN-regulated genes.
Masori Maria, Hamamoto Akiko, Kazuaki Mawatari, Nagakatsu Harada, Akira Takahashi and Yutaka Nakaya : Angiotensin Decreases Glucose Uptake by Downregulation of GLUT1 in the Cell Membrene of the Vascular Smooth Muscule Cell Line A10, Journal of Cardiovascular Pharmacology, Vol.50, No.3, 267-273, 2007.
(Summary)
Recent evidence suggests a crosstalk between angiotensin II (Ang II) and insulin. However, whether this crosstalk affects glucose uptake, particularly in terms of actin filament involvement, has not yet been studied in vascular smooth muscle cells. Pretreatment of cells with either Ang II or cytochalasin D disarranged actin filaments in a time-dependent manner and inhibited glucose uptake. However, insulin increased actin reorganization and glucose uptake. Membrane fractionation studies showed that Ang II decreased GLUT-1 at the cell membrane, whereas it increased GLUT-1 in the cytoplasm, indicating that Ang II may cause internalization of GLUT-1 via actin disorganization, consequently decreasing glucose uptake. The effects of Ang II on glucose uptake and actin reorganization were blocked by AT1 receptor antagonist, but not by AT2 antagonist. Either P38 or ERK1/2 inhibitors partially reversed the Ang II-inhibited actin reorganization and glucose uptake, suggesting that MAPK signaling pathways could be involved as downstream events in Ang II signaling, and this signaling may interfere with insulin-induced actin reorganization and glucose uptake. These data imply that Ang II induces insulin resistance by decreasing glucose uptake via disarrangement of actin filaments, which provides a novel insight into understanding of insulin resistance by Ang II at the molecular level.
(Keyword)
Actins / Angiotensin II / Animals / Cell Fractionation / Cell Line / Cell Membrane / Cytochalasin D / Down-Regulation / Glucose / Glucose Transporter Type 1 / Insulin / Insulin Resistance / MAP Kinase Signaling System / Muscle, Smooth, Vascular / Rats / Time Factors
Ono Kaori, Kazuaki Mawatari, Nagakatsu Harada, Akira Takahashi, Tohru Sakai, Ogoshi Shohei and Yutaka Nakaya : Nucleoside and nucleotide mixture OG-VI rescues cytotoxicity induced by chemotherapeutic agents in intestinal-like epithelial cell., The Journal of Medical Investigation : JMI, Vol.54, No.3,4, 235-242, 2007.
(Summary)
Immune cells and cells undergoing rapid turn-over can obtain exogenous nucleotides via salvage synthesis. We evaluated whether or not the balanced nucleoside and nucleotide mixture OG-VI, could rescue intestinal epithelial-like Caco-2 cells from the cytotoxic effects of several chemotherapeutic agents, in the presence and absence of glutamine (Gln). Cells were exposed to 5-fluorouracil (5FU), methotrexate (MTX) or 6-mercaptopurine (6MP), after which proliferation and cell cycle analyses were performed. Following exposure to the chemotherapeutic agents, we observed that cells treated with OG-VI proliferated well, whereas those without the supplement did not proliferate. Furthermore, following treatment with either 5FU or MTX, we observed that the number of cells in the G0/G1 phase decreased and those in the S phases increased. However, these cell cycle alterations were prevented by the addition of OG-VI. With the exception of 6MP-treated cells, we did not observe any effects on proliferation or cell cycle regulation that could be ascribed to the presence of Gln. Thus, we have demonstrated that OG-VI rescues cells from the cytotoxic effects of several chemotherapeutic agents.
Masayuki Nakano, Akira Takahashi, Y Sakai, M Kawano, Nagakatsu Harada, Kazuaki Mawatari and Yutaka Nakaya : Catecholamine-induced stimulation of growth in Vibrio species., Letters in Applied Microbiology, Vol.44, No.6, 649-653, 2007.
(Summary)
To evaluate the effect of norepinephrine (NE) and related compounds on the growth of bacteria, we have examined the effect of the neuroendocrine hormone NE and related compounds on the growth of Vibrio parahaemolyticus and other human-pathogenic Vibrio species (Vibrio cholerae, Vibrio vulnificus, and Vibrio mimicus). The effects on bacterial growth were examined using the serum-based medium and viable cells were counted using agar plates. We have shown that NE and its related compounds stimulate growth of V. parahaemolyticus in serum-based medium. This NE-induced growth stimulation was dependent upon the presence of transferrin. NE also stimulated growth of V. mimicus, but not V. cholerae and V. vulnificus. These results suggest that the Vibrio species differ in their ability to respond to NE. It is possible that NE and related compounds modulate the pathogenicity of V. parahaemolyticus and V. mimicus.
Nakamura Akiyo, Shinji Kawahito, Takashi Kawano, Nazari Hossein, Akira Takahashi, Hiroshi Kitahata, Yutaka Nakaya and Shuzo Oshita : Differential Effects of Etomidate and Midazolam on Vascular Adenosine Triphosphate-sensitive Potassium Channels: Isometric Tension and Patch Clamp Studies., Anesthesiology, Vol.106, No.3, 515-522, 2007.
(Summary)
The aim of this study was to investigate the effects of two imidazoline-derived intravenous anesthetics, etomidate and midazolam, on vascular adenosine triphosphate-sensitive potassium (KATP) channel activity. In isolated rat aorta, isometric tension was recorded to examine the anesthetic effects on vasodilator response to levcromakalim, a selective KATP channel opener. Using the patch clamp method, the anesthetic effects were also examined on the currents through (1) native vascular KATP channels, (2) recombinant KATP channels with different combinations of various types of inwardly rectifying potassium channel (Kir6.0 family: Kir6.1, 6.2) and sulfonylurea receptor (SUR1, 2A, 2B) subunits, (3) SUR-deficient channels derived from a truncated isoform of Kir6.2 subunit (Kir6.2DeltaC36 channels), and (4) mutant Kir6.2DeltaC36 channels with reduced sensitivity to adenosine triphosphate (Kir6.2DeltaC36-K185Q channels). Etomidate (> or = 10 m), but not midazolam (up to 10 m), inhibited the levcromakalim-induced vasodilation, which was sensitive to glibenclamide (IC50: 7.21 x 10 m; maximum inhibitory concentration: 1.22 x 10 m). Etomidate (> or = 3 x 10 m), but not midazolam (up to 10 m), inhibited the native KATP channel activity in both cell-attached and inside-out configurations with IC50 values of 1.68 x 10 m and 1.52 x 10 m, respectively. Etomidate (10 m) also inhibited the activity of various types of recombinant SUR/Kir6.0KATP channels, Kir6.2DeltaC36 channels, and Kir6.2DeltaC36-K185Q channels with equivalent potency. Clinical concentrations of etomidate, but not midazolam, inhibit the KATP channel activity in vascular smooth muscle cells. The inhibition is presumably through its effects on the Kir6.0 subunit, but not on the SUR subunit, with the binding site different from adenosine triphosphate at the amino acid level.
Katsuya Tanaka, Takashi Kawano, Akiyo Nakamura, Hossein Nazari, Shinji Kawahito, Shuzo Oshita, Akira Takahashi and Yutaka Nakaya : Isoflurane activates sarcolemmal adenosine Triphosphate-sensitive potassium channels in vascular smooth muscle cells: A role of protein kinase A, Anesthesiology, Vol.106, No.5, 984-991, 2007.
(Summary)
Recent evidence indicates that vascular adenosine triphosphate-sensitive potassium (K(ATP)) channels in vascular smooth muscle cells are critical in the regulation of vascular tonus under both physiologic and pathophysiologic conditions. Studies of the interaction of volatile anesthetics with vascular K(ATP) channels have been limited. In the current study, the authors investigated the molecular mechanism of isoflurane's action on vascular K(ATP) channels. Electrophysiologic experiments were performed using cell-attached and inside-out patch clamp techniques to monitor native vascular K(ATP) channels, and recombinant K(ATP) channels comprised of inwardly rectifying potassium channel subunits (Kir6.1) and the sulfonylurea receptor (SUR2B). Isometric tension experiments were performed in rat thoracic aortic rings without endothelium. Application of isoflurane (0.5 mM) to the bath solution during cell-attached recordings induced a significant increase in K(ATP) channel activity, which was greatly reduced by pretreatment with a selective inhibitor of protein kinase A (PKA), Rp-cAMPS (100 microM). In inside-out patches, isoflurane did not activate K(ATP) channels. Isoflurane significantly activated wild-type recombinant SUR2B/Kir6.1 in cell-attached patches. Isoflurane-induced activation of wild-type channels was diminished in the PKA-insensitive mutant SUR2B-T633A/Kir6.1, SUR2B-S1465A/Kir6.1, and SUR2B/Kir6.1-S385A. In addition, the authors demonstrated that isoflurane-induced PKA activation was associated with isoflurane-induced decreases in isometric tension in the rat aorta. These results indicate that isoflurane activates K(ATP) channels via PKA activation. PKA-dependent vasodilation induced by isoflurane also was observed in isometric tension experiments. Analysis of expressed vascular-type K(ATP) channels suggested that PKA-mediated phosphorylation of both Kir6.1 and SUR2B subunits plays a pivotal role in isoflurane-induced vascular K(ATP) channel activation.
Nagakatsu Harada, A Kusuyama, M Morishima, Kazuko Okada, Akira Takahashi and Yutaka Nakaya : Bezafibrate improves bacterial lipopolysaccharide-induced dyslipidemia and anorexia in rats., Metabolism: Clinical and Experimental, Vol.56, No.4, 517-522, 2007.
(Summary)
Bacterial endotoxin/lipopolysaccharide (LPS)-induced cachexia is characterized by weight loss, anorexia, and a disturbance in lipid metabolism, namely, hypertriacylglycerolemia. The aim of this study in rats with acute endotoxicity induced by an injection of LPS was to investigate whether bezafibrate, a ligand for peroxisome proliferator-activated receptor alpha and a lipoprotein lipase (LPL) activator, improved cachectic conditions, including impaired lipid metabolism. Short-term administration of LPS in the rats resulted in impairment of triacylglycerol clearance in plasma after the intake of fresh cream. In addition, LPS increased whole-body energy expenditure, reduced fasting body weight and caused anorexia in the rats. Bezafibrate treatment resulted in significant improvements in LPS-induced dyslipidemia and anorexia, but had no effect on energy expenditure, respiratory quotient, or fasting body weight in the endotoxic rats. Administration of LPS was also associated with a decrease in the level of messenger RNA (mRNA) expression for LPL in white adipose tissue and skeletal muscle and an increase in the mRNA levels for uncoupling protein 3 in skeletal muscle. Bezafibrate treatment reversed the decline in LPL mRNA levels in white adipose tissue but not in the skeletal muscle tissue of the rats. The enhanced uncoupling protein 3 mRNA level in the endotoxic rats was not affected by bezafibrate treatment. Plasma concentration of leptin was increased by short-term LPS treatment. Bezafibrate decreased the level of plasma leptin significantly without affecting the level of leptin mRNA expression. These results suggest that bezafibrate may be an effective drug not only for impaired triacylglycerol metabolism, but also for anorexia in cachectic states induced by bacterial infections.
Y Wang, Morishima Masaki, M Zheng, T Uchino, K Mannen, Akira Takahashi, Yutaka Nakaya, I Komuro and K Ono : Transcription factors Csx/Nkx2.5 and GATA4 distinctly regulate expression of Ca2+ channels in neonatal rat heart., Journal of Molecular and Cellular Cardiology, Vol.42, No.6, 1045-1053, 2007.
(Summary)
The cardiac transcription factors Csx/Nkx2.5 and GATA4 play important roles in vertebrate heart development. Although mutations of Csx/Nkx2.5 or GATA4 are associated with various congenital heart diseases, their mechanism of action on cardiomyocyte function is not completely elucidated. In this study, we therefore investigated the actions of these transcription factors on the electrophysiological features and expression of ion channels in cardiomyocytes. Genes for transcription factors Csx/Nkx2.5 and GATA4 were transfected into rat neonatal cardiomyocytes by adenoviral infection. Action potentials, L-, T-type Ca(2+) channels and hyperpolarization-activated cation current (I(h)) of rat neonatal myocytes were recorded by patch clamp technique after adenoviral infection. Expression of ion channels was confirmed by real-time PCR. In Csx/Nkx2.5 overexpression myocytes, the spontaneous beating rate was markedly increased with an up-regulation of the Ca(v)3.2 T-type Ca(2+) channel, while in GATA4 overexpression myocytes, the T-type Ca(2+) channel was unchanged. On the other hand, the L-type Ca(2+) channel was down-regulated by both Csx/Nkx2.5 and GATA4 overexpression; the level of Ca(v)1.3 mRNA was dramatically decreased by Csx/Nkx2.5 overexpression. These results indicate that Csx/Nkx2.5 and GATA4 play important roles on the generation of pacemaker potentials modulating voltage-dependent Ca(2+) channels in the neonatal cardiomyocyte.
M Nakano, Akira Takahashi, Y Sakai and Yutaka Nakaya : Modulation of Pathogenicity with Norepinephrine Related to the Type III Secretion System of Vibrio parahaemolyticus., The Journal of Infectious Diseases, Vol.195, No.9, 1353-1360, 2007.
(Summary)
Norepinephrine (NE) controls the functions of the gastrointestinal tract, but its role in the pathogenicity of enteropathogens is not clear. We examined the effect of NE on the pathogenicity of Vibrio parahaemolyticus with regard to its type III secretion systems (TTSSs). To evaluate the effect of NE on pathogenicity of V. parahaemolyticus, we examined the cytotoxic activity to Caco-2 cells and enterotoxicity by use of the rat ileal loop model. It has been reported that TTSS1 causes cytotoxicity and that TTSS2 causes enterotoxicity in the animal ileal loop model. Our results showed that, although NE alone did not affect the viability of Caco-2 cells, NE stimulated the cytotoxic activity of V. parahaemolyticus. Furthermore, NE increased the transcription of the TTSS1-related genes vscQ and vscU. These results indicate that NE regulates V. parahaemolyticus cytotoxic activity. The enterotoxicity of V. parahaemolyticus was increased by NE through interaction with alpha (1)-adrenergic receptors. These results indicate that alpha (1)-adrenergic receptors on the intestinal epithelium appear to interact with V. parahaemolyticus enterotoxicity. The present findings suggest that enteric NE may modulate V. parahaemolyticus pathogenicity.
Kazuyoshi Kitaoka, Atsushi Hattori, Sachiko Chikahisa, Ken-ichi Miyamoto, Yutaka Nakaya and Hiroyoshi Sei : Vitamin A deficiency induces a decrease in EEG delta power during sleep in mice, Brain Research, Vol.1150, 121-130, 2007.
(Summary)
Recent report (Maret, S., Franken, P., Dauvilliers, Y., Ghyselinck, N.B., Chambon, P., Tafti, M., 2005. Retinoic acid signaling affects cortical synchrony during sleep. Science 310, 111-113.) has suggested that vitamin A (retinol and its derivatives) is genetically involved in the electroencephalogram (EEG) delta oscillation during sleep. However, this finding has not yet been confirmed by other studies. In this study, we attempted to record the sleep EEG and behavior, and to quantify striatal monoamines in mice fed a vitamin A-deficient (VAD) diet for 4 weeks, in order to clarify the linkage between the delta oscillation and vitamin A. VAD mice demonstrated a significant decrease in the delta power of the EEG. However, 6-h sleep deprivation caused the recovery of the delta power in VAD mice to a level similar to that of the control. VAD also caused the decrease of spontaneous activity throughout 24-h period. Furthermore, dihydroxyphenylacetic acid, a metabolite of dopamine, was decreased significantly in the striatal tissue of VAD mice. Our present results suggest that the deficiency of vitamin A causes the attenuation of delta power in NREM sleep and spontaneous activity. These attenuations may be related to the alteration of striatal dopaminergic function.
(Keyword)
3,4-Dihydroxyphenylacetic Acid / Analysis of Variance / Animals / Behavior, Animal / Body Weight / Corpus Striatum / Delta Rhythm / Dopamine / Exploratory Behavior / Male / Mice / Mice, Inbred C57BL / Motor Activity / Serotonin / Sleep / Sleep Deprivation / Spectrum Analysis / Vitamin A / Vitamin A Deficiency
Hiroyuki Ikefuji, Masahiro Nomura, Yutaka Nakaya, Toshifumi Mori, Noriyasu Kondo, Kiyoshi Leishi, Sayuri Fujimoto and Susumu Ito : Visualization of cardiac dipole using a current density map: detection of cardiac current undetectable by electrocardiography using magnetocardiography., The Journal of Medical Investigation : JMI, Vol.54, No.1-2, 116-123, 2007.
(Summary)
A close relationship exists between electric current and the magnetic field. However, electricity and magnetism have different physical characteristics, and magnetocardiography (MCG) may provide information on cardiac current that is difficult to obtain by electrocardiography (ECG). In the present study, we investigated the issue of whether the current density map method, in which cardiac current is estimated from the magnetic gradient, facilitates the visualization of cardiac current undetectable by ECG. The subjects were 50 healthy adults (N group), 40 patients with left ventricular overloading (LVO group), 15 patients with right ventricular overloading (RVO group), 10 patients with an old inferior myocardial infarction (OMI group), and 30 patients with diabetes mellitus (DM group). MCGs were recorded with a second derivative superconducting quantum interference device (SQUID) gradiometer using liquid helium. Isopotential maps and current density maps from unipolar precordial ECG leads and MCGs, respectively, were prepared, and the cardiac electric current was examined. The current density map at the ventricular depolarization phase showed one peak of current density in the N group. However, in the OMI group, the current density map showed multiple peaks of current density areas. In the RVO group, two peaks of current densities were detected at the right superior region and left thoracic region and these two diploles appeared to be from the right and left ventricular derived cardiac currents, respectively. Moreover, there was a significant correlation between the magnitude of the current density from the right ventricle and the systolic pulmonary arterial pressure. The current density map at the ventricular repolarization phase in the N group showed only a single current source. However, abnormal current sources in the current density maps were frequently detected even in patients showing no abnormalities on isopotential maps in the LVO, DM, and OMI groups. The findings herein suggest that opposing dipoles of the ventricular depolarization and repolarization vectors were summed and evaluated as a single dipole in the electrocardiogram. However, MCG facilitated the detection of multiple dipoles because of its superior spatial resolution as well as difference in physical properties between magnetic and electrical fields. Our results suggest that MCG with a current density map is useful for detecting cardiac current undetectable by ECG in an early stage.
A late evening snack improves the catabolic state in patients with advanced liver cirrhosis. We tested whether long-term (3 mo) late evening snacking that included a branched-chain amino acid (BCAA)-enriched nutrient mixture produces a better nutritional state and better quality of life than ordinary food in patients with hepatitis C virus-positive liver cirrhosis. In a multicenter, randomized study, 48 patients with liver cirrhosis received late-evening supplementation with the BCAA-enriched nutrient mixture or ordinary food, such as a rice ball or bread, for 3 mo. During the study period, each patient was instructed on energy and protein intake. Blood biochemical data, nitrogen balance, respiratory quotient, and health-related quality of life (Short Form 36 questionnaire) were evaluated at baseline and at the end of the study. Total and late-evening energy intakes were similar in the two groups at 3 mo. Serum albumin level, nitrogen balance, and respiratory quotient were significantly improved by the BCAA mixture but not by ordinary food. The parameters of the Short Form 36 did not statistically significantly improve over 3 mo in either group. Long-term oral supplementation with a BCAA mixture is better than ordinary food in a late evening snack at improving the serum albumin level and the energy metabolism in patients with cirrhosis.
(Keyword)
Aged / Amino Acids, Branched-Chain / Blood Chemical Analysis / Dietary Proteins / Dietary Supplements / Energy Intake / energy metabolism / Female / Humans / Liver Cirrhosis / Male / Nutritional Status / oxygen consumption / quality of life / Serum Albumin / Severity of Illness Index
Hossein Nazari, Akira Takahashi, Nagakatsu Harada, Kazuaki Mawatari, Masayuki Nakano, Kazuhiro Kishi, Yousuke Ebina and Yutaka Nakaya : Angiotensin II inhibits insulin-induced actin stress fiber formation and glucose uptake via ERK1/2., The Journal of Medical Investigation : JMI, Vol.54, No.1,2, 19-27, 2007.
(Summary)
There is crosstalk in intracellular signaling between Angiotensin II (Ang II) and insulin. We hypothesized that the underlying mechanism might be related to changes in cytoskeleton. In the presence of 100 nM of Ang II, insulin-induced glucose uptake was decreased and insulin-induced actin filament organization was inhibited. PKC inhibitors, including GF109203x and p38MAPK inhibitor (SB203580) neither improved insulin-induced actin reorganization nor glucose uptake. In contrast, the Ang II-induced inhibition of glucose uptake and actin filament disorganization was reversed by 10 micromol ERK 1/2 MAPK inhibitor (PD98059). Pretreatment of Ang II increased ERK1/2 phosphorylation and inhibited insulin-induced Akt phosphorylation. The effect of Ang II on ERK1/2 phosphorylation was blocked by Ang II type 1 receptor antagonists, RNH6270 and PD98059 but not by SB203580 or Guanosine-5'-O-(2-ThioDiphosphate), a G-protein inhibitor. We next tested the effect of broad-spectrum matrix metalloproteinase (MMP) inhibitor (GM6001) on Ang II-inhibition of insulin signaling pathway. GM6001 did not improve Ang II-induced actin filament disorganization and did not inhibit ERK1/2 phosphorylation. From these data in L6 myotube, we conclude that Ang II negatively regulates the insulin signal not through MMP signaling pathway but specifically through MMP-independent ERK1/2 activation pathway, providing an alternative molecular mechanism for angiotensin-induced insulin resistance.
(Keyword)
Angiotensin II / Cell Line / glucose / Humans / insulin / MAP Kinase Signaling System / Mitogen-Activated Protein Kinase 1 / Mitogen-Activated Protein Kinase 3 / phosphorylation / Proto-Oncogene Proteins c-akt / Receptor, Angiotensin, Type 1 / Stress Fibers
Masahiro Nomura, Yutaka Nakaya and Kimiko Nakayasu : Evaluation of an infarction vector by magnetocardiogram: Detection of electromotive forces that cannot be deduced from an electrocardiogram., International Congress Series, Vol.1300, 512-515, 2007.
Kazuhiro Kishi, Kazuaki Mawatari, K Sakai-Wakamatsu, Tomoyuki Yuasa, M Wang, M Ogura-Sawa, Yutaka Nakaya, S Hatakeyama and Yousuke Ebina : APS-mediated Ubiquitination of the Insulin Receptor Enhances its Internalization but does not Induce its Degradation., Endocrine Journal, Vol.54, No.1, 77-88, 2007.
(Summary)
APS, a tyrosine kinase adaptor protein with pleckstrin homology and Src homology 2 domains, is rapidly and strongly tyrosine-phosphorylated by insulin receptor kinase upon insulin stimulation. We have previously shown that APS knockout mice have increased insulin sensitivity, and that this enhancement is possibly due to increased insulin-response on adipose tissues. However, the function of APS in insulin signaling has so far been controversial. Here, we report that APS enhanced ligand-dependent multi-ubiquitination of the insulin receptor (IR) in CHO cells overexpressing the IR. APS-mediated ubiquitination of the IR induced enhancement of the IR internalization, but did not affect the IR degradation. This finding shows one of the pleiotropic functions of APS in insulin signaling.
(Keyword)
Adaptor Proteins, Signal Transducing / Animals / CHO Cells / Cricetinae / Cricetulus / Humans / Insulin / Mice / Protein Processing, Post-Translational / Protein Transport / Receptor, Insulin / Signal Transduction / Transfection / Ubiquitin
Nagakatsu Harada, S Hara, M Yoshida, T Zenitani, Kazuaki Mawatari, M Nakano, Akira Takahashi, Toshio Hosaka, Katsuhiko Yoshimoto and Yutaka Nakaya : Molecular cloning of a murine glycerol-3-phosphate acyltransferase-like protein 1 (xGPAT1)., Molecular and Cellular Biochemistry, Vol.297, No.1-2, 41-51, 2007.
(Summary)
A novel murine glycerol-3-phosphate acyltransferase-like protein 1 (named xGPAT1) has been cloned. The mouse xGPAT1 gene is located on mouse Chromosome 2, spans >19 kb, and consists of at least 23 exons. The protein is 32% identical and 72% similar to mouse mitochondrial GPAT (mtGPAT) on the amino acid level. Sequencing analysis confirmed that xGPAT1 has a 2403-bp open reading frame (ORF) that encodes an 801-amino acid protein with an estimated molecular mass of 89.1 kDa. A hydropathy plot of the deduced xGPAT1 protein showed a high degree of similarity with that of the mtGPAT protein. Using 5'-rapid amplification of cDNA ends, two alternate, untranslated exon 1 (1a and b) isoforms were obtained, generating variants xGPAT1-v1 and xGPAT1-v2. xGPAT1-v1 is expressed in mouse heart, liver, spleen, kidney and murine inner medullary collecting duct 3 (mIMCD3) cells, while xGPAT1-v2 is expressed in mouse liver, spleen, kidney, white and brown adipose tissues and 3T3-L1 pre- and post-adipocytes. xGPAT1 was distributed in the membrane fraction and showed GPAT activity when epitope-tagged xGPAT1 was expressed in Chinese hamster ovary (CHO)-K1 cells.
A Nakamura, Nagakatsu Harada, Akira Takahashi, Kazuaki Mawatari, M Nakano, K Tsutsumi and Yutaka Nakaya : NO-1886, a lipoprotein lipase activator, attenuates vascular smooth muscle contraction in rat aorta, European Journal of Pharmacology, Vol.554, No.2-3, 183-190, 2007.
(Summary)
The chemical compound [4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester (NO-1886) is a lipoprotein lipase activator having beneficial effects on both diabetes control and the cardiovascular system. Preventing accumulation of lipids in the cell wall, in addition to improving insulin actions on vasculature, may indirectly contribute to the reducing effect of NO-1886 on vascular resistance. However, the direct effect of NO-1886 on vascular resistance, i.e., whether NO-1886 directly modulates the function of vascular endothelium and/or smooth muscle cells has not been investigated. In this study we therefore investigated the direct effect of NO-1886 on vascular contractility using rat aortic rings and cultured smooth muscle cell-line A10. The results show that administration of NO-1886 attenuated aortic contraction induced by phenylephrine and/or a high K(+) environment, in both the presence and absence of aortic endothelium. 1-(5-Chloronaphthalene-1-sulfonyl)homopiperazine hydrochloride (ML-9), a myosin light chain kinase (MLCK) inhibitor, blocked this inhibitory effect of NO-1886, whereas inhibitors of other signaling molecules such as calmodulin, protein kinase C and Rho-kinase had no effect. The vasorelaxant effect of NO-1886 was blocked in the absence of extracellular Ca(2+), or in the presence of the Ca(2+) channel inhibitor, verapamil. NO-1886 attenuated smooth muscle contraction induced by the cumulative addition of CaCl(2). In A10 cells, NO-1886 inhibited the membrane depolarization-induced initial peak of [Ca(2+)](i) in the presence of extracellular Ca(2+). This inhibition did not occur in the absence of extracellular Ca(2+). Taken together these results demonstrate that NO-1886 attenuates smooth muscle contraction and causes vasorelaxation by an extracellular Ca(2+)- and MLCK-dependent mechanism.
Akira Takahashi, SI Miyoshi, N Takata, M Nakano, A Hamamoto, Kazuaki Mawatari, Nagakatsu Harada, S Shinoda and Yutaka Nakaya : Haemolysin produced by Vibrio mimicus activates two Cl secretory pathways in cultured intestinal-like Caco-2 cells., Cellular Microbiology, Vol.9, No.3, 583-595, 2007.
(Summary)
Haemolysin (VMH) is a virulent factor produced by Vibrio mimicus, a human pathogen that causes diarrhoea. As intestinal epithelial cells are the primary targets of haemolysin, we investigated its effects on ion transport in human colonic epithelial Caco-2 cells. VMH increased the cellular short circuit current (Isc), used to estimated ion fluxes, and 125I efflux of the cells. The VMH-induced increases in Isc and 125I efflux were suppressed by depleting Ca2+ from the medium or by pretreating the cells with BAPTA-AM or by Rp-adenosin 3',5'-cyclic monophosphorothioate triethylammonium salt (Rp-cAMPS). The Cl- channel inhibitors 4,4'-disothiocyanatostibene-2,2'-disulfonic acid (DIDS), glybenclamide, and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) suppressed the VMH-induced increases in Isc and 125I efflux. Moreover, VMH increased the intracellular concentrations of Ca2+ and cAMP. Thus, VMH stimulates Caco-2 cells to secrete Cl- by activating both Ca2+ -dependent and cAMP-dependent Cl- secretion mechanisms. VMH forms ion-permeable pores in the lipid bilayer that are non-selectively permeable to small ions. However, the ion permeability of these pores was not inhibited by glybenclamide and DIDS, and VMH did not change the cell membrane potential. These observations indicate that the pores formed on the cell membrane by VMH are unlikely to be involved in VMH-induced Cl- secretion. Notably, VMH stimulated fluid accumulation in the iliac loop test that was fully suppressed by a combination of DIDS and glybenclamide. Thus, Ca2+-dependent and cAMP-dependent Cl- secretion may be important therapeutic targets with regard to the diarrhoea that is induced by Vibrio mimicus.
M. Urata, H Fukuno, Masahiro Nomura, T Ogata, Susumu Ito, Kimiko Nakayasu and Yutaka Nakaya : Gastric motility and autonomic activity during obstructive sleep apnea., Alimentary Pharmacology & Therapeutics, Vol.24, No.Suppl 4, 132-140, 2006.
T Furukawa, CX Bai, A Kaihara, E Ozaki, Takashi Kawano, Yutaka Nakaya, M Awais, M Sato, Y Umezawa and J Kurokawa : Ginsenoside Re a main phytosterol of Panax ginseng activates cardiac potassium channels via a nongenomic pathway of sex hormones., Molecular Pharmacology, Vol.70, No.6, 1916-1924, 2006.
(Summary)
Ginseng root is one of the most popular herbs throughout the world and is believed to be a panacea and to promote longevity. It has been used as a medicine to protect against cardiac ischemia, a major cause of death in the West. We have previously demonstrated that ginsenoside Re, a main phytosterol of Panax ginseng, inhibits Ca(2+) accumulation in mitochondria during cardiac ischemia/reperfusion, which is attributable to nitric oxide (NO)-induced Ca(2+) channel inhibition and K(+) channel activation in cardiac myocytes. In this study, we provide compelling evidence that ginsenoside Re activates endothelial NO synthase (eNOS) to release NO, resulting in activation of the slowly activating delayed rectifier K(+) current. The eNOS activation occurs via a nongenomic pathway of each of androgen receptor, estrogen receptor-alpha, and progesterone receptor, in which c-Src, phosphoinositide 3-kinase, Akt, and eNOS are sequentially activated. However, ginsenoside Re does not stimulate proliferation of androgen-responsive LNCaP cells and estrogen-responsive MCF-7 cells, implying that ginsenoside Re does not activate a genomic pathway of sex hormone receptors. Fluorescence resonance energy transfer experiments with a probe, SCCoR (single cell coactivator recruitment), indicate that the lack of genomic action is attributable to failure of coactivator recruitment. Thus, ginsenoside Re acts as a specific agonist for the nongenomic pathway of sex steroid receptors, and NO released from activated eNOS underlies cardiac K(+) channel activation and protection against ischemia-reperfusion injury.
Yasunobu Hayabuchi, Yutaka Nakaya, Yasui Sonoko, Kazuaki Mawatari, Kazuhiro Mori, Suzuki Mitsujiro and Shoji Kagami : Angiotensin II activates intermediate-conductance Ca2+-activated K+ channels in arterial smooth muscle cells., Journal of Molecular and Cellular Cardiology, Vol.41, No.6, 972-929, 2006.
(Summary)
Angiostensin II (Ang II) regulates the migration and proliferation of vascular smooth muscle cells. Recent studies indicate that intermediate-conductance Ca2+ -activated K+ (IKca) channels have an important role in cell migration and proliferation. It is not known, however, whether the action of Ang II is linked to IKca channel regulation. Here, we investigated the modulation of IKca channels by Ang II in artery smooth muscle cells. Functional IKca channel expression in cultured embryonic rat aorta smooth muscle (A10) cells was studied using the patch-clamp technique. These cells predominantly express IKca channels. In contrast, large-conductance Ca2+ -activated K+ (BKca) currents were rarely observed in excised patches. Ang II increased the IKca current in a contration-dependent manner. Losartan (1.0 microM), an AT1 selective antagonist, abolished the activation of IKca channels by Ang II. Pretreatment with 100 microM myristoylated protein kinase C inhibitor peptide 20-28 or 10 microM GF109203X completely abolished the AngII-induced activation of IKca currents, whereas the action of Ang II was not prevented in the presence of 100 microM Rp-cyclic 3', 5'-hydrogen phosphotiate adenosine triethylammonium, a protein kinase A inhibitor, or 1.0 microM KT-5823, a protein kinase G inhibitor. A membrane permeant analogue of diacylglycerol 1, 2-dioctanoyl-sn-glycerol (10 microM) induced the activation of IKca currents. These data suggest that Ang II activates IKca channels through the activation of protein kinase C, and the AT1 receptor is involved in the regulation of these channels.
(Keyword)
Angiotensin II / Angiotensin II Type 1 Receptor Blockers / Animals / Cells, Cultured / Diglycerides / Enzyme Inhibitors / Intermediate-Conductance Calcium-Activated Potassium Channels / Losartan / Muscle, Smooth, Vascular / Myocytes, Smooth Muscle / Patch-Clamp Techniques / Protein Kinase C / Rats / Receptor, Angiotensin, Type 1 / Signal Transduction
Matsushima Rie, Nagakatsu Harada, Webster J. G. Nicholas, Tsutsumi M. Yasuo and Yutaka Nakaya : Effect of TRB3 on Insulin and Nutrient-stimulated Hepatic p70 S6 Kinase Activity, The Journal of Biological Chemistry, Vol.281, No.40, 29719-29729, 2006.
(Summary)
Insulin and nutrients activate hepatic p70 S6 kinase (S6K1) to regulate protein synthesis. Paradoxically, activation of S6K1 also leads to the development of insulin resistance. In this study, we investigated the effect of TRB3, which acts as an endogenous inhibitor of Akt, on S6K1 activity in vitro and in vivo. In cultured cells, overexpression of TRB3 completely inhibited insulin-stimulated S6K1 activation by mammalian target of rapamycin, whereas knockdown of endogenous TRB3 increased both basal and insulin-stimulated activity. In C57BL/6 mice, adenoviral overexpression of TRB3 inhibited insulin-stimulated activation of hepatic S6K1. In contrast, overexpression of TRB3 did not inhibit nutrient-stimulated S6K1 activity. We also investigated the effect of starvation, feeding, or insulin treatment on TRB3 levels and S6K1 activity in the liver of C57BL/6 and db/db mice. Both insulin and feeding activate S6K1 in db/db mice, but only insulin activates in the C57BL/6 strain. TRB3 levels were 3.5-fold higher in db/db mice than C57BL/6 mice and were unresponsive to feeding or insulin, whereas both treatments reduced TRB3 in C57BL/6 mice. Akt was activated by insulin alone in the C57BL/6 strain and but not in db/db mice. Both insulin and feeding activated mammalian target of rapamycin similarly in these mice; however, feeding was unable to activate the downstream target S6K1 in C57BL/6 mice. These results suggest that the nutrient excess in the hyperphagic, hyperinsulinemic db/db mouse primes the hepatocyte to respond to nutrients resulting in elevated S6K1 activity. The combination of elevated TRB3 and constitutive S6K1 activity results in decreased insulin signaling via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway.
Tetsuya Tsujikawa, Masahiro Nomura, Kimiko Nakayasu, Tomohito Kawano, Yutaka Nakaya, Susumu Ito and Hiromu Nishitani : Risk factors associated with soft coronary artery plaques in Japanese as determined by 16 slice multidetector-row computed tomography., The Journal of Medical Investigation : JMI, Vol.53, No.3-4, 310-316, 2006.
(Summary)
The acute coronary syndrome is often caused by the rupture of plaques and thrombus formation even without significant stenosis, and patients with soft plaques, but without significant stenosis evidenced by coronary angiography (CAG), often develop an acute coronary syndrome. To address this discrepancy, a qualitative diagnosis of coronary plaques using a 16 slice multidetector-row CT was conducted. Volume rendering and cross-sectional MPR images were obtained. Based on the CT values, plaques on the coronary artery wall were classified as lipid-rich soft plaques (CT value<50 HU) and non-soft plaques (>50 HU).A significant correlation was observed between the percent stenosis determined in cross-sectional MPR images and those determined by CAG (r=+0.92, p<0.01). Diffuse plaques with CT values of less than 50 HU often caused stenosis at level of 75% or less, which were not indicated by percutaneous transluminal coronary angioplasty. Although diffuse soft plaques with CT values less than 50 HU are not an indication of intervention, a risk of an acute coronary syndrome exists, due to rupture. These soft plaques must be stabilized by treatment even when they do not cause significant stenosis, and MDCT is considered to be useful for their evaluation.
Harada Shinji, Masahiro Nomura, Yutaka Nakaya and Susumu Ito : Nateglinide with glibenclamide examination using the respiratory quotient (RQ)., The Journal of Medical Investigation : JMI, Vol.53, No.3-4, 303-309, 2006.
(Summary)
The respiratory quotient (RQ) is useful for evaluating glucose and lipid metabolism in vivo. We previously reported that the RQ value, even after fasting, was high in diabetics being treated with sulphonylurea (SU), which might explain the accumulation of fat, leading to weight gain in such individuals. In the present study, we measured the RQ in type II diabetic patients who were being treated with a rapid-onset/short-duration insulinotropic agent, nateglinide, and compared it with those being treated with SU. A glucose tolerance test was performed in 20 patients with type II diabetes mellitus treated with nateglinide and in 14 patients treated with SU, and the RQ was simultaneously measured. The RQ values in the patients treated with nateglinide, were similar to those in healthy adults, but was lower than in those treated with SU. No weight gain was observed in patients treated with nateglinide. A significant weight gain was reported in subjects treated with SU, accompanied by an increase in RQ. However, weight gain was less frequent in diabetics treated with nateglinide.
Hiroyuki Sakakibara, Kaori Ishida, Oliver Grundmann, Jun-ichiro Nakajima, Shujiro Seo, Veronika Butterweck, Yuko Minami, Satomi Saito, Yoshichika Kawai, Yutaka Nakaya and Junji Terao : Antidepressant effect of extracts from Ginkgo biloba leaves in behavioral models, Biological & Pharmaceutical Bulletin, Vol.29, No.8, 1767-1770, 2006.
(Summary)
Extracts of Ginkgo biloba (EGB) are a complex product prepared from green leaves of the Ginkgo biloba tree. In the present study, the antidepressant effect of EGB was examined using two behavioral models, the forced swimming test (FST) in rats and tail suspension test (TST) in mice. EGB significantly reduced immobility time in the FST at a dosage of 10 and 50 mg/kg body weight after repeated oral treatment for 14 d, although no change of motor dysfunction was observed with the same dosage in the open field test. These results indicate that EGB might possess an antidepressant activity. In addition, EGB markedly shortened immobility time in the TST after acute inter-peritoneal treatment at a dosage of 50 and 100 mg/kg body weight. The present study clearly demonstrated that EGB exerts an antidepressant effect in these two behavioral models.
Akira Takahashi, Chiyo Yamamoto, Toshio Kodama, Kanami Yamashita, Nagakatsu Harada, Masayuki Nakano, Takeshi Honda and Yutaka Nakaya : Pore formation of thermostable direct hemolysin secreted from Vibrio parahaemolyticus in lipid bilayers., International Journal of Toxicology, Vol.25, No.5, 409-418, 2006.
(Summary)
Vibrio parahaemolyticus secretes thermostable direct hemolysin (TDH), a major virulence factor. Earlier studies report that TDH is a pore-forming toxin. However, the characteristics of pores formed by TDH in the lipid bilayer, which is permeable to small ions, remain to be elucidated. Ion channel-like activities were observed in lipid bilayers containing TDH. Three types of conductance were identified. All the channels displayed relatively low ion selectivity, and similar ion permeability. The Cl- channel inhibitors, DIDS, glybenclamide, and NPPB, did not affect the channel activity of pores formed by TDH. R7, a mutant toxin of TDH, also forms pores with channel-like activity in lipid bilayers. The ion permeability of these channels is similar to that of TDH. R7 binds cultured cells and liposomes to a lower extent, compared to TDH. R7 does not display significant hemolytic activity and cell cytotoxicity, possibly owing to the difficulty of insertion into lipid membranes. Once R7 is assembled within lipid membranes, it may assume the same structure as TDH. The authors propose that the single glycine at position 62, substituted with serine in the R7 mutant toxin, plays an important role in TDH insertion into the lipid bilayer.
Sachiko Chikahisa, Hiroyoshi Sei, Masaki Morishima, Atsuko Sano, Kazuyoshi Kitaoka, Yutaka Nakaya and Yusuke Morita : Exposure to music in the perinatal period enhances learning performance and alters BDNF/TrkB signaling in mice as adults., Behavioural Brain Research, Vol.169, No.2, 312-319, 2006.
(Summary)
Music has been suggested to have a beneficial effect on various types of performance in humans. However, the physiological and molecular mechanism of this effect remains unclear. We examined the effect of music exposure during the perinatal period on learning behavior in adult mice, and measured the levels of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), which play critical roles in synaptic plasticity. In addition, we measured the levels of 3-phosphoinositide-dependent protein kinase-1 (PDK1) and mitogen-activated protein kinase (MAPK), downstream targets of two main pathways in BDNF/TrkB signaling. Music-exposed mice completed a maze learning task with fewer errors than the white noise-exposed mice and had lower levels of BDNF and higher levels of TrkB and PDK1 in the cortex. MAPK levels were unchanged. Furthermore, TrkB and PDK1 protein levels in the cortex showed a significant negative correlation with the number of errors on the maze. These results suggest that perinatal exposure of mice to music has an influence on BDNF/TrkB signaling and its intracellular signaling pathway targets, including PDK1, and thus may induce improved learning and memory functions.
Aeromonas sobria hemolysin (ASH) is one of the major virulence factors produced by A. sobria, a causative agent of diarrhea in humans. We investigated the effects of ASH on anion transport in human colonic epithelial cells. ASH increased short circuit currents across the intestinal epithelia, which were suppressed by anion channel antagonists, such as carbonic anhydrase inhibitors, and by the removal of external HCO3-. Iliac fluid accumulation was also inhibited by carbonic anhydrase inhibitors. The results suggest that ASH activates HCO3- secretion, whose level correlates with the severity of diarrhea.
Tomonori Watanabe, Masahiro Nomura, Kimiko Nakayasu, Tomohito Kawano, Susumu Ito and Yutaka Nakaya : Relationships between thermic effect of food insulin resistance and autonomic nervous activity., The Journal of Medical Investigation : JMI, Vol.53, No.1,2, 153-158, 2006.
(Summary)
The thermic effect of food (TEF) is higher in lean than in obese human subjects. Relationships between TEF and insulin resistance during meals, from the point of view of autonomic nervous activity, were evaluated. Autonomic nervous activity was evaluated in 20 young adults using the spectral analysis of heart rate variability from one hour before to two hours after a meal. Heart rate data were analyzed based on low frequency components (LF power, 0.04-0.15 Hz), high frequency components (HF power, 0.15-0.40 Hz), and LF/HF ratios. Energy expenditure and the TEF were measured 30 min after a meal. Homeostasis model of insulin resistance index (HOMA-IR) was also measured. The LF/HF ratio was significantly increased 30 min after a meal (p<0.05). No correlation between LF power and HF power with TEF was found, but the LF/HF ratio was significantly and positively correlated with TEF (r=+0.56, p<0.05). Moreover, a significant negative correlation was found between the HOMA-IR and TEF (r=-0.601, p<0.05). The findings suggest that a reduction in insulin sensitivity induces a poor response of sympathetic nervous activity in the postprandial phase and a reduction in postprandial energy expenditure.
(Keyword)
Adult / Autonomic Nervous System / energy metabolism / Female / Food / Heart Rate / Humans / insulin resistance / Male / Models, Neurological / obesity
Y Ozaki, Masahiro Nomura, T Nakayama, T Ogata, Kimiko Nakayasu, Yutaka Nakaya and Susumu Ito : Effects of thrombus suction therapy on myocardial blood flow disorders in males with acute inferior myocardial infarction., The Journal of Medical Investigation : JMI, Vol.53, No.1-2, 167-173, 2006.
(Summary)
Several studies have reported that the use of a distal protection device decreases the incidence of slow-flow and/or no-reflow in patients with myocardial infarctions. In the present study, we investigated the influence of a RESCUE/Thrombuster system and a PercuSurge GuardWire catheter on coronary microcirculation disorders in patients with acute myocardial infarction using the natriuretic polypeptide (ANP), the brain natriuretic peptide (BNP), and (99m)Tc-tetrofosmin myocardial scintigraphy (TF). The group consisted of a 77 patients with initial inferior myocardial infarction who had undergone emergency coronary angioplasty. The patients were randomly divided into: Group D (n=28), in which a direct stent alone was inserted, Group R/T (n=25), in which a stent was inserted after RESCUE system or a Thrombuster system was performed, and Group P (n=24), in which a stent was inserted after thrombus suction using a PercuSurge GuardWire catheter. Patients with coronary slow-flow/no-reflow were 3, 2 and 0 cases in Group D, Group R / T and Group P, respectively. In the present study, patients with good-reflow were enrolled in order to investigate the coronary microcirculation disorder in patients with visually similar coronary blood flow obtained in coronary angiography after percutaneous coronary reperfusion therapy. TF myocardial scintigraphy was performed 10+/-3 days after admission. Bull's eye images were divided into 8 sections, and each section was evaluated in 4 grades. The grade of each segment was regarded as the defect score. The results were compared with the database prepared based on bull's eye maps from 50 healthy adults in our hospital, and count areas of -2 x SD (standard deviation) or less were calculated as the extent score (%), reflecting the area in which myocardial blood flow was decreased. The extent and severity scores in Groups P and R/T were significantly lower than those in Group D. Coronary angiography at the chronic stage (6 months after surgery) showed the patency of the responsible vascular lesion in all patients. However, the ANP, BNP, cardiac index, and pulmonary capillary wedge pressure (PCWP) were significantly improved in Groups R/T and P, compared to Group D (p<0.01). These results suggest that the use of a RESCUE/Thrombuster system and a PercuSurge GuardWire catheter system in patients with acute inferior wall infarction improves coronary microcirculation disorders and acute- to chronic-phase cardiac function.
K Koshiba, Masahiro Nomura, Yutaka Nakaya and Susumu Ito : Efficacy of glimepiride on insulin resistance adipocytokines and atherosclerosis., The Journal of Medical Investigation : JMI, Vol.53, No.1-2, 87-94, 2006.
(Summary)
Plasma adiponectin levels increase after the administration of glimepiride. This unique effects would also be expected to improve other adipocytokines and have anti-atherosclerotic action in patients with metabolic syndrome. Thirty-four patients with type 2 diabetes mellitus who were administrated glibenclamide were randomly divided into two groups. In 20 patients glibenclamide was changed to glimepiride (GP group), and the administration of glibenclamide (GB group) was continued in 14 patients. Twelve patients receiving insulin therapy (INS group) were enrolled for comparison. The levels of plasma adiponectin, high sensitive-CRP, TNF-alpha, interleukin-6, homeostasis model assessment-insulin resistance (HOMA-IR), brachial-ankle pulse wave velocity (baPWV) and augmentation index (AI) were measured before and 28 weeks after the therapy. HOMA-IR in the GP group was significantly decreased compared to the GB group. Plasma adiponectin levels were significantly increased in the GP group but not in the other groups. TNF-alpha, interleukin-6 and high sensitive-CRP levels were significantly decreased in the GP group, but not in the other groups. The baPWV and AI levels did not change in either the GB or the INS group, but were significantly decreased in the GP group. Glimepiride appears to improve insulin resistance and atherosclerotic disorders.
T Kawaguchi, Masahiro Nomura, T Tujikawa, Yutaka Nakaya and Susumu Ito : (123)I-metaiodo-benzylguanidine myocardial scintigraphy in the Brugada-type ECG., The Journal of Medical Investigation : JMI, Vol.53, No.1-2, 95-102, 2006.
(Summary)
The degree of ST-segment elevation and amplitude of J waves, which may change in patients with the Brugada-type electrocardiogram (ECG) over time, are influenced by autonomic nervous activity and the administration of antiarrhythmic drugs. In the present study, we evaluated whether the shape of ST-segment elevation in patients with a Brugada-type ECG might alter the parameters of an 123I-MIBG myocardial scintigraphy and body surface signal-averaged ECG (SAECG). The subjects consisted of 12 patients with a Brugada-type ECG and 15 healthy volunteers (N group). The patients with a Brugada-type ECG were classified into the following 2 groups based on the type of ST-segment elevation: 6 patients with the coved type ST-segment elevation (C group), and 6 patients with the saddle-back type ST-segment elevation (S group). Planar and SPECT images were obtained 15 minutes (early images) and 3 hours (delayed images) after the administration of 123I-MIBG, respectively. In addition, the washout rate (% WR) of 123I-MIBG was obtained in a bull's eye map of the SPECT image. There were no significant differences in the early H/M ratio between the C and S groups. In the C group, however, there were some patients who showed a decreased accumulation or defect of 123I-MIBG in the planar and SPECT images. Furthermore, in contrast to the N and S groups, the C group showed a decreased delayed H/M ratio and increased % WR. SAECG did not show any significant differences between the S and C groups. These results of the present study suggest that the shape of ST-segment elevation may be associated with myocardial autonomic nervous function. In addition, the electric heterogeneity of the action potential in the right ventricular epicardial myocardium, which is frequently influenced by autonomic nervous activity, is closely associated with the development of Brugada syndrome.
T Ogata, Masahiro Nomura, Yutaka Nakaya and Susumu Ito : Evalution of episodes of sleep apnea in patients with liver cirrhosis, The Journal of Medical Investigation : JMI, Vol.53, No.1,2, 159-166, 2006.
(Summary)
Obstructive sleep apnea syndrome (OSAS) has been reported to be a new complication of liver cirrhosis with ascites. This fact prompted a study of episodes of sleep apnea as a function of the severity of cirrhosis. Forty eight patients with type C liver cirrhosis were divided according to the Child-Pugh score into 3 groups: Group A (16 patients with grade A cirrhosis), Group B (16 patients with grade B cirrhosis), and Group C (16 patients with grade C cirrhosis). Portable sleep polygraphs (Fuji RC, Inc. Tokyo, Japan) were attached to the subjects, and oronasal respiration, tracheal sounds, respiratory movements of the chest, and percutaneous arterial oxygen saturation continuously were recorded. A decrease in the mean airflow to 50% or less was defined as hypopnea, and the number per hour of episodes of apnea and hypopnea per hour lasting 10 seconds or longer (AHI) was counted. A Holter ECG was also recorded, and spectral heart rate variability during sleep was analyzed by measuring low frequency power (0.04-0.15 Hz, LF power), high frequency power (0.15-0.40 Hz, HF power), the ratio of LF power to HF power (LF/HF ratio), and very low frequency power (0.008-0.04 Hz, VLF power). The difference in QT interval between the lead CM5 and the lead CM1 (QTc dispersion) was also examined. AHI was significantly higher in Group C than in Groups A and B (p<0.05). In Group C, 6 patients with 20 times or more AHI per hour, obstructive sleep apnea, in which respiratory chest movements occur but oronasal respiration decreases or disappears, was observed. Spectral analyses of heart rate variability showed a decrease in HF power without sleep apnea, but increases in HF power and VLF power were observed during sleep apnea. The QTc dispersion increased during episodes of sleep apnea. As the stage of liver cirrhosis advanced, sleep apnea appeared, and changes in autonomic nervous activities were observed. Furthermore, QTc dispersion was increased during episodes of sleep apnea, presumably increasing the risk of ventricular arrhythmia.
N Kageyama, Masahiro Nomura, Yutaka Nakaya, T Watanabe and Susumu Ito : Relationship between adhesion molecules with hs-CRP and changes therein after ARB (Valsartan) administration in patients with obstructive sleep apnea syndrome, The Journal of Medical Investigation : JMI, Vol.53, No.1,2, 134-139, 2006.
(Summary)
It has been reported that a relationship exists between obstructive sleep apnea syndrome (OSAS) and cardiovascular and cerebrovascular diseases. To address this issue, we evaluated whether OSAS is associated with adhesion molecules and inflammatory signs, important indicators of atherosclerosis. Levels of high-sensitivity CRP (hs-CRP) and intercellular adhesion molecule-1 (ICAM-1) were measured in 30 patients with ischemic heart disease, confirmed by coronary arteriography (IHD group). Twenty healthy volunteers without sleep apnea were used as controls (Group N). Sleeping respiratory information was collected using a portable sleep polygraph, together on information about oronasal flow, tracheal sound, chest respiration, and percutaneous oxygen saturation (SpO2) to obtain the apnea-hypopnea index (AHI). In the IHD group, 9 (30%) of the 30 patients showed evidence of OSAS [IHD(AHI> or = 40) group] and 21 did not [IHD(AHI<40) group]. The levels of hs-CRP and ICAM-1 were significantly higher in the IHD group than in the N group (p<0.01). Moreover, the levels of hs-CRP and ICAM-1 were significantly higher in the IHD(AHI > or = 40) group than in the IHD(AHI<40) group (p<0.01). However, after the administration of valsartan, angiotensin II receptor antagonists (ARB) to both IHD groups, the levels of hs-CRP and ICAM-1 decreased significantly in both groups. Moreover, a multivariate analysis revealed that the levels of hs-CRP and ICAM-1 were associated with the severity of sleep apnea. These findings suggest that, in OSAS the levels of hs-CRP and ICAM-1 are decreased and that the administration of ARB decreases the risk of atherosclerosis.
Rie Matsushima, Akira Takahashi, Yutaka Nakaya, Hiroshi Maezawa, Mari Miki, Youichi Nakamura, Fumitaka Ohgushi and Susumu Yasuoka : Human airway trypsin-like protease stimulates human bronchial fibroblast proliferation in a protease-activated receptor-2-dependent pathway., American Journal of Physiology. Lung Cellular and Molecular Physiology, Vol.290, No.2, 385-395, 2006.
(Summary)
Human airway trypsin-like protease (HAT) was isolated from airway secretions and localized to bronchial epithelial cells by immunohistochemistry. In the present study, we examined whether HAT could stimulate DNA synthesis and proliferation of primary human bronchial fibroblasts (HBF). HAT significantly stimulated the proliferation of HBF by 20-55%, a level similar to that of the mitogenic activity of lung mast cell tryptase (MCT). HAT also stimulated the incorporation of [3H]thymidine in HBF, and this HAT-induced DNA synthesis was abolished by leupeptin. Protease-activated receptor-2 (PAR-2) mRNA was expressed and localized to the cell surface in HBF. PAR-2 activating peptide (AP) also enhanced DNA synthesis, and both HAT and PAR-2 AP induced receptor internalization, similar to the response to trypsin. Pretreatment of HBF with anti-PAR-2 antibody significantly suppressed both HAT and PAR-2 AP-induced DNA synthesis. In addition, HAT and PAR-2 AP induced intracellular Ca2+ mobilization in HBF. The HAT-induced increase in Ca2+ was desensitized by pretreatment with trypsin or PAR-2 AP. U0126, a specific MAPK inhibitor, completely inhibited HAT-induced DNA synthesis as well as HAT-induced phosphorylation of MAPK. The effect of HAT and MCT together was additive, whereas the effect of HAT and insulin together on HBF DNA synthesis was synergistic. These results indicate that HAT stimulates fibroblast proliferation in bronchial airways through a PAR-2-dependent MEK-MAPK mediated pathway and that HAT is linked to airway processes involving fibroblasts.
(Keyword)
trypsin-like protease / HAT / PAR--2 / bronchial fibroblasts
M Morishima, Nagakatsu Harada, S Hara, Atsuko Sano, Hiromasa Seno, Akira Takahashi, Yusuke Morita and Yutaka Nakaya : Monoamine Oxidase A Activity and Norepinephrine Level in Hippocampus Determine Hyperwheel Running in SPORTS Rats., Neuropsychopharmacology, Vol.31, No.12, 2627-2638, 2006.
(Summary)
An understanding of neurological mechanisms for wheel running by rodents, especially with high exercise activity, would be applicable to a strategy for promotion of exercise motivation in humans. One of several brain regions that are candidates for the regulation of physical exercise is the hippocampus. Here we examined the running activity of Spontaneously-Running-Tokushima-Shikoku (SPORTS) rat, a new animal model for high levels of wheel-running activity, and its relation with the hippocampal norepinephrine (NE) system including the levels of NE, adrenergic receptors, and degradation enzymes for monoamines. In the hippocampus of SPORTS rats, the level of NE in extracellular fluid was augmented, whereas the level in the homogenate of the whole tissue was decreased even for sedentary conditions. Elevated extracellular NE caused downregulation of alpha(2)-adrenergic receptors in the hippocampus of SPORTS rats. Local administration of alpha(2)-adrenergic receptor antagonist yohimbine, but not of alpha(2)-agonist clonidine, into the hippocampus suppressed high running activity in SPORTS rats. The protein expression and the activity levels of monoamine oxidase A (MAOA), a critical enzyme for the degradation of NE, were decreased in the hippocampus of SPORTS rats to increase extracellular NE level. Thus, inhibition of oxidase activity in normal Wistar rats markedly increased wheel-running activity. These results indicate that decreased MAOA activity, elevation of extracellular NE, and alpha(2)-adrenergic receptors in the hippocampus determine the neural basis of the psychological regulation of exercise behavior in SPORTS rats.
MT Takase, Ichiro Hashimoto, Hideki Nakanishi, Yutaka Nakaya, Nagakatsu Harada, Hiromichi Sedo and I Kanda : Sarpogrelate hydrochloride an antagonist of 5-hydroxytryptamine receptor improves skin flap survival and suppresses thrombus formation in injured microvessels of rabbits., Journal of Reconstructive Microsurgery, Vol.22, No.1, 59-65, 2006.
(Summary)
The authors carried out two studies to examine the effects of the 5-hydroxytryptamine receptor antagonist, sarpogrelate hydrochloride (SH), on flap necrosis. The first study measured survival rates and included histologic examination of random-pattern skin flaps in rabbits. The second study assessed the time to complete obstruction of blood flow with the artificial thrombus formation method, and the time for leukocytes to adhere to the endothelium of microvessels in a rabbit-ear chamber. The treatment groups were injected with SH. The survival rates of skin flaps in the SH-treated group were increased significantly. Histologic examination of vessels in the control group revealed that vessels in the deep dermis were obstructed completely by thrombi, whereas such vessels were not obstructed in the SH-treated group. Thrombus formation time and leukocyte adhesion time in the SH-treated group were prolonged and decreased, respectively. Thus, SH maintained flap circulation and promoted flap survival by preventing thrombus formation.
Hiroyuki Sakakibara, Kaori Ishida, Yuki Izawa, Yuko Minami, Satomi Saito, Yoshichika Kawai, Veronika Butterweck, Toshiaki Tamaki, Yutaka Nakaya and Junji Terao : Effects of forced swimming stress on rat brain function, The Journal of Medical Investigation : JMI, Vol.52, No.Suppl., 300-3001, 2005.
(Summary)
Chronic stress has been reported to be an essential factor for depression. In this study, the effect of forced swimming stress on neurotransmitters and cellular signaling pathway contributing to brain functions was investigated using the forced swimming test (FST) in order to understanding of mechanisms to regulate stress signals in brain. Antidepressant drug, imipramine, significantly reduced the immobility time of male rats in the FST by 85% at a dose of 15 mg/kg for 2 weeks. This result indicated that the swimming stress caused a depressed state in the rats without administration of imipramine. Swimming stress significantly lowered the serotonergic ratio and also markedly enhanced the phosphorylation of ERK1/2 in the hypothalamus region compared to the rats without FST. These phenomena may be included in key mechanisms of the development of depression.
(Keyword)
Animals / Antidepressive Agents, Tricyclic / brain / Chromatography, High Pressure Liquid / Enzyme Activation / Hippocampus / Hydroxyindoleacetic Acid / Imipramine / Immunoblotting / Male / Mitogen-Activated Protein Kinase 3 / Motor Activity / phosphorylation / Rats / Rats, Inbred Strains / Serotonin / signal transduction / Stress, Physiological / Swimming / Time Factors
(Tokushima University Institutional Repository: 98233)
113.
Masahiro Nomura, Yutaka Nakaya, Kimiko Nakayasu and Tomohito Kawano : 抗不整脈薬の作用機序と心電図変化, 検査と技術, Vol.33, No.13, 1528-1532, 2005.
114.
Yutaka Nakaya, Y Hata, K Ishida, Akira Takahashi, Kyoko Morita and Kazuhito Rokutan : Approach to novel functional foods for stress control 2. Microarray assessment of exercise in healthy volunteers., The Journal of Medical Investigation : JMI, Vol.52, No.Suppl, 242-243, 2005.
(Summary)
DNA microarray was used to measure stress response by exercise in peripheral blood leukocytes. Aerobic exercise did not alter mRNA pattern or urinary secretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Strenuous exercise increased urinary secretion of 8-OHdG and altered mRNA pattern in microarray. These results suggest that moderate exercise, i. e. aerobic exercise, did not show any change in 8-OHdG, an oxidative stress marker, or mRNA expression in the leukocytes, which might reflect whole body neurohormanal changes. In addition, strenuous exercise produced quite different expression pattern from those of psychological stress.
Yutaka Nakaya, M Morishima-Yamato, K Ishida, Nagakatsu Harada and M Nakano : Approach to novel functional foods for stress control 3. Establishment of stress-resistant rat model and its mechanism., The Journal of Medical Investigation : JMI, Vol.52 Suppl, 244, 2005.
(Summary)
A stress-resistant rat model was introduced. SPORTS (Spontaneously-Running-Tokushima-Shikoku) rats showed significantly shorter time of immobility in the forced swim test compared to control Wister rats. Increase norepinephrine concentration secondary to decreased activity of monoamine oxidase A (MAOA) in hippocampus was observed in this model rats. This model rats are considered to be useful for studying the mechanism of psychological stress.
Yukie Iwasa, Kimiko Nakayasu, Masahiro Nomura, Yutaka Nakaya, Ken Saito and Susumu Ito : The relationship between autonomic nervous activity and physical activity in children, Pediatrics International, Vol.47, No.4, 361-371, 2005.
(Summary)
There have been few studies that have reported on heart rate variability and the development of autonomic nervous function in children. This study investigated the relationship between heart rate variabilities at night and physical activity in children. The study subjects were 29 children, including 17 boys and 12 girls. The daily activity product and heart rate variabilities during sleep at night (00.00-05.00 hours) were measured and several aspects of these parameters were analyzed. In one child (an 8-year-old girl), heart rate variability and the physical activity product were measured for 12 days. There was a negative correlation between the mean R-R interval and the duration (min) of heavy exercise per day (r = -0.39, P < 0.05). In the 8-year-old girl, from whom data was obtained for 12 days, the duration of heavy exercise per day was negatively correlated with the mean R-R interval (r = -0.63, P < 0.05), the number of changes in successive R-R intervals greater than 50 msec (RR50) (r = -0.74, P < 0.01), and the high frequency (HF) component (r = -0.66, P < 0.05). Furthermore, the daily number of steps was negatively correlated with the mean R-R interval (r = -0.66, P < 0.05), RR50 (r = -0.71, P < 0.05) and the HF component (r = -0.66, P < 0.05). There was a negative correlation between the amounts of energy consumption and the mean R-R interval (r = -0.69, P < 0.05). There was a negative correlation between the amounts of energy consumption and RR50 (r = -0.76, P < 0.01). Moreover, there was also a negative correlation between the amount of energy consumption and the HF component (r = -0.71, P < 0.05). These findings suggested that physical activities increase heart rate during sleep, but reduce parasympathetic nervous activity at night. Because both the HF component and RR50 reduce with growth, the exercise-related inhibition of parasympathetic nervous activity may be a developmental stimulus to reach a balanced autonomic nervous pattern in adults.
Masahiro Nomura, Kimiko Nakayasu and Yutaka Nakaya : Current density map による心筋虚血ベクトルの検出, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.18, No.1, 2005.
118.
Sae Kujime, Syuji Inoue, Masahiro Nomura, Jyunko Endo, Nobutaka Uemura, Seiichiro Kishi, Yutaka Nakaya and Susumu Ito : Evaluation of gastric emptying by electrogastrography and ultrasonography in gastroesophageal reflux disease, Digestive Endoscopy, Vol.17, No.2, 131-137, 2005.
Akira Takahashi, N Tanoue, M Nakano, A Hamamoto, K Okamoto, Y Fujii, Nagakatsu Harada and Yutaka Nakaya : A pore-forming toxin produced by Aeromonas sobria activates Ca2+ dependent Cl- secretion., Microbial Pathogenesis, Vol.38, No.4, 173-180, 2005.
(Summary)
Bacteria produce many types of hemolysin that induce diarrhea by mechanisms that are not completely understood. Aeromonas sobria hemolysin (ASH) is a major virulence factor produced by A. sobria, a human pathogen that causes diarrhea. Since epithelial cells in the intestine are the primary targets of hemolysin, we investigated the effects of ASH on ion transport in human colonic epithelial (Caco-2) cells. ASH increased short-circuit currents (Isc) in a dose-dependent manner, and it also activated a 125I efflux from Caco-2 cells. ASH-induced Isc increases and 125I efflux activations were both suppressed by low Ca2+ levels in the extracellular solution or by pretreatment with the Ca2+ chlelator BAPTA-AM. Intracellular Ca2+ levels were increased by ASH in a biphasic fashion characterized by a rapid sharp increase (peak 1) followed by a sustained low plateau (peak 2). ASH-induced peak 1 was inhibited by pretreatment with pertussis toxin, indicating that Ca2+ was mobilized from intracellular stores, and peak 2 was induced by an influx of extracellular Ca2+. Peak 2 but not peak 1 was related to Cl- secretion. These results indicate that ASH activates Ca2+-dependent Cl- secretion.
Yanjmaa Bira, Kenji Tani, Yasuhiko Nishioka, juuya Miyata, Keiko Sato, Akihito Hayashi, Yutaka Nakaya and Saburo Sone : Transforming growth factor β stimulates rheumatoid synovial fibroblasts via the type receptor, Modern Rheumatology, Vol.15, No.2, 108-113, 2005.
(Summary)
Transforming growth factor (TGF)-beta regulates the function of fibroblasts, and has been shown to have a role in the pathogenesis of rheumatoid arthritis (RA) because several studies have demonstrated the presence of TGF-beta in the synovial tissue and synovial fluids of RA patients. In this study, we examined the expression of TGF-beta receptors in synovial fibroblasts of patients with RA and demonstrated the significance in functional responses of synovial fibroblasts to TGF-beta in this disorder. Transforming growth factor beta1 stimulated the expression of connective tissue growth factor (CTGF) in fibroblasts of patients with RA more than in those of patients with osteoarthritis (OA). Transforming growth factor beta1 induced the chemotactic migration of RA synovial fibroblasts and inhibited their proliferation significantly more than OA synovial fibroblasts. Both RA and OA synovial fibroblasts expressed detectable amounts of TGF-beta receptor type II mRNA, but the expression was higher in RA patients than in OA patients, as assessed by reverse transcriptase-polymerase chain reaction. There was no significant difference in the expression of TGF-beta receptor type I or type III in synovial fibroblasts between RA and OA patients. These results indicate that synovial fibroblasts of RA patients express the increased TGF-beta receptor type II, which is associated with altered responses to TGF-beta observed in CTGF expression, chemotaxis, and proliferation of RA synovial fibroblasts, and may have an important role in the pathogenesis of RA.
Noriyasu Kondo, Masahiro Nomura, Yutaka Nakaya, Susumu Ito and Takashi Ohguro : Association of Inflammatory Marker and Highly Sensitive C-Reactive Protein With Aerobic Exercise Capacity, Maximum Oxygen Uptake and Insulin Resistance in Healthy Middle-Aged Volunteers, Circulation Journal, Vol.69, No.4, 452-457, 2005.
(Summary)
Increased levels of inflammation markers, such as C-reactive protein (CRP) and tumor necrosis factor-alpha , have been found in insulin resistance syndrome. Those with elevated levels of high-sensitive CRP (hs-CRP) are at a higher risk for coronary heart disease. In the present study, we evaluated whether maximum oxygen uptake and insulin resistance are related to hs-CRP for the primary prevention of coronary heart disease. The subjects were 50 subjects who did not have diabetes mellitus. A multi-step treadmill exercise test was performed to obtain the maximum oxygen uptake when assessed by computerized breath-by-breath analysis. As an index of insulin resistance, the homeostasis model insulin resistance index (HOMA-R; fasting glucose x fasting insulin/405) was used. In addition, bodyweight, body mass index, subcutaneous fat thickness, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride were measured. Multivariate analysis revealed that hs-CRP was significantly correlated with HDL-cholesterol, uric acid, gamma-glutamyl transpeptidase and maximum oxygen uptake. The maximum oxygen uptake showed the smallest odds ratio was in terms of the relationship with hs-CRP. The present study suggests that the development of exercising habits increases the maximum oxygen uptake. Furthermore, an elevated maximum oxygen uptake decreases HOMA-R and reduces the inflammatory marker CRP, suggesting that exercising habit plays an important role in the primary prevention of coronary heart disease.
(Keyword)
Exercising habits / High-sensitive C-reactive protein / insulin resistance / Maximum oxygen uptake
Masaki Morishima-Yamato, Fumiko Hisaoka, Sachiko Shinomiya, Nagakatsu Harada, Akira Takahashi, Hideki Matoba and Yutaka Nakaya : Cloning and establishment of a line of rats for high levels of voluntary running, Life Sciences, Vol.77, No.5, 551-561, 2005.
(Summary)
We generated an original Wistar line of rats that displayed increased levels of wheel running, which we named SPORTS (Spontaneously-Running-Tokushima-Shikoku). Male SPORTS rats ran voluntarily in a running wheel almost six times longer than male control Wistar rats, established without selection for their running activity. The running phenotype of female SPORTS rats was the same as female control Wistar rats. However, male offspring from the cross-mating between a female SPORTS rat and a male control rat also showed a similar level of hyper-running activity as the original SPORTS line. Compared to control rats, male SPORTS rats had lower levels of mean body weight, abdominal fat and plasma insulin after 4 weeks of running. It is likely that all these beneficial changes observed in the SPORTS rats reflected the increases in glucose disposal we observed in oral glucose tolerance tests carried out on the animals. We also found hyper-running caused a significant increase in skeletal muscle oxidative capacity, measured as the ratio of malate dehydrogenase to phosphofructokinase activity, an index of aerobic metabolism. These results indicate that the SPORTS rat may be a good animal model for determining the mechanisms responsible for up-regulation of running motivation, in addition to investigating changes in nutrient metabolism induced by high intensity exercise.
Naomi Tanoue, Akira Takahashi, Keinosuke Okamoto, Yoshio Fujii, Yutaka Taketani, Nagakatsu Harada, Masayuki Nakano and Yutaka Nakaya : A pore-forming toxin produced by Aeromonas sobria activates cAMP-dependent Cl- secretory pathways to cause diarrhea, FEMS Microbiology Letters, Vol.242, No.2, 195-201, 2005.
(Summary)
Aeromonas sobria hemolysin (ASH) is one of the major virulence factors produced by A. sobria, a human pathogen that causes diarrhea. We investigated the effects of ASH on Cl(-) transport in human colonic epithelial cells. ASH increased short-circuit currents (Isc) and (125)I efflux from Caco-2 cells, indicating ASH activate Cl(-) secretion. Additions of inhibitors of cyclic AMP dependent Cl(-) channels, glybenclamide and NPPB suppressed the Isc and (125)I efflux increases induced by ASH. And ASH increased the intracellular cyclic AMP concentration. Moreover, ASH stimulated fluid accumulation in the iliac loop test, and glybenclamide and NPPB suppressed this fluid accumulation. Thus, cAMP-dependent Cl(-) secretory pathway could be related with diarrhea induced by A. sobria.
Ketamine inhibits adenosine triphosphate-sensitive potassium (KATP) channels, which results in the blocking of ischemic preconditioning in the heart and inhibition of vasorelaxation induced by KATP channel openers. In the current study, the authors investigated the molecular mechanisms of ketamine's actions on sarcolemmal KATP channels that are reassociated by expressed subunits, inwardly rectifying potassium channels (Kir6.1 or Kir6.2) and sulfonylurea receptors (SUR1, SUR2A, or SUR2B). The authors used inside-out patch clamp configurations to investigate the effects of ketamine on the activities of reassociated Kir6.0/SUR channels containing wild-type, mutant, or chimeric SURs expressed in COS-7 cells. Ketamine racemate inhibited the activities of the reassociated KATP channels in a SUR subtype-dependent manner: SUR2A/Kir6.2 (IC50 = 83 microM), SUR2B/Kir6.1 (IC50 = 77 microM), SUR2B/Kir6.2 (IC50 = 89 microM), and SUR1/Kir6.2 (IC50 = 1487 microM). S-(+)-ketamine was significantly less potent than ketamine racemate in blocking all types of reassociated KATP channels. The ketamine racemate and S-(+)-ketamine both inhibited channel currents of the truncated isoform of Kir6.2 (Kir6.2DeltaC36) with very low affinity. Application of 100 mum magnesium adenosine diphosphate significantly enhanced the inhibitory potency of ketamine racemate. The last transmembrane domain of SUR2 was essential for the full inhibitory effect of ketamine racemate. These results suggest that ketamine-induced inhibition of sarcolemmal KATP channels is mediated by the SUR subunit. These inhibitory effects of ketamine exhibit specificity for cardiovascular KATP channels, at least some degree of stereoselectivity, and interaction with intracellular magnesium adenosine diphosphate.
Eiji Takeda, Junji Terao, Yutaka Nakaya, Ken-ichi Miyamoto, Yoshinobu Baba, Hiroshi Chuman, Ryuji Kaji, Tetsuro Ohmori and Kazuhito Rokutan : Stress control and human nutrition, The Journal of Medical Investigation : JMI, Vol.51, No.3-4, 139-145, 2004.
(Summary)
Stress is a pervasive factor in everyday life that critically affects development and functioning. Severe and prolonged stress exposure impairs homeostatic mechanisms, particularly associated with the onset of depressive illness. Brain food is aimed at preventing as well as treating a growing number of stress-related mental disorders. Some topics on the association of stress and nutrition is reviewed. (1) An increased activity of serotonergic neurons in the brain is an established consequence of stress. An increase in brain tryptophan levels on the order of that produced by eating a carbohydrate-rich/protein-poor meal causes parallel increases in the amounts of serotonin released into synapses. (2) Eating is thought to be suppressed during stress, due to anorectic effects of corticotrophin releasing hormone, and increased during recovery from stress, due to appetite stimulating effects of residual cortisol. (3) A strong inverse association between coffee intake and risk of suicide. (4) Night eating syndrome has been found to occur during periods of stress and is associated with poor results at attempts to lose weight and disturbances in the hypothalamic-pituitary-adrenal axis. (5) Dietary antioxidants present in fruits and vegetables may improve cognitive function. Therefore, it is concluded that the establishment of functional foods that correctly regulate stress response must be firmly based upon scientific knowledge and legal regulation.
Kazuaki Mawatari, Kakui Sae, Nagakatsu Harada, Takamasa Ohnishi, Yasuharu Niwa, Kazuko Okada, Akira Takahashi, Keisuke Izumi and Yutaka Nakaya : Endothelin-1(1 31) levels are increased in atherosclerotic lesions of the thoracic aorta of hypercholesterolemic hamsters, Atherosclerosis, Vol.175, No.2, 203-212, 2004.
(Summary)
The novel vaso-constricting 31-amino acid-length endothelin-1 [ET-1(1-31)] is selectively produced by human mast cell chymase via its action on big ET-1. However, the pathological role of ET-1(1-31) in atherosclerosis remains unclear. The aim of this study was to clarify vasoconstrictive response and expression of ET-1(1-31) in atherosclerotic aorta. Syrian golden hamster, was used for preparing the atherosclerotic models by the administration of a high cholesterol diet (HC), treatment with the nitric oxide synthase inhibitor (Nomega-nitro-L-arginine methylester, L-NAME) alone, or both (HC and L-NAME) for 40 weeks. Early atherosclerosis was observed in the case of HC or L-NAME alone treatments respectively and severe atherosclerosis was observed in the case of combined HC and L-NAME treatment. Vasoconstriction induced by ET-1(1-31) was not altered by the atherosclerotic changes, but the expression pattern of ET-1(1-31) was different at each stage of the atherosclerotic aorta. ET-1(1-31) was observed rarely in normal aortas or in early atherosclerotic lesions, but ET-1(1-31) expression was dramatically increased in aortic neointima and adventitia in a state of atherosclerosis with severe inflammation. ET-1(1-31) might play in a role of promoting atherosclerosis, and especially be involved in inflammatory mediation during the progression of atherosclerosis.
Takashi Kawano, Shuzo Oshita, Akira Takahashi, Yasuo Tsutsumi, Yoshinobu Tomiyama, Hiroshi Kitahata, Yasuhiro Kuroda and Yutaka Nakaya : Molecular Mechanisms of the Inhibitory Effects of Bupivacaine, Levobupivacaine, and Ropivacaine on Sarcolemmal Adenosine Triphosphate-sensitive Potassium Channels in the Cardiovascular System., Anesthesiology, Vol.101, No.2, 390-398, 2004.
(Summary)
Sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channels in the cardiovascular system may be involved in bupivacaine-induced cardiovascular toxicity. The authors investigated the effects of local anesthetics on the activity of reconstituted KATP channels encoded by inwardly rectifying potassium channel (Kir6.0) and sulfonylurea receptor (SUR) subunits. The authors used an inside-out patch clamp configuration to investigate the effects of bupivacaine, levobupivacaine, and ropivacaine on the activity of reconstituted KATP channels expressed in COS-7 cells and containing wild-type, mutant, or chimeric SURs. Bupivacaine inhibited the activities of cardiac KATP channels (IC50 = 52 microm) stereoselectively (levobupivacaine, IC50 = 168 microm; ropivacaine, IC50 = 249 microm). Local anesthetics also inhibited the activities of channels formed by the truncated isoform of Kir6.2 (Kir6.2 delta C36) stereoselectively. Mutations in the cytosolic end of the second transmembrane domain of Kir6.2 markedly decreased both the local anesthetics' affinity and stereoselectivity. The local anesthetics blocked cardiac KATP channels with approximately eightfold higher potency than vascular KATP channels; the potency depended on the SUR subtype. The 42 amino acid residues at the C-terminal tail of SUR2A, but not SUR1 or SUR2B, enhanced the inhibitory effect of bupivacaine on the Kir6.0 subunit. Inhibitory effects of local anesthetics on KATP channels in the cardiovascular system are (1) stereoselective: bupivacaine was more potent than levobupivacaine and ropivacaine; and (2) tissue specific: local anesthetics blocked cardiac KATP channels more potently than vascular KATP channels, via the intracellular pore mouth of the Kir6.0 subunit and the 42 amino acids at the C-terminal tail of the SUR2A subunit, respectively.
Masahiro Nomura, Kohzou Uehara, Kenji Harada, Eiko Uemura, Akiko Iga, Tomohito Kawano, Akiyoshi Nishikado, Ken Saito, Yutaka Nakaya and Susumu Ito : Impairment of gastrointestinal motility by nitrate administration: evaluation based on electrogastrographic changes and autonomic nerve activity, Alimentary Pharmacology & Therapeutics, Vol.20, No.s1, 118-124, 2004.
(Summary)
Nitrates decrease the tone of the lower oesophageal sphincter, and may thus induce gastro-oesophageal reflux. In the present study, we evaluated electrogastrographic changes and heart-rate variability before and after the administration of nitrates. In 15 patients with chest pain treated with nitrates, electrocardiography and percutaneous electrogastrography were performed before and after administration of nitrates. Autonomic nervous system function was evaluated by spectral analysis of heart-rate variability and serial changes in low frequency and high frequency power, and the low frequency/high frequency ratio were compared. Electrogastrograms were analysed by obtaining peak power amplitudes and their dominant frequencies. After the administration of nitrates (isosorbide dinitrate), high frequency power, an index of parasympathetic nervous activity, was significantly decreased, whereas the low frequency/high frequency ratio, an index of sympathetic nervous activity, was significantly increased. The mean peak amplitude of the electrogastrogram significantly increased postprandially both before and after treatment. After isosorbide dinitrate treatment, however, mean peak amplitudes after a meal were significantly lower than those obtained before treatment. The mean dominant frequency of the electrogastrogram did not vary before and after treatment. The present study suggests that nitrates inhibit gastrointestinal motility by decreasing autonomic nervous activity.
Nagakatsu Harada, Chika Ninomiya, Yoshie Osako, Masaki Morishima, Kazuaki Mawatari, Akira Takahashi and Yutaka Nakaya : Taurine alters respiratory gas exchange and nutrient metabolism in type 2, Obesity Research, Vol.12, No.7, 1077-1084, 2004.
(Summary)
To assess the effect of taurine supplementation on respiratory gas exchange, which might reflect the improved metabolism of glucose and/or lipid in the type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Male OLETF rats (16 weeks of age) were randomly divided into two groups: unsupplemented group and taurine-supplemented (3% in drinking water) group. After 9 weeks of treatment, indirect calorimetry and insulin tolerance tests were conducted. The amounts of visceral fat pads, tissue glycogen, the blood concentrations of glucose, triacylglycerol, taurine, and electrolytes, and the level of hematocrit were compared between groups. A nondiabetic rat strain (Long-Evans Tokushima Otsuka) was used as the age-matched normal control. The indirect calorimetry showed that the treatment of OLETF rats with taurine could reduce a part of postprandial glucose oxidation possibly responsible for the increase of triacylglycerol synthesis in the body. Taurine supplementation also improved hyperglycemia and insulin resistance and increased muscle glycogen content in the OLETF rats. Supplementation with taurine increased the blood concentration of taurine and electrolyte and fluid volume, all of which were considered to be related to the improvement of metabolic disturbance in OLETF rats. Taurine supplementation may be an effective treatment for glucose intolerance and fat/lipid accumulation observed in type 2 diabetes associated with obesity. These metabolic changes might be ascribed, in part, to the alteration of circulating blood profiles, where the improved hyperglycemia and/or the blood accumulation of taurine itself would play roles.
Kimiko Nakayasu, Yutaka Nakaya, Oki Yuko, Masahiro Nomura and Susumu Ito : Long Term Follow-up in Japanese Public Office Workers of the Influence of Blood Pressure on ECG Changes, Circulation Journal, Vol.68, No.6, 563-567, 2004.
(Summary)
The relationship between annual changes in blood pressure (BP) and the electrocardiogram (ECG) was studied to clarity what factors give early detection of complications and predict the outcome of therapy. The influence of BP on the ECG was assessed in 830 Japanese office workers. Those with hypertension (HT) more frequently developed left atrial and ventricular overload compared with normotensive subjects. In addition, those with borderline HT (systolic pressure 140-160 mmHg and/or diastolic pressure 90-95 mmHg) and even those with lower blood pressure (systolic pressure 130-140 mmHg and/or diastolic pressure 85-90 mmHg) developed left atrial and ventricular overload more frequently than normotensive subjects. Based on these results, BP should be closely followed up when routine systolic and diastolic pressure levels exceed 130 mmHg and 85 mmHg, respectively, in persons in their 40 s to 50 s and the goal of antihypertensive therapy should be lower than reported previously.
(Keyword)
Adult / blood pressure / Body Weight / Electrocardiography / Follow-Up Studies / Humans / hypertension / Incidence / Japan / Middle Aged / Practice Guidelines as Topic / Retrospective Studies / Ventricular Dysfunction / Workplace
Yoshiko Kanezaki, Toshiyuki Obata, Rie Matsushima, Asako Minami, Tomoyuki Yuasa, Kazuhiro Kishi, Yoshimi Bando, Hisanori Uehara, Keisuke Izumi, Tasuku Mitani, Mitsuru Matsumoto, Yukari Takeshita, Yutaka Nakaya, Toshio Matsumoto and Yousuke Ebina : KATP Channel Knockout Mice Crossbred with Transgenic Mice Expressing a Dominant-Negative Form of Human Insulin Receptor have Glucose Intolerance but not Diabetes, Endocrine Journal, Vol.51, No.2, 133-144, 2004.
(Summary)
Impaired insulin secretion and insulin resistance are thought to be two major causes of type 2 diabetes mellitus. There are two kinds of diabetic model mice: one is a K(ATP) channel knockout (Kir6.2KO) mouse which is defective in glucose-induced insulin secretion, and the other is a transgenic mouse expressing the tyrosine kinase-deficient (dominant-negative form of) human insulin receptor (hIR(KM)TG), and which has insulin resistance in muscle and fat. However, all of these mice have no evidence of overt diabetes. To determine if the double mutant Kir6.2KO/hIR(KM)TG mice would have diabetes, we generated mutant mice by crossbreeding, which would show both impaired glucose-induced insulin secretion and insulin resistance in muscle and fat. We report here that: 1) blood glucose levels of randomly fed and 6 h fasted double mutant (Kir6.2KO/hIR(KM)TG) mice were comparable with those of wild type mice; 2) in intraperitoneal glucose tolerance test (ipGTT), Kir6.2KO/hIR(KM)TG mice had an impaired glucose tolerance; and 3) during ipGTT, insulin secretion was not induced in either Kir6.2KO/hIR(KM)TG or Kir6.2KO mice, while the hIR(KM)TG mice showed a more prolonged insulin secretion than did wild type mice; 4) hyperinsulinemic euglycemic clamp test revealed that Kir6.2KO, Kir6.2KO/hIR(KM)TG and hIR(KM)TG mice, showed decreased whole-body glucose disposal compared with wild type mice; 5) Kir6.2KO, but not Kir6.2KO/hIR(KM)TG mice had some obesity and hyperleptinemia compared with wild type mice. Thus, the defects in glucose-induced insulin secretion (Kir6.2KO) and an insulin resistance in muscle and fat (hIR(KM)TG) were not sufficient to lead to overt diabetes.
Takashi Kawano, Shuzo Oshita, Akira Takahashi, Yasuo Tsutsumi, Yoshinobu Tomiyama, Hiroshi Kitahata, Yasuhiro Kuroda and Yutaka Nakaya : Molecular mechanisms of the inhibitory effects of propofol and thiamylal on sarcolemmal adenosine triphosphate-sensitive potassium channels., Anesthesiology, Vol.100, No.2, 338-346, 2004.
(Summary)
Both propofol and thiamylal inhibit adenosine triphosphate-sensitive potassium (KATP) channels. In the current study, the authors investigated the effects of these anesthetics on the activity of recombinant sarcolemmal KATP channels encoded by inwardly rectifying potassium channel (Kir6.1 or Kir6.2) genes and sulfonylurea receptor (SUR1, SUR2A, or SUR2B) genes. The authors used inside-out patch clamp configurations to investigate the effects of propofol and thiamylal on the activity of recombinant KATP channels using COS-7 cells transfected with various types of KATP channel subunits. Propofol inhibited the activities of the SUR1/Kir6.2 (EC50 = 77 microm), SUR2A/Kir6.2 (EC50 = 72 microm), and SUR2B/Kir6.2 (EC50 = 71 microm) channels but had no significant effects on the SUR2B/Kir6.1 channels. Propofol inhibited the truncated isoform of Kir6.2 (Kir6.2DeltaC36) channels (EC50 = 78 microm) that can form functional KATP channels in the absence of SUR molecules. Furthermore, the authors identified two distinct mutations R31E (arginine residue at position 31 to glutamic acid) and K185Q (lysine residue at position 185 to glutamine) of the Kir6.2DeltaC36 channel that significantly reduce the inhibition of propofol. In contrast, thiamylal inhibited the SUR1/Kir6.2 (EC50 = 541 microm), SUR2A/Kir6.2 (EC50 = 248 microm), SUR2B/Kir6.2 (EC50 = 183 microm), SUR2B/Kir6.1 (EC50 = 170 microm), and Kir6.2DeltaC36 channels (EC50 = 719 microm). None of the mutants significantly affects the sensitivity of thiamylal. These results suggest that the major effects of both propofol and thiamylal on KATP channel activity are mediated via the Kir6.2 subunit. Site-directed mutagenesis study suggests that propofol and thiamylal may influence Kir6.2 activity by different molecular mechanisms; in thiamylal, the SUR subunit seems to modulate anesthetic sensitivity.
Masahiro Nomura, Seiji Kannuki, Kazuyuki Kuwayama, Yukio Kohyama, Yoshinori Hayashi, Erika Yamamoto, Tadayoshi Kaji, Kohzou Uehara, Akiyoshi Nishikado, Susumu Ito, Yutaka Nakaya and Sinji Nagahiro : A patient with Wallenberg's syndrome induced by severe cough, Journal of Clinical Neuroscience, Vol.11, No.2, 179-182, 2004.
(Summary)
A 45-year-old man developed severe cough with cervical pain. The patient was unable to hold an upright position. The origin of the right posterior inferior cerebellar artery was not enhanced by angiography. MRI showed a high signal intensity string-like structure of the right vertebral artery. In young patients, Wallenberg's syndrome related to mild head trauma has been reported. However, none of the previous studies related to vertebral arterial dissection was induced by severe cough. When cervical pain is present in young patients with severe cough, MRI should be performed to evaluate the possibility of vertebral arterial dissection.
(Keyword)
Cerebral Angiography / Cough / Humans / Lateral Medullary Syndrome / magnetic resonance imaging / Male / Middle Aged
Sae Kakui, Kazuaki Mawatari, Takamasa Ohnishi, Yasuharu Niwa, Naomi Tanoue, Nagakatsu Harada, Akira Takahashi, Keisuke Izumi and Yutaka Nakaya : Localization of the 31-amino-acid endothelin-1 in hamster tissue, Life Sciences, Vol.74, No.11, 1435-1443, 2004.
(Summary)
Endothelin (ET)-1(1-31) is a novel vasoconstrictor peptide produced by human mast cell chymase, which selectively cleaves big ET-1 at the Try(31)-Gly(32) bond. We investigated the localization of ET-1(1-31) in various hamster tissues by immunohistochemistry and compared it to the distribution of ET-1(1-21). We found that the localization and amount of ET-1(1-31) were different from those of ET-1(1-21) in each tissue. ET-1(1-31)-like immunoreactivities (IR) in the heart, lung, and adrenal gland were observed in the same areas as ET-1(1-21) but were significantly weaker, suggesting that ET-1(1-31) might play a role only in mast cell/chymase-related pathological conditions in these tissues. In the liver, ET-1(1-31)-like IR was strongly detected in Kupffer cells where ET-1(1-21)-like IR was seen more weakly. In the kidney, ET-1(1-31)-like IR was slightly higher than ET-1(1-21). These results suggest that ET-1(1-31) might have physiological roles distinct from those of ET-1(1-21) in some hamster tissues.
Kanji Kusunoki, Masahiro Nomura, Norihito Kageyama, Akiyoshi Nisikado, Masafumi Harada, Yutaka Nakaya and Susumu Ito : Detection of coronary arterial microvascular discorders using 99mTc-tetrofosm in uptake increase during exercise and coronary blood flow velocity patterns obtained by magnetic resonance imaging., Heart and Vessels, Vol.19, No.1, 1-7, 2004.
(Summary)
This study reports an evaluation of coronary arterial blood flow patterns in patients with diabetes mellitus and healthy subjects using magnetic resonance coronary angiography (MRCA). Twenty patients with diabetes mellitus (DM group) and 20 healthy subjects (N group) were studied using MRCA and myocardial SPECT images using (99m)Tc-tetrofosmin (TF). The rate of change in myocardial TF uptake was measured during a 1-day protocol of exercise and rest. Initial and delayed exercise single photon emission computed tomography (SPECT) images were acquired 30 min and 3 h after injection (370 MBq of TF) (TF1 and TF2, respectively). Thereafter, 740 MBq of TF was administered intravenously, again, and resting SPECT images (TF3) were acquired 30 min later. The myocardial counts of these three points of acquisition were defined, and the rate of change of myocardial TF uptake between exercise and rest was determined. The % increase in uptake was significantly lower in the DM group than in the N group in all myocardial segments. The average coronary arterial diastolic velocity determined using MRCA was slightly lower in the DM group than in the N group, and the average systolic peak velocity (ASPV) was slightly greater in the DM group than in the N group, although these values were not statistically significant. The diastolic/systolic velocity ratio (DSVR) in the DM group was significantly lower than that in the N group ( P < 0.05). There was a significant correlation between DSVR and % uptake increase ( r = 0.605, P < 0.05). These results indicate that the measurements made using MRCA and the % uptake increase measured using TF myocardial scintigraphy represent a potentially useful noninvasive method for diagnosing microvascular dysfunction in diabetic patients.
Jyunji Yamashita, Masahiro Nomura, Kohzou Uehara, Yutaka Nakaya, Eiko Uemura, Akiko Iga, Yuko Sawa, Akiyoshi Nishikado, Ken Saito and Susumu Ito : Influence of sleep apnea on autonomic nervous activity and QT dispersion in patients with essential hypertension and old myocardial infarction, Journal of Electrocardiology, Vol.37, No.1, 31-40, 2004.
(Summary)
Sleep apnea syndrome (SAS) is an important cardiovascular risk factor in patients with hypertension or myocardial infarction (MI). We evaluated the influence of SAS on autonomic nervous activity and QT dispersion in patients with hypertension or coronary artery disease with old MI. A portable sleep polygraph was attached to 30 healthy volunteers (N group), 30 patients with essential hypertension (HT group), and 30 patients with old myocardial infarction (MI group) to serially record oronasal respiration, tracheal sound, thoracic respiratory movement, and percutaneous arterial oxygen saturation. In addition, a digital Holter ECG was used to examine heart rate variability during nighttime sleep. Heart rate variability was analyzed by obtaining low-frequency (LF) power, high-frequency (HF) power, the LF/HF ratio, and very low-frequency (VLF) power. Dispersion of QT intervals was obtained by CM5 and CM1 leads. VLF and LF powers were significantly higher in the HT-SAS group (hypertensive patients with SAS) than the N and HT-NSAS groups (hypertensive patients without SAS). The HF power was significantly lower in the HT-NSAS group than the N group, but the decrease in HF power in hypertension was not observed in the HT-SAS group. The LF/HF ratio was significantly higher in the HT-NSAS group than the N group, and this value was further increased in the HT-NSAS group. Percutaneous arterial oxygen saturation was decreased, and QT dispersion was significantly increased in the MI group during sleep apnea episodes. More severe autonomic nervous dysfunction and increased QTc dispersion were observed in hypertensive patients with SAS during episodes of apneas and hypopneas compared to those without SAS. These findings suggest that SAS may be associated with the future development of cardiac events.
F Kishi, Masahiro Nomura, E Uemura, N Kageyama, S Kujime, M Kaji, Y Noda, N Kondo, T Kawaguchi, Y Ozaki, K Koshiba, K Yamaguchi, Yutaka Nakaya and Susumu Ito : Evaluation of myocardial sympathetic nerve function in patients with mitral valve prolapse using iodine-123-metaiodobenzylguanidine myocardial scintigraphy., Journal of Medicine, Vol.35, No.1-6, 187-199, 2004.
(Summary)
Mitral valve prolapse (MVP) is closely related to myocardial sympathetic nerve function. This study evaluated the presence of impaired myocardial sympathetic nerve function by Iodine-123-metaiodobenzylguanidine (MIBG) scintigraphy in ten patients with MVP. For comparison, 15 healthy subjects without heart disease were investigated (control group). Single photon emission computed tomography (SPECT) and anterior planar myocardial scintigraphy were performed 15 min (initial images) and 3 hours (delayed images) after injection of MIBG (111 MBq). The location and degrees of reduced tracer uptake were evaluated. Myocardial MIBG uptake was quantified by uptake ratio of the heart (H) to upper mediastinum (M) on the anterior planar images (H/M). Percentage washout of MIBG in nine sectors of all oblique slices along the short-axis was calculated. The washout rates were higher at the inferoposterior and septal segments in patients with anterior leaflet prolapse, and at inferoposterior and lateral segments in patients with posterior leaflet prolapse. The bull's eye map showed increased washout rate in the apical and posteroseptal basal segments. There was no significant difference in the H/M ratio between MVP patients and the control group. These results indicate that MIBG can be used to evaluate localized myocardial sympathetic nerve function in MVP.
Masahiro Nomura, Yutaka Nakaya and Susumu Ito : 心磁図法は循環器病診療に貢献できるのか?, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.17, No.1, 16-17, 2004.
140.
Toru Nakayama, Masahiro Nomura, Hiroyuki Fujinaga, Hiroyuki Ikefuji, Masaru Kimura, Kazumasa Chikamori, Yutaka Nakaya and Susumu Ito : Does Coronary Artery Stenting for Acute Myocardial Infarction Improve Left Ventricular Overloading at the Chronic Stage?, Japanese Heart Journal, Vol.45, No.2, 217-229, 2004.
(Summary)
In the present study, we evaluated whether stenting is useful for cardiac overloading, using ANP, BNP, and sup99m/supTc-tetrofosmin myocardial scintigraphy. It has been reported that coronary artery stenting is useful for cardiac functions for acute myocardial infarction (AMI). The subjects were 110 patients with AMI successfully treated by direct angioplasty. These patients were subgrouped into two groups: the S group (underwent stenting; 54 patients) and the P group (underwent POBA alone; 56 patients). Extent scores reflecting decreased myocardial blood flow were calculated at myocardial areas showing a radioactivity count of less than -2 × standard deviations compared to the database of normal subjects.The ratio of extent scores to defect scores (extent/defect ratio) was compared between the P and S groups. Both ANP and BNP levels in the S group were lower than in the P group at the chronic stage (1 and 3 months after reperfusion therapy). Moreover, the end-diastolic volume index from the left ventriculography 3 months after reperfusion therapy was significantly larger in the P than the S group. The extent/defect ratio was significantly lower in the P group (2.8 ± 0.2) than the S group (3.5 ± 0.3), suggestive of a microcirculation disorder. These results suggest that cardiac overloading and left ventricular remodeling are decreased more by stenting than by POBA alone, probably because stenting prevents decreased myocardial blood flow around the infarct myocardium.br
Y Tomokane, Masahiro Nomura, S Kujime, Y Noda, Naoki Kondo, Yutaka Nakaya and Susumu Ito : Clinical Study on the Effects of Nizatidine on Gastric Motillity and Cardiac Autonomic Function, Arzneimittel-Forschung, Vol.54, No.8, 427-435, 2004.
(Summary)
Nizatidine (CAS 76963-41-2, Acinon), an H2 receptor antagonist, not only inhibits acid secretion but also improves gastrointestinal motility. However, autonomic nervous function has not been studied in detail using electrogastrography (EGG). In the present study, two protocols were adopted to study nizatidine's effects on cardiac autonomic function and gastric motility. Protocol I--Acute: "Group C-I": 10 healthy volunteers received a single oral dose of nizatidine 150 mg. Protocol II--Chronic: "Group DM without N": 15 patients with diabetes mellitus (DM) were observed prior to administration of nizatidine. "Group DM with N": The same 15 patients with DM received nizatidine 300 mg/day for more than 30 days. "Group C-II": This control group was composed of 15 healthy volunteers not receiving nizatidine. In all groups, EGGs were recorded before and after a meal, and autonomic nervous function and QT interval of ECG dispersions were simultaneously evaluated. In Group C-I, nizatidine significantly increased the peak power amplitude of 3 cycles/min (cpm) frequency, but did not significantly change the dominant frequency of the 3-cpm waves. In Group DM with N, nizatidine administration significantly increased the peak power amplitude from 2.4 cpm or a lower frequency (bradygastria) to 3 cpm. Prior to nizatidine administration but after eating a meal, the peak power amplitude on EGG was not increased in Group DM without N. In Group DM with N, however, the EGG peak power amplitude increased to levels similar to those of the healthy subjects (Group C-II). Neither the single nor the chronic administration of nizatidine significantly prolonged the QT interval or increased the QT dispersion. A spectral analysis of heart rate variability showed that nizatidine administration, whether acute or chronic, did not significantly change the indices of autonomic nervous activity. Nizatidine may promote gastric emptying by inhibiting acetylcholine esterase, thus increasing cholinergic activity, and by acting directly on gastric smooth muscle. The results indicate that because nizatidine increases gastric motility without exerting a negative influence on the autonomic nerves, it may be a useful drug in patients with diabetic neuropathy.
S Manabe, I Kuroda, Kazuko Okada, Masaki Morishima, Nagakatsu Harada, Akira Takahashi, K Sasaki and Yutaka Nakaya : Decreased blood levels of lactic acid and urinary excretion of 3-methylhistidine after exercise by chronic taurine treatment in rats, Journal of Nutritional Science and Vitaminology, Vol.49, No.6, 375-380, 2003.
(Summary)
Taurine is reported to increase contractility of skeletal muscle and cardiac myocyte, which can increase exercise performance. The present study aimed to clarify taurine's effect on chronic endurance exercise, especially accumulation of lactic acid (LA), a marker of fatigue and ability of aerobic exercise, and urinary secretion of 3-methylhistidine (3-MH), a marker of muscle breakdown in rats. After exercise blood levels of LA and urinary excretion of 3-MH were significantly increased and this increase was significantly less in those with chronic treatment of taurine. Taurine treatment also significantly decreased fat accumulation and blood levels of cholesterol and triglyceride, which might improve insulin resistance and utilization of fat and glucose. These results indicate taurine treatment is useful for reducing physical fatigue and muscle damage during exercise training in rats, presumably due to antioxidant property and improvement of muscle and cardiac functions by taurine.
A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS(-/-)) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. APS(-/-) mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS(-/-) mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes.
Tomohito Kawano, Masahiro Nomura, Akiyoshi Nisikado, Yutaka Nakaya and Susumu Ito : Supplementation of L-arginine improves hypertension and lipid metabolism but not insulin resistance in diabetic rats, Life Sciences, Vol.73, No.23, 3017-3026, 2003.
(Summary)
Nitric oxide (NO) plays an important role in glucose and lipid metabolism. We previously reported that NO synthesis inhibitors, such as NG-nitro-L-arginine methyl ester (L-NAME), deteriorate insulin sensitivity and lipid metabolism, while the addition of L-arginine reverses this deterioration. L-arginine is a precursor of NO, and is used as a supplement in the US. In the present study, we evaluated whether the administration of L-arginine alone improves insulin resistance and serum lipid levels in insulin-resistant and hypertriglycemic rat models. Diabetic rats were divided into 3 groups: the control (Cont) group (standard diet), the L-NAME group (diet containing L-NAME), and the Arg group (diet containing L-arginine). After 4 weeks of breeding, urinary NOx, glucose infusion rate (GIR), glucose and lipid tolerance tests were performed. Urinary NOx levels were significantly lower in the L-NAME group than in the Cont group. The GIR in the L-NAME group was significantly lower than that in the Cont group, suggesting increased insulin resistance. However, the administration of L-arginine did not influence insulin resistance in the Arg group. Oral lipid administration significantly increased plasma triglyceride levels in the L-NAME group and plasma triglyceride levels were significantly lower in the Arg group than in the Cont group. The area under the curve of plasma triglyceride levels after oral lipid administration was larger in the L-NAME group than in the Cont group. The administration of L-NAME increased insulin resistance and decreased lipid metabolism. L-arginine significantly increased urinary NO secretion but did not improve insulin resistance, although it did improve lipid metabolism. These findings suggest that supplementation of L-arginine cannot improve insulin resistance in diabetic rats probably due to increased insulin secretion by L-arginine.
Yoshiko Kanezaki, Rie Matsushima, Toshiyuki Obata, Yutaka Nakaya, Toshio Matsumoto and Yousuke Ebina : Injection of the Insulin receptor alpha subunit increases blood glucose levels in mice, Biochemical and Biophysical Research Communications, Vol.309, No.3, 572-577, 2003.
(Summary)
Using the expression vector of the truncated human insulin receptor (hIR), we have constructed a stable Chinese hamster ovary (CHO) cell line which secretes the His-tagged alpha subunit (insulin-binding domain) of hIR into medium. To examine characteristics of the His-tagged hIRalpha, we purified the protein secreted from the CHO cells. The His-tagged hIRalpha was glycosylated and processed a dimer. The molecule bound insulin with an affinity similar to that of the intact hIR. The His-tagged full length of hIR was autophosphorylated by insulin stimulation in CHO cells. Injection of the purified His-tagged hIRalpha into veins of mice increased in the concentration of blood glucose within 30 min. The intraperitoneal glucose tolerance test (ipGTT) done after injection of the purified His-tagged hIRalpha showed evidence of a marked hyperglycemia. These findings provide direct evidence that the presence of hIRalpha in the blood stream inhibits insulin actions by binding with plasma insulin.
Hiroshi Okamoto, Masahiro Nomura, Yutaka Nakaya, Kohzou Uehara, Ken Saito, Masaru Kimura, Kazumasa Chikamori and Susumu Ito : Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Neuropathy and Gastroparesis, Internal Medicine, Vol.42, No.8, 655-664, 2003.
(Summary)
Diabetic patients with severe autonomic nervous disorder show delayed gastric emptying accompanied by diabetic gastroparesis, which decreases the electric activity of the stomach associated with gastric motility. It is reported that epalrestat, an aldose reductase inhibitor, is useful for treating diabetic neuropathy. Therefore, we evaluated whether this drug improves the decreased gastric motility in diabetic patients. The present study evaluated the electrogastrograms (EGG) and autonomic nervous activity in 15 healthy volunteers (N group), and in 15 diabetic patients before and after the administration of epalrestat (DM group). Autonomic nervous activity was evaluated by spectral analysis of heart rate variability. The EGGs were recorded before and after oral administration of epalrestat (3 months or more) in the DM group. The dominant frequency of EGG was 3 cycles/min (cpm) in the N group. However, these 3 cpm waves disappeared with bradygastria, and postprandial increases in the peak powers of EGG were not observed in the DM group. Both the amplitude of 3 cpm waves and the postprandial peak powers were significantly increased after the administration of epalrestat. The parameters of autonomic nervous activities (LF power, HF power, and the LF/HF ratio) were significantly lower in the DM group before the administration of epalrestat than in the N group. However, these parameters were improved after the administration of epalrestat. Since gastroparesis is a form of diabetic dysautonomia, complication by gastroparesis may influence blood sugar control and the absorbance of oral antidiabetics. Epalrestat significantly increased the amplitude of 3 cpm waves on EGG and improved the spectral analytical parameters of heart rate variability. These findings suggest that epalrestat is useful for the treatment of diabetic gastroparesis.
Kansei Katoh, Masahiro Nomura, Akiko Iga, Aya Hiasa, Kohzou Uehara, Kenji Harada, Yutaka Nakaya and Susumu Ito : Comparison of gastric peristalsis inhibition by scopolamine butylbromide and glucagon:evaluation by electrogastrography and analysis of heart rate variability, Journal of Gastroenterology, Vol.38, No.7, 629-635, 2003.
(Summary)
Activation of glucagon receptors of the smooth muscle membrane suppresses gastric peristalsis. We evaluated autonomic nervous activity by two methods, electrogastrography (EGG) and analysis of heart rate variability, to compare the inhibiting effects of glucagon and scopolamine butylbromide on gastric peristalsis. Heart rate variability, EGG, and blood catecholamine levels were measured before and after administration of glucagon (G group), scopolamine butylbromide (SB group), or physiological saline (C group). Autonomic nervous function was evaluated using spectral analysis of heart rate variability, and low frequency (LF) and high frequency (HF) power; the LF/HF ratios were also determined. After administration of scopolamine butylbromide, HF power, an index of parasympathetic nervous activity, decreased; and the LF/HF ratio, an index of sympathetic nervous activity, increased. In contrast, no significant change was observed in autonomic nervous activity after administration of glucagon. The peak power amplitudes of the EGG decreased significantly in the G and SB groups after intramuscular injection, but the difference between the groups was not significant. Furthermore, the dominant frequency increased significantly in the G and SB groups after injection. Serum catecholamine levels showed no significant changes after administration of scopolamine butylbromide or glucagon. Inhibition of gastric peristalsis by glucagon via glucagon receptors on smooth muscles did not influence autonomic nervous activity, unlike the results obtained after administration of scopolamine butylbromide. Therefore, glucagon may be safe for use with elderly patients and those with cardiopulmonary complications.
Akiko Iga, Masahiro Nomura, Yuki Sawada, Susumu Ito and Yutaka Nakaya : Autonomic nervous dysfunction in patients with liver cirrhosis using 123I-metaiodobenzylguanidine myocardial scintigraphy and spectrum analysis of heart-rate variability, Journal of Gastroenterology and Hepatology, Vol.18, No.6, 611-752, 2003.
Kohzou Uehara, Masahiro Nomura, Yuji Ozaki, Hiroyuki Fujinaga, Hiroyuki Ikefuji, Masaru Kimura, Kazumasa Chikamori, Yutaka Nakaya and Susumu Ito : High-sensitivity C-reactive protein and left ventricular remodeling in patients with acute myocardial infarction, Heart and Vessels, Vol.18, No.2, 67-74, 2003.
(Summary)
Inflammatory cytokines are suspected to play an important role in the pathophysiology of left ventricular (LV) remodeling. We investigated whether high-sensitivity C-reactive protein (CRP) (hs-CRP) is a predictor for LV remodeling in patients with acute myocardial infarction (AMI) with successful reperfusion, and also whether such a situation can be avoided by the administration of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). The subjects were 139 patients with an initial attack of anterior myocardial infarction successfully treated by reperfusion therapy. They were randomly divided into the following two groups: an angiotensin (AG) group (91 patients treated with ACEI/ARB) and a NON-AG group (48 patients not treated with ACEI/ARB). Levels of hs-CRP, creatine kinase, human atrial natriuretic polypeptide, brain natriuretic peptide (BNP), fasting blood glucose, serum lipids, fibrinogen, fibrin degradation product, prothromloin time, and activated partial thromboplastin time were measured immediately after 1, 2, 3, and 7 days, and 1 months after the onset of AMI. ACEI or ARB administration lowered hs-CRP levels and prevented the development of LV remodeling. Peak CRP levels significantly correlated with BNP levels during the acute stage (r = +0.54, P < 0.0001), end-diastolic volume index (r = +0.78, P < 0.0001), end-systolic volume index (r = +0.36, P = 0.0405), ejection fraction (r = -0.45, P = 0.0052), left ventricular end-diastolic diameter (r = +0.61, P < 0.0001), cardiac output (r = -0.52, P = 0.0005), cardiac index (r = -0.41, P = 0.0099), and systolic pulmonary arterial pressure (r = +0.48, P = 0.0017) 1 month after the onset of AMI in the NON-AG group but not in the AG group. Logistic multivariate analysis revealed that peak CRP alone was an independent risk factor for the development of LV remodeling in the NON-AG group (odds ratio = 1.79, P = 0.002). These results suggest that hs-CRP is a useful factor for predicting LV remodeling. Furthermore, ACEI or ARB administration to AMI patients showing increased hs-CRP levels during the early stage of the disease could prevent LV remodeling.
(Keyword)
Aged / Angiotensin-Converting Enzyme Inhibitors / C-Reactive Protein / Echocardiography / Female / Humans / Logistic Models / Male / Middle Aged / Multivariate Analysis / Myocardial Infarction / Predictive Value of Tests / Ventricular Remodeling
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12756602
Manabu Kinoshita, Masahiro Nomura, Masafumi Harada, Shigenobu Bando, Yutaka Nakaya and Susumu Ito : Myocardial perfusion magnetic resonance imaging for diagnosing coronary arterial stenosis:evaluation by signal-intensity time curves, Japanese Heart Journal, Vol.44, No.3, 323-334, 2003.
(Summary)
It has been reported that myocardial perfusion MRI is a useful method for evaluating the severity of myocardial ischemia. We evaluated whether the severity of coronary arterial stenosis could be assessed by the signal-intensity time curve (SITC) obtained by myocardial perfusion MRI.br The subjects consisted of 10 patients who showed no abnormalities on coronary angiographies (CAG) (A group), 12 with single-vessel disease of 75-90% stenosis on CAG (B group), and 15 with single-vessel disease of 90% or more stenosis (C group). After infusion of dipyridamole for 4 minutes, gadolinium-diethylenetriamine pentaacetic acid was administered intravenously, followed by serial acquisition of T1-weighted left ventricular short-axis MR images. These images were evaluated after dividing them into the following 3 myocardial segments: anterior wall, lateral wall, and inferior wall. Mean values of the slope of SITC (1.4 ± 0.2 vs 1.1 ± 0.2, iP /i 0.01), and increases to the peak corrected SI (ΔSI) (47.5 ± 1.9 % vs 33.7 ± 2.4%, iP/i 0.01) in normal myocardial segments were significantly greater than in ischemic segments in the C group, while there was no significant distinction between normal and ischemic segments in the B group. The mean values of time to the peak SI were not significantly different between normal and ischemic regions in the B and C groups.br The results suggest that myocardial segments exhibiting 30% decreases in both the slope and ΔSI of SITC can be diagnosed as having 90% or more severe coronary stenosis. The present study shows that visual and SITC evaluations of myocardial perfusion MR images may be useful for clinically evaluating the severity of coronary stenosis.br
Mari Miki, Yoichi Nakamura, Akira Takahashi, Yutaka Nakaya, Hiroshi Eguchi, Tsukio Masegi, Kazuo Yoneda, Susumu Yasuoka and Saburo Sone : Effect of human airway trypsin-like protease on intracellular free Ca2+ concentration in human bronchial epithelial cells, The Journal of Medical Investigation : JMI, Vol.50, No.1-2, 95-107, 2003.
(Summary)
It has been shown that human airway trypsin-like protease (HAT) is localized in human bronchial epithelial cells (HBEC), and trypsin activates protease-activated receptor-2 (PAR-2). Activation of PAR-2 activates G-protein followed by an increase of intracellular free Ca2+, [Ca2+]in. This study was undertaken to clarify whether HAT can activate PAR-2 in HBEC or not. RT-PCR showed that HAT mRNA is expressed in HBEC, and PAR-2 mRNA is the most strongly expressed of the known PARs in HBEC. Both PAR-2 agonist peptide (PAR-2 AP) and HAT increased [Ca2+]in in HBEC in a biphasic fashion; a prompt, sharp increase (peak I) and a sustained low plateau (peak II). PAR-2 AP over 100-200 microM and HAT over 200-300 mU/ml (0.08-0.12 microM) induced both peak I and II, and PAR-2 AP below 100 microM and HAT below 200 mU/ml induced only peak II. Both PAR-2 AP-induced and HAT-induced peak I were induced by Ca2+ mobilization from intracellular stores, because they appeared even in Ca2+-free medium. Both PAR-2 AP-induced and HAT-induced peak II were induced by an influx of extracellular Ca2+, because they were abolished in Ca2+-free medium. The Ca2+ response to HAT was desensitized by exposure of HBEC to PAR-2 AP. These results indicate that HBEC have a functional PAR-2, and HAT regulates cellular functions of HBEC via activation of PAR-2.
(Tokushima University Institutional Repository: 110683, PubMed: 12630574)
153.
Kenji Harada, Masahiro Nomura, Akiyoshi Nishikado, Kouzoh Uehara, Yutaka Nakaya and Susumu Ito : Clinical efficacy of efonidipine hydrochloride, a T-type calcium channel inhibitor, on sympathetic activities, --- Examination using spectral analysis of heat rate/blood pressure variabilities and 123I-metaiodobenzylguanidine myocardial scintigraphy ---, Circulation Journal, Vol.67, No.2, 139-145, 2003.
(Summary)
Dihydropyridine Ca antagonists cause reflex tachycardia related to their hypotensive effects. Efonidipine hydrochloride has inhibitory effects on T-type Ca channels, even as it inhibits reflex tachycardia. In the present study, the influence of efonidipine hydrochloride on heart rate and autonomic nervous function was investigated. Using an electrocardiogram and a tonometric blood pressure measurement, autonomic nervous activity was evaluated using spectral analysis of heart rate/systolic blood pressure variability. Three protocols were used: (1) a single dose of efonidipine hydrochloride was administered orally to healthy subjects with resting heart rate values of 75 beats/min or more (high-HR group) and to healthy subjects with resting heart rate values less than 75 beats/min (low-HR group); (2) efonidipine hydrochloride was newly administered to untreated patients with essential hypertension, and autonomic nervous activity was investigated after a 4-week treatment period; and (3) patients with high heart rate values (>/=75 beats/min) who had been treated with a dihydropyridine L-type Ca channel inhibitor for 1 month or more were switched to efonidipine hydrochloride and any changes in autonomic nervous activity were investigated. In all protocols, administration of efonidipine hydrochloride decreased the heart rate in patients with a high heart rate, reduced sympathetic nervous activity, and enhanced parasympathetic nervous activity. In addition, myocardial scintigraphy with (123)I-metaiodobenzylguanidine showed significant improvement in the washout rate and H/M ratio of patients who were switched from other dihydropyridine Ca antagonists to efonidipine hydrochloride. Efonidipine hydrochloride inhibits increases in heart rate and has effects on the autonomic nervous system. It may be useful for treating hypertension and angina pectoris, and may also have a cardiac protective function.
Masahiro Nomura, Yutaka Nakaya, 上村 英子, 友兼 優子, 伊賀 彰子, 蔭山 徳人, 山下 潤司, Tomohito Kawano, 楠 完治, 岡本 博司, 加藤 寛正, 永石 竜起 and 糸崎 秀夫 : 糖尿病例の心室再分極相におけるcurrent density map, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.16, 66-67, 2003.
155.
Masahiro Nomura, Yutaka Nakaya, Eiko Uemura, Yuko Sawa, Akiko Iga, N Kageyama, Toru Nakayama, Kanji Kusunoki, Tomohito Kawano, K Katoh, Hiroshi Okamoto, Akiyoshi Nishikado, Ken Saito and Susumu Ito : Effects of Benidipine Hydrochloride on Autonomic Nervous Activity in Hypertensive Patients with High- and Low-salt Diets, Arzneimittel-Forschung, Vol.53, No.5, 314-320, 2003.
(Summary)
The effects of benidipine hydrochloride (CAS 91559-74-5, Coniel) on autonomic nervous activity in hypertensive patients with high- and low-salt diets were investigated. Six patients having a urinary sodium excretion of 80 mEq/day or less (low salt group) and 6 patients having a urinary sodium excretion of 200 mEq/day or more (high salt group) were orally given benidipine hydrochloride (4 mg). Before and four weeks after the treatment with benidipine, 24-h circadian variation in blood pressure and 24-h Holter electrocardiogram (ECG) were recorded. The low frequency power spectrum of heart rate (LF power; 0.04-0.15 Hz), high frequency power spectrum of heart rate (HF power; 0.15-0.40 Hz), and the ratio of LF to HF (LF/HF) were calculated, and these parameters were averaged every hour in every subject. HF power was significantly lower and LF/HF ratio was significantly higher in the high-salt group than in the low-salt group before the treatment. However, the benidipine treatment significantly increased the HF power in both groups, particularly in the high-salt group, and significantly decreased the LF/HF ratio in both groups. Moreover, there was no significant difference in the antihypertensive effect of benidipine between the high- and low-salt intake groups. These results suggest that benidipine favourably influences blood pressure and autonomic nervous activity in hypertensive patients with a high-salt intake. It is concluded that benidipine may be useful for improving the development of salt-induced hypertension and its accompanying haemodynamic responses.
Junko Endo, Masahiro Nomura, Satofumi Morishita, Nobutaka Uemura, Shuji Inoue, Seiichiro Kishi, Ritsuko Kawaguchi, Susumu Ito and Yutaka Nakaya : Influence of mosapride citrate on gastric motility and autonomic nervous function:evaluation by spectral analyses of heart rate and blood pressure variabilities,and by electrogastrography, Journal of Gastroenterology, Vol.37, No.11, 888-895, 2002.
(Summary)
Mosapride citrate selectively acts on serotonin (5-HT(4)) receptors, thus accelerating gastrointestinal motility via acetylcholine. However, few studies have evaluated the influence of mosapride citrate on autonomic nervous activity and hemodynamics. The changes in autonomic nervous activity, QT interval, and QT dispersion resulting from the administration of mosapride citrate were studied. Blood pressure, electrocardiograms (ECGs), percutaneous electrogastrograms (EGGs), and ultrasonography were recorded in 20 healthy adult volunteers before and after mosapride citrate (10 mg) was administered. Autonomic nervous activity was evaluated by spectral analyses of heart rate and blood pressure variabilities. Serial changes in low-frequency components (LF, 0.04-0.15 Hz), high-frequency components (HF, 0.15-0.40 Hz), and the LF/HF ratio were investigated. The mean peak power of EGG increased significantly, from 86 +/- 34 microV to 131 +/- 49 microV, after the administration of mosapride citrate (P < 0.05). Gastric emptying significantly increased after the administration of mosapride citrate (P < 0.05). However, neither blood pressure nor heart rate changed significantly after the drug was administrated. In addition, spectral analyses of heart rate and blood pressure variabilities showed no significant changes in autonomic nervous activity parameters, QT intervals, or QT dispersions. Mosapride citrate increased gastric motility and emptying without influencing autonomic nervous activity, suggesting that it may be very useful for elderly patients or patients with autonomic imbalance.
Yoshie Ochi, Masahiro Nomura, Seisuke Okamura, Mitsuyasu Yano, Ken Saito, Yutaka Nakaya and Susumu Ito : Changes in autonomic nervous activity during endoscopic retrograde cholangiopancreatography:a possible factor in cardiac complications., Journal of Gastroenterology and Hepatology, Vol.17, No.9, 1021-1029, 2002.
(Summary)
The changes of autonomic nervous activity during endoscopic retrograde cholangiopancreatography (ERCP) are closely related to the development of cardiovascular complications, such as arrhythmias and acute coronary syndrome. In the present study, the correlation between changes in hemodynamics and autonomic nervous activity during ERCP procedures was evaluated by analyzing heart rate variability and blood catecholamine levels. Twenty-three patients who underwent ERCP (ERCP group) and 15 control subjects who were only premedicated (C group) were studied. Ambulant ECG, blood pressure, arterial oxygen saturation, and blood level of catecholamine were measured. Autonomic nervous function was assessed by analyzing the spectral analysis and 1/f fluctuation. The low frequency power (LF power; 0.04-0.15 Hz), high frequency power (HF power; 0.15-0.40 Hz, indicator of parasymapathetic tone), the ratio of LF power to HF power (LF/HF ratio, indicator of sympathetic tone), and 1/f fluctuation (indicator of pleasant mood) were calculated. Blood pressure and heart rate were increased and arterial oxygen saturation was decreased in the ERCP group during the endoscopic procedure. Changes in the parameters of autonomic nervous function (LF power, HF power, LF/HF ratio, and 1/f fluctuation) were significantly greater in the ERCP group than in the C group, especially during cholangiography. Moreover, blood levels of catecholamines were significantly increased during the ERCP procedure. In the C group, however, blood levels of catecholamines did not significantly change except directly after premedication. Autonomic nervous activity varied greatly during cholangiography, demonstrating that ERCP has more than a little influence on the cardiovascular system. The results of the present study indicated that attention should be focused on changes in hemodynamics in patients with cardiovascular complications by monitoring the aforementioned hemodynamic parameters during ERCP.
N. Uemura, Masahiro Nomura, S. Inoue, J. Endo, S. Kishi, Ken Saito, Susumu Ito and Yutaka Nakaya : Changes in Hemodynamics and Autonomic Nervous Activity in Patients Undergoing Laparoscopic Cholecystectomy:Differences Between the Pneumo-Peritoneum and Abdominal Wall-Lifting Method, Endoscopy, Vol.34, No.8, 643-650, 2002.
(Summary)
Intraoperative changes in circulatory hemodynamics and autonomic nervous activity were evaluated in 33 patients with cholelithiasis who underwent laparoscopic cholecystectomy. Of these patients, 18 were treated using a pneumoperitoneum (group G) and 15 using the abdominal wall-lifting method (group WL). Their ECG, blood pressure, arterial oxygen saturation, and expiratory carbon dioxide partial pressure were monitored. Autonomic nervous function was evaluated by spectral analysis of the heart rate. Mean blood pressure increased significantly in group G during surgery, but did not vary in group WL during any stage of surgery. The high-frequency (HF) power, an index of parasympathetic activity, decreased significantly in group G after pneumoperitoneum. However, the HF power did not decrease significantly in group WL. The LF/HF ratio, an index of sympathetic activity, increased significantly in group G after pneumoperitoneum, but did not vary in group WL. In addition, the incidence of ventricular or supraventricular arrhythmias and the severity of the arrhythmias as determined by Lown's classification were higher in group G than in group WL. These findings suggest that intraoperative changes in autonomic nervous activity, due to increased intra-abdominal pressure, were smaller in patients undergoing laparoscopic cholecystectomy using the abdominal wall-lifting method than in those undergoing laparoscopic cholecystectomy using pneumoperitoneum. The results also demonstrated that hemodynamic changes were smaller in patients undergoing the abdominal wall-lifting method than in those undergoing pneumoperitoneum. It was concluded that hemodynamics should be carefully monitored during pneumoperitoneum, and that the abdominal wall-lifting approach in laparoscopic cholecystectomy is a method worthy of consideration for elderly patients or those with cardiopulmonary complications.
(Keyword)
Abdominal Muscles / Aged / Aged, 80 and over / Autonomic Nervous System / blood pressure / Cholecystectomy, Laparoscopic / Cholelithiasis / female / Humans / Intraoperative Period / male / Middle Aged / Pneumoperitoneum, Artificial
Yutaka Nakaya, Nagakatsu Harada, Sae Kakui, Kazuko Okada, Akira Takahashi, Junnya Inoi and Susumu Ito : Severe catabolic state after prolonged fasting in cirrhotic patients: effect of oral branched-chain amino-acid-enriched nutrient mixture, Journal of Gastroenterology, Vol.37, No.7, 531-536, 2002.
(Summary)
Cirrhotic patients frequently undergo various medical procedures, such as diagnostic gastrointestinal endoscopy, without taking breakfast. The aim of the present study was to clarify the effect of longer fasting (> 12 h) on energy metabolism, and to test whether supplementation of an oral branched-chain amino-acid-enriched nutrient mixture (BCAA mixture), which contains various nutrients in addition to BCAA, could improve the catabolic state. Metabolic measurement was performed in 30 cirrhotic patients and 13 normal subjects, using indirect calorimetry. Compared with that in the normal subjects, the respiratory quotient (RQ) was significantly lower after an overnight fast in the cirrhotic patients, indicating accelerated fat oxidation and a catabolic state. In addition, RQ in cirrhotic patients (n = 7) decreased rapidly with longer fasting, whereas that in the normal subjects (n = 5) showed relatively stable values. These results indicate that special care should be taken with medical procedures that are carried out in patients who have fasted. The effect of oral glucose, a carbohydrate-rich snack (rice ball), and the BCAA mixture (each, 210 kcal) on RQ was studied in 6 normal subjects and 6 patients with liver cirrhosis after an overnight fast. Supplementation of the carbohydrate-rich snack and the BCAA mixture (210 kcal each) elevated RQ and blood glucose levels to a similar degree in the cirrhotic patients. Oral administration of glucose (210 kcal) led to significantly greater elevation of blood glucose levels than the other snacks, which may be unfavorable for cirrhotic patients, who frequently have glucose intolerance. In the 30 cirrhotic patients, supplementation with the BCAA mixture in the late evening significantly improved RQ in the early morning. Carbohydrate-rich meals are used as a late evening snack in cirrhotic patients, but our study indicates that supplementation with a BCAA mixture can also be used to reduce fat oxidation in the early morning, with results similar to those with carbohydrate-rich snacks.
Manabu Kinoshita, Yutaka Nakaya, Nagakatsu Harada, Akira Takahashi, Masahiro Nomura and Shigenobu Bando : Combination Therapy of Exercise and Angiotensin-Converting Enzyme Inhibitor Markedly Improves Insulin Sensitivities in Hypertensive Patients With Insulin Resistance, Circulation Journal, Vol.66, No.7, 655-658, 2002.
(Summary)
The contraction of muscle enhances the release of bradykinin (BK) and improves glucose uptake by the muscle. Angiotensin-converting enzyme inhibitor (ACEI) slows the breakdown of BK, thus the effect of BK is augmented in the presence of ACEI. The present study investigated whether the combination of exercise (increased production of BK) and ACEI (delay in breakdown of BK) might further improve insulin sensitivity in hypertensive patients with insulin resistance (HOMA-R>1.8). Patients were assigned either to increased walking distance (Walking group) or taking 2mg remocapril, an ACEI, daily (ACEI group) for 8 weeks. Then both interventions were given to all patients for 8 weeks (ACEI+Walking group). Blood concentrations of triglycerides were slightly lower in the ACEI+Walking group than at baseline, although there were no significant differences in total cholesterol or high density lipoprotein-cholesterol among the 2 groups. Blood glucose was not significantly different with each treatment, but blood concentrations of insulin and HOMA-R were significantly lower in the Walking and ACEI groups compared with the Control group. The combination of walking and ACEI further lowered blood concentrations of insulin and HOMA-R, which suggests that this treatment is beneficial for hypertensive patients with insulin resistance.
Takashi Kawano, Shuzo Oshita, Yasuo Tsutsumi, Yoshinobu Tomiyama, Hiroshi Kitahata, Yasuhiro Kuroda, Akira Takahashi and Yutaka Nakaya : Clinically relevant concentrations of propofol have no effect on adenosine triphosphate-sensitive potassium channels in rat ventricular myocytes., Anesthesiology, Vol.96, No.6, 1472-1477, 2002.
(Summary)
Activation of adenosine triphosphate-sensitive potassium (K(ATP)) channels produces cardioprotective effects during ischemia. Because propofol is often used in patients who have coronary artery disease undergoing a wide variety of surgical procedures, it is important to evaluate the direct effects of propofol on K(ATP) channel activities in ventricular myocardium during ischemia. The effects of propofol (0.4-60.1 microg/ml) on both sarcolemmal and mitochondrial K(ATP) channel activities were investigated in single, quiescent rat ventricular myocytes. Membrane currents were recorded using cell-attached and inside-out patch clamp configurations. Flavoprotein fluorescence was measured to evaluate mitochondrial oxidation mediated by mitochondrial K(ATP) channels. In the cell-attached configuration, open probability of K(ATP) channels was reduced by propofol in a concentration-dependent manner (EC(50) = 14.2 microg/ml). In the inside-out configurations, propofol inhibited K(ATP) channel activities without changing the single-channel conductance (EC(50) = 11.4 microg/ml). Propofol reduced mitochondrial oxidation in a concentration-dependent manner with an EC(50) of 14.6 microg/ml. Propofol had no effect on the sarcolemmal K(ATP) channel activities in patch clamp configurations and the mitochondrial flavoprotein fluorescence induced by diazoxide at clinically relevant concentrations (< 2 microm), whereas it significantly inhibited both K(ATP) channel activities at very high, nonclinical concentrations (> 5.6 microg/ml; 31 microm).
K Katoh, Masahiro Nomura, Yutaka Nakaya, Akiko Iga, Tomomi Nada, Aya Hiasa, Y Ochi, R Kawaguchi, N Uemura, Hirohito Honda, Ichiro Shimizu and Susumu Ito : Autonomic nervous activity before and after eradication of Helicobacter pylori in patients with chronic duodenal ulcer, Alimentary Pharmacology & Therapeutics, Vol.16, No.Suppl.2, 180-186, 2002.
(Summary)
Helicobacter pylori infection is involved in the formation of chronic peptic ulcer. However, a previously reported hypothesis concerning the involvement of central autonomic nervous disorder in this condition cannot be ruled out. To use spectrum analysis of heart rate viability to examine autonomic nervous activity before and after H. pylori eradication. Twenty patients with chronic duodenal ulcer (duodenal ulcer group) and 20 age-matched normal adults (N group). In both groups, 24-h Holter electrocardiograms (ECGs) were recorded and spectrum analysis of heartrate variability was performed. In the duodenal ulcer group, Holter ECG was recorded before and after H. pylori eradication. In the N group, analysis of heart rate variability showed that high frequency (HF) power, an index of parasympathetic activity, was high at night, while the low frequency (LF)/HF ratio, an index of sympathetic function, was high during the daytime. In the duodenal ulcer group, HF power was higher at night than during the daytime, showing a similar pattern to the N group, but the power value was higher than in the N group (P < 0.05). In the duodenal ulcer group, LF/HF at night was significantly higher than that of the N group. In addition, in the duodenal ulcer group, autonomic activity after H. pylori eradication did not differ significantly from that before H. pylori eradication. In patients with chronic peptic ulcer, both sympatheticotonia and parasympatheticotonia may occur at night, and this abnormality in autonomic nervous activity may cause increased gastric acid secretion and gastric mucosal vasoconstriction. Abnormalities in autonomic activity persist even after H. pylori eradication, suggesting that they may be an independent risk factor in the formation of chronic peptic ulcer in addition to H. pylori infection.
Asako Minami, Noriko Ishimura, Sadaichi Sakamoto, Eiko Takishita, Kazuaki Mawatari, Kazuko Okada and Yutaka Nakaya : Effect of eicosapentaenoic acid ethyl ester v. oleic acid-rich safflower oil on insulin resistance in type 2 diabetic model rats with hypertriacylglycerolaemia, British Journal of Nutrition, Vol.87, No.2, 157-162, 2002.
(Summary)
The purpose of the present study was to test whether hyperlipidaemia and insulin resistance in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats can be improved by dietary supplementation with purified eicosapentaenoic acid (EPA) or oleic acid (OA). Male OLETF rats were fed powdered chow (510 g fat/kg) alone (n 8) or chow supplemented with 10 g EPA- (n 8) or OA- (n 8) rich oil/kg per d from 5 weeks until 30 weeks of age. An oral glucose tolerance test and hyperinsulinaemic euglycaemic clamp was performed at 25 and 30 weeks of age. EPA supplementation resulted in significantly (P<0.05) reduced plasma lipids, hepatic triacylglycerols, and abdominal fat deposits, and more efficient in vivo glucose disposal compared with OA supplementation and no supplementation. OA supplementation was associated with significantly increased insulin response to oral glucose compared with EPA supplementation and no supplementation. Inverse correlation was noted between glucose uptake and plasma triacylglycerol levels (r -086, P<0.001) and abdominal fat volume (r -0.80, P<0.001). The result of oral glucose tolerance test study showed that the rats fed EPA tended to improve glucose intolerance, although this was not statistically significant. Levels of plasma insulin at 60 min after glucose was significantly increased in rats fed OA compared with the other two groups. The results indicate that long-term feeding of EPA might be effective in preventing insulin resistance in diabetes-prone rats, at least in part, due to improving hypertriacylglycerolaemia.
Masahiro Nomura, Yutaka Nakaya, Hitoshi Miyajima, H Nada, Yoshie Ochi, Ritsuko Kawaguchi, S Morishita, Akiyoshi Nishikado, Hiroshi Shibata, Hirohito Honda, Ken Saito and Susumu Ito : Detection of myocardial damage caused by hepatitis C virus using signal averaged electrocardiogram and I-BMIPP myocardial scintigraphy, Journal of Electrocardiology, Vol.30, 379-383, 2002.
167.
Ming Li, Azusa Marubayashi, Yutaka Nakaya, Kiyoshi Fukui and Seiji Arase : Minoxidil-Induced hair growth is mediated by adenosine in cultured dermal papilla cells: possible involvement of sulfonylurea receptor 2B as a target of minoxidil, The Journal of Investigative Dermatology, Vol.117, No.6, 1594-1600, 2001.
(Summary)
The mechanism by which minoxidil, an adenosine-triphosphate-sensitive potassium channel opener, induces hypertrichosis remains to be elucidated. Minoxidil has been reported to stimulate the production of vascular endothelial growth factor, a possible promoter of hair growth, in cultured dermal papilla cells. The mechanism of production of vascular endothelial growth factor remains unclear, however. We hypothesize that adenosine serves as a mediator of vascular endothelial growth factor production. Minoxidil-induced increases in levels of intracellular Ca(2+) and vascular endothelial growth factor production in cultured dermal papilla cells were found to be inhibited by 8-sulfophenyl theophylline, a specific antagonist for adenosine receptors, suggesting that dermal papilla cells possess adenosine receptors and sulfonylurea receptors, the latter of which is a well-known target receptor for adenosine-triphosphate-sensitive potassium channel openers. The expression of sulfonylurea receptor 2B and of the adenosine A1, A2A, and A2B receptors was detected in dermal papilla cells by means of reverse transcription polymerase chain reaction analysis. In order to determine which of the adenosine receptor subtypes contribute to minoxidil-induced hair growth, the effects of subtype-specific antagonists for adenosine receptors were investigated. Significant inhibition in increase in intracellular calcium level by minoxidil or adenosine was observed as the result of pretreatment with 8-cyclopentyl-1,3-dipropylxanthine, an antagonist for adenosine A1 receptor, but not by 3,7-dimethyl-1-propargyl-xanthine, an antagonist for adenosine A2 receptor, whereas vascular endothelial growth factor production was blocked by both adenosine A1 and A2 receptor antagonists. These results indicate that the effect of minoxidil is mediated by adenosine, which triggers intracellular signal transduction via both adenosine A1 and A2 receptors, and that the expression of sulfonylurea receptor 2B in dermal papilla cells might play a role in the production of adenosine.
Akira Takahashi, Wada Akihiro, Ogushi Ken-ichi, Maeda Kyoko, Kawahara Tsukasa, Kazuaki Mawatari, Hisao Kurazono, Moss Joel, Hirayama Toshiya and Yutaka Nakaya : Production of L-defensin-2 by human colonic epithelial cells induced by Salmonella enteritidis flagella filament structural protein, FEBS Letters, Vol.508, No.3, 484-488, 2001.
(Summary)
We recently showed that FliC of Salmonella enteritidis increased human beta-defensin-2 (hBD-2) expression, and now describe the signaling responsible pathway. FliC increased the intracellular Ca(2+) concentration ([Ca(2+)](in)) in Caco-2 cells. The [Ca(2+)](in) increase induced by FliC was prevented by U73122 and heparin, but not by chelating extracellular Ca(2+) or pertussis toxin. The FliC-induced increase in hBD-2 promoter activity via nuclear factor kappaB (NF-kappaB) was also inhibited by chelation of intracellular Ca(2+) or by U73122. We conclude that FliC increased [Ca(2+)](in) via inositol 1,4,5-trisphosphate, which was followed by up-regulating hBD-2 mRNA expression via an NF-kappaB-dependent pathway.
Keisuke Ishizawa, Masanori Yoshizumi, Koichiro Tsuchiya, Eiko Takishita, Yutaka Nakaya, Kazuhiro Kishi, Yousuke Ebina, Hitoshi Houchi, Kazuo Minakuchi and Toshiaki Tamaki : Effects of losartan in combination with or without exercise on insulin resistance in Otsuka Long-Evans Tokushima Fatty rats., European Journal of Pharmacology, Vol.430, No.2-3, 359-367, 2001.
(Summary)
Hypertension often complicates type 2 diabetes mellitus, and angiotensin converting enzyme inhibitor treatment has been shown to improve insulin resistance in such cases. However, the effect of angiotensin II type-1 (AT(1)) receptor antagonists on insulin resistance is still controversial. To gain further information on this effect, we examined the effect of losartan on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. Losartan administration alone lowered systolic blood pressure, but did not improve oral glucose tolerance test or insulin resistance in OLETF rats. However, the administration of losartan with exercise significantly improved both systolic blood pressure and insulin resistance relative to control OLETF rats. On the other hand, losartan treatment, regardless of exercise, increased glucose uptake in excised soleus muscle and fat cells. To explore the beneficial effect of losartan on skeletal muscle glucose uptake, we examined intracellular signaling of soleus muscle. Although Akt activity and glucose transporter type 4 (GLUT4) expressions were not affected by losartan with or without exercise, extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein (MAP) kinase activities were increased by both interventions. These results indicate that angiotensin AT(1) receptor antagonist improved local insulin resistance, but not systemic insulin resistance. These findings may explain the controversy over the effect of angiotensin AT(1) receptor antagonists on insulin resistance in clinical use. The enhancing effect of angiotensin AT(1) receptor antagonist on skeletal muscle glucose uptake may be attributable to MAP kinase activation or other mechanisms rather than phosphatidylinositol 3-kinase activation.
(Keyword)
Adipocytes / Animals / Antihypertensive Agents / Blood Glucose / Blood Pressure / Blotting, Western / Body Weight / Deoxyglucose / Diabetes Mellitus, Type 2 / Enzyme Activation / Glucose / Glucose Tolerance Test / Glucose Transporter Type 4 / Heart Rate / Insulin / Insulin Resistance / JNK Mitogen-Activated Protein Kinases / Losartan / Male / Mitogen-Activated Protein Kinase 1 / Mitogen-Activated Protein Kinase 3 / Mitogen-Activated Protein Kinases / Monosaccharide Transport Proteins / Muscle Proteins / Muscle, Skeletal / Phosphorylation / Physical Conditioning, Animal / Protein-Serine-Threonine Kinases / Proto-Oncogene Proteins / Proto-Oncogene Proteins c-akt / Rats / Rats, Inbred OLETF / p38 Mitogen-Activated Protein Kinases
Yasuo Tsutsumi, Shuzo Oshita, Takashi Kawano, Hiroshi Kitahata, Yoshinobu Tomiyama, Yasuhiro Kuroda and Yutaka Nakaya : Lidocaine and mexiletine inhibit mitochondrial oxidation in rat ventricular myocytes., Anesthesiology, Vol.95, No.3, 766-770, 2001.
(Summary)
Accumulating evidence suggests that mitochondrial rather than sarcolemmal adenosine triphosphate-sensitive K+ (K(ATP)) channels may have an important role in the protection of myocardium during ischemia. Because both lidocaine and mexiletine are frequently used antiarrhythmic drugs during myocardial ischemia, it is important to investigate whether they affect mitochondrial K(ATP) channel activities. Male Wistar rats were anesthetized with ether. Single, quiescent ventricular myocytes were dispersed enzymatically. The authors measured flavoprotein fluorescence to evaluate mitochondrial redox state. Lidocaine or mexiletine was applied after administration of diazoxide (25 microM), a selective mitochondrial K(ATP) channel opener. The redox signal was normalized to the baseline flavoprotein fluorescence obtained during exposure to 2,4-dinitrophenol, a protonophore that uncouples respiration from ATP synthesis and collapses the mitochondrial potential. Diazoxide-induced oxidation of flavoproteins and the redox changes were inhibited by 5-hydroxydecanoic acid, a selective mitochondrial K(ATP) channel blocker, suggesting that flavoprotein fluorescence can be used as an index of mitochondrial oxidation mediated by mitochondrial K(ATP) channels. Lidocaine (10(-3) to 10 mM) and mexiletine (10(-3) to 10 mM) reduced oxidation of the mitochondrial matrix in a dose-dependent manner with an EC50 of 98+/-63 microM for lidocaine and 107+/-89 microM for mexiletine. Both lidocaine and mexiletine reduced flavoprotein fluorescence induced by diazoxide in rat ventricular myocytes, indicating that these antiarrhythmic drugs may produce impairment of mitochondrial oxidation mediated by mitochondrial K(ATP) channels.
Hitoshi Miyajima, Masahiro Nomura, Naoki Muguruma, Toshiya Okahisa, Seisuke Okamura, Hirohito Honda, Ichiro Shimizu, Masafumi Harada, Ken Saito, Yutaka Nakaya and Susumu Ito : Relationship among gastric motility,autonomic activity,and portal hemodynamics in patients with liver cirrhosis, Journal of Gastroenterology and Hepatology, Vol.16, No.6, 647-659, 2001.
(Summary)
We examined the effects of the autonomic nervous function and the volume of portal blood flow to clarify the mechanism of the abnormal gastric motility in patients with liver cirrhosis. Heart rate variability, electrogastrogram (EGG), and volume of portal blood flow were measured before and after a meal in 27 patients with liver cirrhosis (LC group) and in 20 normal subjects (N group). Autonomic nervous function was evaluated by using spectral analysis of heart rate variability. We used the cine phase-contrast (PC) method, using magnetic resonance imaging (MRI) to measure the portal flow, while the peak frequency and spectral power of the EGG were measured at pre- and postprandial change. The ratio of low frequency power to high frequency power (LF/HF) was significantly higher, and the HF power was significantly lower in the LC group than in the N group both before and after a meal. In both groups, the electrogastrographic peak power ratio before and after a meal showed a positive correlation with the HF ratio, and an inverse correlation with the LF/HF ratio. In addition, portal blood flow volume was significantly decreased in the LC group than in the N group. However, the increased rate of portal blood flow after a meal correlated positively with the increased rate of electrogastrographic peak power. Moreover, gastric motility was positively correlated with esophageal varices and coma scale with the use of multivariate analysis. Parasympathetic hypofunction, sympathetic hyperfunction and portal hemodynamics were closely related with gastric motility in cirrhotic patients. In addition, gastric motility was decreased, at least in part, by the ingestion of food in cirrhotic patients because of abnormalities in autonomic functions and portal blood flow following a meal.
(Keyword)
Aged / Autonomic Nervous System / Electrophysiology / Female / Gastrointestinal Motility / Heart Rate / Hemodynamics / Humans / Liver Cirrhosis / Magnetic Resonance Imaging / Male / Middle Aged / Portal System
Satofumi Morishita, Yuki Kondo, Masahiro Nomura, Hitoshi Miyajima, Tomomi Nada, Susumu Ito and Yutaka Nakaya : Imparied retension of technetium-99m tetrofosmin in hypertrophic cardiomyopathy., The American Journal of Cardiology, Vol.87, No.6, 743-747, 2001.
Masahiro Nomura, Yutaka Nakaya, 永石 竜起 and 糸崎 秀夫 : 32チャンネル高温超伝導量子干渉計を用いた心起電力の可視化, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.14, 110-111, 2001.
Akiyoshi Nishikado, Masahiro Nomura, Ken Saito and Yutaka Nakaya : 心房細動治療に関するアンケート調査 ‐徳島県と全国の比較‐, Cardioangiology, Vol.49, 560-561, 2001.
176.
T Nada, Masahiro Nomura, A Iga, R Kawaguchi, Y Ochi, Ken Saito, Yutaka Nakaya and Susumu Ito : Autonomic nervous function in patients with peptic ulcer studied by spectral analysis of the heart rate variability, Journal of Medicine, Vol.32, No.5-6, 333-347, 2001.
(Summary)
This study is intended to clarify the relationship between occurrence of peptic ulcer disease and dysfunction of the autonomic nervous system. We studied heart rate variability and assessed the circadian rhythm of autonomic nervous function in 20 patients with peptic ulcer (PU group) and 20 age-matched healthy controls (N group) using 24-hour Holter monitoring. Moreover, the relationship between gastric juice secretion and autonomic activity was examined under intravenous injection of insulin or butylscopolamine in adult mongrel dogs. High frequency spectral (HF) power, an indicator of parasympathetic tone, was increased markedly at night in the PU group. Low frequency spectral (LF) power, an indicator of sympathetic tone modified by vagal tone, was higher during the day than at night in the N group, whereas this normal circadian rhythm of LF power disappeared in 11 cases (55%) in the PU group. In addition, the LF power was increased significantly at night (p<0.01) in the PU group. HF power and gastric juice secretion was increased by the administration of insulin. High sympatho-vagal tone at night may result in spasm of gastric arteries and excess secretion of gastric acid in the PU group. These results suggest that the nocturnal acceleration of LF, HF, and LF/HF is related to peptic ulcer diseases.
Masahiro Nomura, Yutaka Nakaya, H Miyajima, H Nada, S Morishita, K Saito and Susumu Ito : Clinical application of QT dispersion on ventricular hypertrophy using magnetocardiogram, Biomag, 504-507, 2001.
178.
Yutaka Nakaya, Masahiro Nomura and H Miyajima : Current sources of initial QRS forces in left ventricular hypertrophy,WPW syndrome,and left bundle branch brock - origin of septal vector, Biomag, 561-564, 2001.
179.
R Oura, Masahiro Nomura, Yutaka Nakaya, S Shichijyo and Susumu Ito : Evaluation of the total health promotion plan in japan,as related to health promotion effects and the prevention of lifestyle-related diseases, Journal of Medicine, Vol.32, No.5-6, 365-379, 2001.
(Summary)
The present study was undertaken to investigate whether health-promoting activities in Japan are useful for preventing the development of lifestyle-related diseases and for promoting health. One thousand, one hundred and sixty-seven Japanese workers were given a medical health check and had their maximum oxygen uptake measured according to the total health promotion plan (THP) protocol, which the Japanese Ministry of Health, Labor and Welfare is actively planning. Correlations between the maximum oxygen uptake and performance on health check items were statistically evaluated. The maximum oxygen uptake was positively correlated with the duration of a worker's ability to stand on one leg, and on the frequency with which they performed upper body weight lifting. In addition, the maximum oxygen uptake was negatively correlated with age, body weight, thickness of subcutaneous fat in the upper arms and shoulders, body fat ratios, body mass index (BMI), maximum and minimum blood pressures, resting heart rates, and total cholesterol levels. Moreover, the maximum oxygen uptake tended to be significantly higher in both male and female subjects who exercised regularly. It is suggested that maximum oxygen uptake and regular exercising play important roles in the inhibition of risk factors for ischemic heart diseases. Therefore, we believe the THP can play an important role in the primary prevention of lifestyle-related diseases. The purpose of the THP in Japan is to promote the achievement of healthy lifestyles in individual subjects, both from mental and physical perspectives. These results suggest that such efforts may help prevent the development of lifestyle-related diseases.
(Keyword)
Adult / aging / Exercise / Exercise Test / Female / Health Planning / health promotion / Humans / Japan / lifestyle / Male / Middle Aged / National Health Programs / oxygen consumption / Physical Examination / Preventive Medicine / Weight Lifting
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11958281
Masahiro Nomura, K Fujimoto, A Higashino, M Denzumi, M Miyagawa, H Miyajima, T Nada, Y Kondo, Y Tada, R Kawaguchi, T Morishita, Ken Saito, Susumu Ito and Yutaka Nakaya : Stress and coping behavior in patients with diabetes mellitus., Acta Diabetologica, Vol.37, No.2, 61-64, 2000.
(Summary)
Diabetes mellitus is a disease which must be controlled over the lifetime of a patient. We investigated the issues of stress and coping for diabetes mellitus which may influence self-management. In addition, we examined the association of these factors with blood glucose control, in order to review self-management instructions for diabetes mellitus. The study included 153 patients with diabetes mellitus. The patients were divided into two subgroups: good-control group, comprising patients with glycohemoglobin (HbA1c) values less than 7.0%; and poor-control group, comprising those with HbA1c values of 7.0% or more. All patients responded to a questionnaire regarding stress tolerance, Jalowiec and Power's coping scale and awareness of diabetes mellitus. Stress tolerance was not significantly different between the good-control and poor-control groups. No significant gender differences in coping score were evident for the good-control group. However, in the poor-control group, the coping score in men was significant higher than that in women. The problem-oriented coping score for men in the poor-control group was significantly higher than that for the good-control group (p < 0.01). In a comparison of awareness of diabetes mellitus, the proportion of patients who replied that they were rigidly following diabetes treatment was higher in the poor-control group than the good-control group. Patients with diabetes mellitus may have a knowledge of the disease and a strong will to resolve problems. This is especially true for male patients in that their will appeared to be stronger, but they may not have the resolve to establish appropriate behavior patterns. In the future, methods for evaluating self-management should be included in diabetes education.
(Keyword)
Adaptation, Psychological / Aged / Awareness / diabetes mellitus / Emotions / female / Humans / male / Middle Aged / problem solving / Stress, Psychological / Surveys and Questionnaires
Toru Hayashi, Masahiro Nomura, Hirohito Honda, Kazuhiro Tezuka, Ryusuke Torisu, Yoshikazu Takeuchi, Yutaka Nakaya and Susumu Ito : Evaluation of autonomic nervous function during upper gastrointestinal endoscopy using heart rate variability, Journal of Gastroenterology, Vol.35, No.11, 815-823, 2000.
(Summary)
To investigate autonomic nervous function during upper gastrointestinal endoscopy, we analyzed R-R interval variability from electrocardiograms obtained during endoscopy. Holter electrocardiogram recordings were made before and after premedication, and during endoscopy. Time- and frequency-domain analyses of heart rate variability were performed in 54 subjects premedicated with scopolamine butylbromide (SB group) and in 66 subjects premedicated with glucagon (G group). To determine the effect of autonomic imbalance on arrhythmia generation during endoscopy, subjects with arrhythmias (A group) were compared with subjects without arrhythmias (N group). In the SB group, high frequency spectral power (HF power; 0.15 to 0.40 Hz), which reflects parasympathetic activity, decreased significantly after premedication, and decreased further during endoscopy (P < 0.01). Moreover, HF power before premedication or during endoscopy in the A group was significantly lower than that in the N group (P < 0.01). This study suggests that the measurement of HF power prior to endoscopy can identify subjects with reduced HF power. This should allow the prevention of cardiovascular complications related to premedication and endoscope insertion.
Masahiro Nomura, Michiko Yukinaka, Hitoshi Miyajima, Tomomi Nada, Yuki Kondo, Toshiya Okahisa, Hiroshi Shibata, Seisuke Okamura, Hirohito Honda, Ichiro Shimizu, Ken Saito, T. Oki, Yutaka Nakaya and Susumu Ito : Is autonomic dysfunction a necessary condition for chronic peptic ulcer formation ?, Alimentary Pharmacology & Therapeutics, Vol.14suppl, No.1, 82-86, 2000.
(Summary)
The relationship between 1/f fluctuation of the heart rate variability and Helicobacter pylori infection was evaluated, in order to clarify whether autonomic nervous dysfunction is a necessary condition for chronic peptic ulcer formation. The subjects were 11 patients with recurrent chronic peptic ulcer and 20 age-matched normal subjects. Holter ECGs were recorded over 24 h, and the 1/f(-x) fluctuation of the heart rate was computed. The 1/f(-x) fluctuation of the heart rate is a novel index of autonomic function that has been shown to reflect a patient's pleasant mood. For 1/f(-x) fluctuation, the slope of the regression line (-x) was determined and cosine fitting of the absolute slope of the regression line over a 24-h period was performed. For the normal group, the absolute slope of the regression line during daytime and night-time were 0.53 +/- 0.16 and 1.05 +/- 0.18, respectively. For the peptic ulcer group, the corresponding values during daytime and night-time were 0.94 +/- 0.15 and 1.84 +/- 0.18, respectively. The mean value of the cosine curve was 0.76 +/- 0.23 in the normal group and 1.12 +/- 0.25 in the peptic ulcer group. Thus, these values were significantly higher for the latter group than for the former group (P<0.05). No statistically significant difference in H. pylori infection between the two groups was observed. Autonomic nervous dysfunction as well as H. pylori infection appears to be a necessary condition for chronic peptic ulcer formation.
Yasuo Tsutsumi, Shuzo Oshita, Hiroshi Kitahata, Yasuhiro Kuroda, Takashi Kawano and Yutaka Nakaya : Blockade of adenosine triphosphate-sensitive potassium channels by thiamylal in rat ventricular myocytes., Anesthesiology, Vol.92, No.4, 1154-1159, 2000.
(Summary)
The adenosine triphosphate (ATP)-sensitive potassium (KATP) channels protect myocytes during ischemia and reperfusion. This study investigated the effects of thiamylal on the activities of KATP channels in isolated rat ventricular myocytes during simulated ischemia. Male Wistar rats were anesthetized with ether. Single, quiescent ventricular myocytes were dispersed enzymatically. Membrane currents were recorded using patch-clamp techniques. In the cell-attached configuration, KATP channel currents were assessed before and during activation of these channels by 2,4-dinitrophenol and after administration of 25, 50, and 100 mg/l thiamylal. The open probability was determined from current-amplitude histograms. In the inside-out configuration, the current-voltage relation was obtained before and after the application of thiamylal (50 mg/1). In the cell-attached configuration, 2,4-dinitrophenol caused frequent channel opening. 2,4-Dinitrophenol-induced channel activities were reduced significantly by glibenclamide, suggesting that the channels studied were KATP channels. Open probability of KATP channels was reduced by thiamylal in a concentration-dependent manner. KATP channels could be activated in the inside-out configuration because of the absence of ATP. Thiamylal inhibited KATP channel activity without changing the single-channel conductance. The results obtained in this study indicate that thiamylal inhibits KATP channel activities in cell-attached and inside-out patches, suggesting a direct action of this drug on these channels.
Zhiyuan Li, Y. Niwa, S. Sakamoto, Masayuki Shono, Chen Xiu and Yutaka Nakaya : Indution of inducible nitric oxide synthanse by ginsenosides in cultured porcine endothelial cells, Life Sciences, Vol.67, 2983-2989, 2000.
(Keyword)
nitric oxide / endothelial cells
187.
Toshihiro Toyoshima, Masahiro Nomura, Akiyoshi Nishikado, Masafumi Harada, Yutaka Nakaya and Susumu Ito : Magnetic Resonance Coronary Angiography in Patients with Ischemic Heart Disease Analysis of Coronary Arterial Blood Flow Velocity Pattern, Japanese Heart Journal, Vol.41, No.2, 153-164, 2000.
(Summary)
Only a few reports evaluating coronary arterial blood flow velocity patterns using magnetic resonance (MR) coronary angiography have appeared to date. This study reports an evaluation of coronary arterial blood flow velocity patterns in patients with ischemic heart disease and in healthy subjects using MR coronary angiography. The subjects consisted of 20 patients with ischemic heart disease (IHD group) and 20 normal healthy subjects (N group). Using the fCARD PC method, ECG-gated MR coronary angiography was performed using an anteroposterior opposing phased array coil. Regions of interest were placed on bilateral coronary arteries to measure coronary arterial blood flow velocity patterns. The IHD group was divided into two subgroups, based on the presence (MI group) or absence (AP group) of infarcted myocardium using 99m Tc-methoxyisobutylisonitrile (MIBI) myocardial scintigraphy. Average diastolic peak velocity (ADPV) was lower in the IHD group than in the N group. In addition, the diastolic / systolic velocity ratio (DSVR) was significantly lower in the MI group. Moreover, in the AP group, both the ADPV and DSVR values were significantly increased in those who had undergone percutaneous transluminal coronary angioplasty postoperatively. Different from the Doppler guidewire method, MR coronary angiography facilitates noninvasive evaluation of coronary arterial blood flow velocity. Therefore, these results indicate that MR coronary angiography represents a potentially useful technique for diagnosing lesions of coronary arteries and evaluating their functions. This noninvasive method can be expected to replace the invasive Doppler guidewire method in the near future with development of MR coronary angiography technology.
Yuki Kondo, Michiko Yukinaka, Masahiro Nomura, Yutaka Nakaya and Susumu Ito : Early diagnosis of interferon-induced myocardial disorder in patients with chronic hepatitis C : evaluation by myocardial imaging with123I-BMIPP, Journal of Gastroenterology, Vol.35, No.2, 127-135, 2000.
(Summary)
Interferon (IFN) therapy for chronic hepatitis C is sometimes associated with cardiac complications. In the present study, we performed myocardial imaging with 123I-labeled beta-methyl-p-iodophenylpentadecanoic acid (123I-BMIPP) in order to evaluate myocardial disorders caused by IFN. We studied 40 healthy subjects (H group) and 25 patients with chronic hepatitis C who had been treated with IFN (IFN group). A Holter electrocardiogram (ECG) was performed and the autonomic nervous function was assessed by analyzing the spectral variability and 1/f fluctuation of heart rate. Myocardial planner imaging with 123I-BMIPP was performed to obtain the time activity curve for 20min immediately after administration of 123I-BMIPP (dynamic study). Early and delayed myocardial single photon emission computed tomography (SPECT) images were expressed as Bull's eyes and the myocardium was divided into four segments to calculate the washout rate for each segment on early and late SPECT images (early and late SPECT study). No significant differences in autonomic nervous function were observed between the two groups in heart rate variability. In a dynamic study, the reduction rate from the time activity curve was significantly higher in the IFN group compared with the H group (reduction rate, IFN group, 5.3 +/- 3.7% vs H group, 1.2 +/- 3.3%; P < 0.05). In the early and delayed myocardial SPECT study, the washout rate for the IFN group was significantly increased in all myocardial areas compared to that in the H group. However, the metabolic disorder of fatty acids caused by IFN was reversed on the second 123I-BMIPP myocardial scintigraphy examination several months after IFN therapy. These results indicate that metabolic disorders of fatty acids caused by IFN therapy can be detected before abnormalities are observed by Holter-ECG or echocardiography.
Michiko Yukinaka, Masahiro Nomura, Tetsuya Saijyo, Tomomi Nada, Hitoshi Miyajima, Yuki Kondo, Ken Saito, Yutaka Nakaya and Susumu Ito : Evaluation of autonomic nervous function in patients with essential hypertension complicated with peptic ulcer, Journal of Gastroenterology and Hepatology, Vol.15, No.1, 40-44, 2000.
H Miyajima, Masahiro Nomura, T Nada, Y Kondo, M Yukinaka, Ken Saito, Y Tada, Susumu Ito and Yutaka Nakaya : Age-related changes in the magnitude of ventricular depolarization vector : analyses by magnetocardiogram, Journal of Electrocardiology, Vol.33, No.1, 31-35, 2000.
(Summary)
The magnetocardiogram has the beneficial feature that permits the strength and location of the current dipole to be estimated. This study examines the issue of whether the magnitude of the heart current during depolarization phase was influenced by the age of healthy subjects. The magnetocardiograms were recorded by means of a second-derivative SQUID (superconducting quantum interference device) magnetometer (BT Corp, Model BMP, San Diego, CA) in 150 healthy subjects. The subjects were subgrouped into 5 age-based categories according to the age. The current dipole of the maximum QRS complex was determined from isofield contour maps during the ventricular depolarization phase, and no significant differences were observed in the magnitude in the current source for any age category. However, the amplitudes of the RV5 and SV1 + RV5 in the standard electrocardiogram were larger in 65 to 74-year-old women than other age groups, and the SV1 + RV5 was smaller for the 45 to 74-year-old men than for the men aged 25 to 44 years. These findings suggest that the age-associated changes in the QRS complex observed by the electrocardiogram are caused by increased electric resistance and not by the heart current itself. The results additionally suggest that no effects of aging were observed in the actual heart current of the heart during the depolarization phase.
Masahiro Nomura, Yutaka Nakaya, 宮島 等, 名田 智美, Ken Saito and Susumu Ito : 心磁図法を用いた心臓異常所見の検出:心電図法で捉えられない心起電力を検出できるか, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.13, 28-29, 2000.
Masahiro Nomura, Yutaka Nakaya, Tomomi Nada, Hitoshi Miyajima, Yuki Kondo, Ken Saito and Susumu Ito : Evaluation of Cardiac Function in Myocardial Infarction Patients by ECG 99mTc-MIBI Gated SPECT Using a Three-dimensional Perfusion/Motion Map Procedure, Japanese Heart Journal, Vol.40, No.4, 413-425, 1999.
(Summary)
Three-dimensional (3D) radionuclear myocardial imaging has improved the evaluation of left ventricular wall motion. However, there have been no studies evaluating left ventricular function using 3D-perfusion/motion map techniques. We hypothesized that the 3D-perfusion/motion map could accurately evaluate left ventricular wall motion even in patients with a history of myocardial infarction. Electrocardiogram (ECG)-gated single photon emission computed tomography (SPECT) using 99mTc-methoxy isobutyl isonitrile (MIBI) was performed in 20 patients with a history of myocardial infarction who underwent left ventriculography. Myocardial imaging data were collected during ECG-gated SPECT using a 3-headed gamma camera. Reconstructed 3D SPECT images were oriented to correspond to standard left ventriculography views (right anterior oblique and left anterior oblique projections), and the shortening fraction (SF) was calculated using the center line method. The SF and left ventricular ejection fraction from 3D SPECT images were compared with those determined by left ventriculography. There was a significant correlation between left ventriculography and the 3D-perfusion/motion map procedure in determining SF for all regions of the left ventricle except the anterobasal and posterior segments by using the Bland and Altman method. The 3D-perfusion/motion map procedure offers the advantage that the influences of contraction-related myocardial torsion and three-dimensional compression are minimized. In addition, this method facilitates evaluation of images from nonstandard projections. We conclude that this method may be useful for evaluating left ventricular function.
Kazuhiro Mori, Yasunobu Hayabuchi, Yasuhiro Kuroda, Yutaka Nakaya, Koichiro Tsuchiya and Hiroyuki Morimoto : Age-related endothelium-dependent vascular relazation in rat thoracic aorta in response to colforsin, Pediatrics International, Vol.41, No.6, 673-681, 1999.
(Summary)
Colforsin, a novel water-soluble forskolin derivative, increases intracellular cyclic AMP by direct stimulation of adenylate cyclase and has strong positive inotropic and vasodilative effects. However, it is not known whether colforsin causes nitric oxide (NO) release and enhances endothelium-dependent vascular relaxation. We studied NO production and relaxation on exposure to colforsin in thoracic aorta from rats aged 4, 12 and 60 weeks. When a low concentration of colforsin was added to a solution bathing ring segments of aorta from 12-week-old rats, relaxation was greater in the ring segments with intact endothelium than in those from which the endothelium had been removed. A high concentration of colforsin induced the same degree of relaxation of ring segments with or without endothelium, probably by a direct effect on vascular smooth muscle cells. Production of NO in response to colforsin by cultured endothelial cells from 12-week-old rat aorta was demonstrated by the electron paramagnetic resonance spin trapping method. A low concentration of colforsin relaxed aortic segments with intact endothelium from 4-week-old rats more than those from 12-week-old or 60-week-old rats. Reversal of relaxation by NG-nitro L-arginine, an NO synthesis inhibitor, was most significant in arteries from 4-week-old rats. Production of NO after exposure to colforsin was greater in aortic segments from 4-week-old rats than older rats, as detected by an NO-selective electrode. Colforsin induces vasodilation in part by releasing NO from the endothelium in rat thoracic aorta. In addition to a direct vasodilative effect on the vascular smooth muscle cells, an endothelium-dependent vasodilative effect is also important in younger arteries.
Masahiro Nomura, 宮島 等, 名田 智美, 近藤 幸, 由岐中 道子, Ken Saito, 大木 崇, Susumu Ito and Yutaka Nakaya : 僧帽弁逸脱におけるT wave alternanceの意義, Heart, Vol.31, No.suppl 2, 96-98, 1999.
200.
Masahiro Nomura, 宮島 等, 名田 智美, 近藤 幸, 由岐中 道子, 多田 由恵, Ken Saito, Susumu Ito and Yutaka Nakaya : QT dispersionの臨床的意義:心臓磁界を用いた左室肥大における検討, 生体磁気学会雑誌, Vol.12, 122-123, 1999.
201.
Yutaka Nakaya, Masaharu Ohnaka, Sadaichi Sakamoto, Yasuharu Niwa, Kazuko Okada, Masahiro Nomura, Tsutomu Hara and Masataka Kusonoki : Respiratory Quotient in Patients with Non-Insulin-Dependent Diabetes mellitus Treated with Insulin and Oral Hypoglycemic Agents, Annals of Nutrition & Metabolism, Vol.42, No.6, 333-340, 1998.
(Summary)
The respiratory quotient (RQ) reflects the amount of energy derived from carbohydrate as apposed to fat metabolism. To assess the metabolic state of patients with non-insulin-dependent diabetes mellitus, the RQ was measured five times a day (at 09.00, 11.00, 13. 00, 14.00, and 17.00 h) in 20 healthy subjects and 60 diabetic patients. Diabetic patients treated with insulin or sulfonylurea showed significantly higher RQ values than normal subjects and nontreated diabetic patients. Diabetic patients without treatment showed higher glucose levels, and their RQ values were significantly lower than those of treated patients. There was a significant inverse correlation between RQ and blood glucose levels at 11.00 h (r = -0.361, p < 0.01) in diabetic patients, but no significant relation with HbA1c. Treated diabetic patients with a higher body mass index tended to show a higher RQ than those with a lower one (r = -0.269, p = 0.083). Within 1 year, 7 of 13 patients, who had RQ > 1.0, gained more than 3 kg, while only 5 of the remaining 32 treated diabetic patients gained more than 3 kg (p < 0.05). This demonstrates that diabetic patients with a higher RQ tended to gain weight despite the use of insulin or oral hypoglycemia agents. The RQ increased by infusing both insulin and glucose in normal subjects. These results suggest that a high RQ results from excess insulin and excess food. The RQ is a good predictor of weight gain in diabetic patients treated with either insulin or oral hypoglycemic agents.
(Keyword)
Calorimetry, Indirect / Diabetes Mellitus, Type 2 / Dietary Carbohydrates / Dietary Fats / energy metabolism / Female / Hemoglobin A, Glycosylated / Humans / Hypoglycemic Agents / insulin / Male / Middle Aged / Weight Gain
Michiko Yukinaka, Masahiro Nomura, Susumu Ito and Yutaka Nakaya : Mismatch between myocardial accumulation of 123I-MIBG and 99mTc-MIBI and late ventricular potentials in patients after myocardial infarction : Association with the development of ventricular arrhythmias, American Heart Journal, Vol.136, No.5, 859-867, 1998.
(Summary)
Late ventricular potentials are widely used to predict life-threatening arrhythmias, although the predictive value is low. To improve prediction, we correlated the incidence of ventricular arrhythmias with mismatches in myocardial 99mTc-methoxyisobutylisonitrile (MIBI)/(123)I-metaiodobenzylguanidine (MIBG) accumulation and late ventricular potentials (LP). Fifty patients with old myocardial infarctions were divided into an LP-positive group (n = 19) and an LP-negative group (n = 31). On bull's-eye single photon emission computed tomographic MIBI and MIBG images, the heart was divided into 9 segments to evaluate the accumulation of the 2 nuclides. There was no difference in total defect score (TDS) for MIBI between the LP-positive and LP-negative groups. However, TDS for MIBG and differences TDS between MIBI and MIBG (ATDS) were significantly greater in the LP-positive group. The incidence of severe ventricular arrhythmias was greater among patients with an increased ATDS in the LP-positive group. Thus the combination of these two methods may improve the prediction of ventricular arrhythmias after myocardial infarction.
Masaharu Ohnaka, Masako Iwamoto, Sadaichi Sakamoto, Yasuharu Niwa, Hideki Matoba, Kimiko Nakayasu, Yutaka Nakaya and Takeshi Miura : Does prolonged exercise alter diet-induced thermogenesis?, Annals of Nutrition & Metabolism, Vol.42, No.6, 311-318, 1998.
(Summary)
Diet-induced thermogenesis (DIT) is mainly an insulin-mediated response and the result of fat and glycogen synthesis. We investigated DIT at rest and after exercise to clarify the mechanism of exercise-induced changes in DIT in 6 healthy men (mean age 36 +/- 16 years). Subjects exercised for 1 h at 58% of maximal O2 consumption on a bicycle ergometer and then rested for 8 h sitting in a comfortable chair (exercise experiment). On a different day, subjects rested for 8 h without preceding exercising (non-exercise experiment). At 12.30 h, the subjects were given their second meal. DIT to individual meal did not differ significantly between the exercise and non-exercise days. Increased insulin sensitivity and increased free fatty acid oxidation by exercise may facilitate the conversion of glucose to glycogen in muscle. On the other hand, insulin secretion expressed as the ratio of plasma levels of insulin to glucose after the meal was significantly decreased in the exercise experiment (p < 0.05). Study of heart rate variability showed that sympathetic tone, a primary hormonal determinant of glucose metabolism during exercise, was increased and parasympathetic tone was decreased during the recovery period in the exercise experiment (p < 0.05). These findings suggest that changes in DIT are affected by many factors and may be related to the balance between these counteracting factors.
(Keyword)
Adult / Autonomic Nervous System / Blood Glucose / Body Temperature Regulation / Diet / Dietary Carbohydrates / Dietary Fats / Electrocardiography, Ambulatory / energy metabolism / Exercise / Humans / insulin / Male / Middle Aged / oxygen consumption
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 9895418
Tetsuya Saijo, Masahiro Nomura, Yutaka Nakaya, Ken Saito, Yuki Kondo, Michiko Yukinaka, Ichiro Shimizu and Susumu Ito : Assessment of autonomic nervous activity during gastrointestinal endoscopy, Journal of Gastroenterology and Hepatology, Vol.13, 816-820, 1998.
205.
Masahiro Nomura, T Nada, J Endo, Y Kondo, M Yukinaka, Ken Saito, Susumu Ito, H Mori, Yutaka Nakaya and H Shinomiya : Brugada syndrome associated with an autonomic disorder, Heart, Vol.80, No.2, 194-196, 1998.
Although endothelium-derived hyperpolarizing factor (EDHF) activity has been demonstrated in arteries from various species, EDHF has not been chemically identified, nor its mechanism of action characterized. To elucidate this mechanism, we tested the effect of EDHF on large-conductance Ca2+-activated K+ (K(Ca)) channels in porcine coronary artery smooth muscle cells. By using a patch-clamp technique, single-channel currents were recorded in cultured smooth muscle cells; the organ bath also contained a strip of porcine coronary with endothelium, which served as the source of endothelium-derived relaxing factor(s) including EDHF. Exposure of endothelium to 10(-6) M bradykinin activated K(Ca) channels in cultured smooth muscle cells in cell-attached patches. When the experiment was performed in the presence of 10 microM indomethacin and 30 microM N(G)-nitro-L-arginine (L-NNA), which block the generation of prostaglandin I2 (PGI2) and NO, respectively, K(Ca) channel activity was stimulated by bradykinin, indicating the direct involvement of EDHF in K(Ca) channel stimulation. Neither 10 microM methylene blue nor 25 microM Rp-cAMPS inhibited bradykinin-induced K(Ca) channel activity. In inside-out patches, the addition of bradykinin to the solution was without effect on K(Ca) channel activation. However, in the presence of 0.5 mM guanosine triphosphate (GTP) and 1.0 mM adenosine triphosphate (ATP) in the bath solution, K(Ca) channels was activated by bradykinin. In outside-out patches, the addition of bradykinin also increased K(Ca) channel activity, when GTP and ATP were added to the pipette solution. The addition of GDP-beta-S (100 microM) in the cytosolic solution completely blocked the activation K(Ca) channels induced by bradykinin in inside-out and outside-out patches. Pretreatment with 30 microM quinacrine, a phospholipase A2 inhibitor, or 3 microM 17-octadecynoic acid (17-ODYA), a cytochrome P450 inhibitor, in addition to indomethacin and L-NNA, abolished bradykinin-stimulated K(Ca) channel activity in cell-attached patches. Both 14,15-epoxyeicosatrienoic acid (EET) and 11,12-EET increased the open probabilities of K(Ca) channels in cell-attached patches. These results suggest that EDHF, released from endothelial cells in response to bradykinin, hyperpolarizes smooth muscle cells by opening K(Ca) channels. Furthermore, our data suggest that EDHF is an endothelium-derived cytochrome P450 metabolite of arachidonic acid. The effect of EDHF on K(Ca) channels is not associated with an increase of cAMP and cGMP. The activation of K(Ca) channels appears to be due to the activation of GTP-binding protein.
Michiko Yukinaka, Masahiro Nomura, Tomoko Mitani, Yuki Kondo, Tomotsugu Tabata, Yutaka Nakaya and Susumu Ito : Cerebrospinal ascites developed 3 years after ventriculoperitoneal shunting in a hydrocephalic patient., Internal Medicine, Vol.37, No.7, 638-641, 1998.
(Summary)
We report a 23-year-old woman who developed ascites 3 years after ventriculoperitoneal shunting. Revision of the shunt to ventricular drainage followed by ventriculo-atrial shunting was required for resolution of ascites. In our patient the pathophysiology of this rare shunt complication most likely involved impaired absorption of fluid within the peritoneum associated with multiple shunt reconstructions and tube extensions resulting in chronic inflammation. Cerebrospinal ascites must be suspected irrespective of post-shunt intervals in similar patients.
Yasunobu Hayabuchi, Yutaka Nakaya, Matsuoka Suguru and Yasuhiro Kuroda : Effect of acidosis on Ca2+-activatecd K+ channels in cultured porcine coronary artery smooth muscle cells, Pflügers Archiv : European Journal of Physiology, Vol.436, 509-514, 1998.
209.
Kazuhiro Kishi, Naoko Muromoto, Yutaka Nakaya, Ikuko Miyata, Akifumi Hagi, Hideki Hayashi and Yousuke Ebina : Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway., Diabetes, Vol.47, No.4, 550-558, 1998.
(Summary)
Physical exercise induces translocation of GLUT4 from an intracellular pool to the cell surface in skeletal muscles and increases glucose uptake via an insulin-independent pathway. However, the molecular mechanism remains to be identified. Some studies have suggested that bradykinin is locally released from contracting muscles and may be responsible for GLUT4 translocation and the increase of glucose transport in skeletal muscles. To determine whether bradykinin directly triggers GLUT4 translocation, we established L6 myotubes, 3T3-L1 adipocytes, and Chinese hamster ovary cells stably expressing c-myc epitope-tagged GLUT4 (GLUT4myc) and bradykinin B2 receptors. We found that bradykinin directly triggered GLUT4myc translocation and increased the rate of glucose uptake in a dose-dependent manner in these cells. The translocation with bradykinin occurred even after pretreatment with an islet-activating protein, wortmannin, and phorbol 12,13-dibutyrate. The signaling pathway does not seem to be mediated by Gi, phosphatidylinositol 3-kinase, or protein kinase C. It is insulin-independent and via trimeric G-protein Gq. Bradykinin is probably one of the factors responsible for exercise-stimulated glucose uptake in skeletal muscles.
(Keyword)
3T3 Cells / Adipocytes / Animals / Biological Transport / Bradykinin / CHO Cells / Cricetinae / GTP-Binding Proteins / gene expression / Genes, myc / glucose / Glucose Transporter Type 4 / Glycogen / Humans / insulin / L Cells (Cell Line) / Mice / Monosaccharide Transport Proteins / Muscle Proteins / Muscle, Skeletal / Protein Kinase C / Receptor, Bradykinin B2 / Receptors, Bradykinin
Kazuhiro Mori, Yutaka Nakaya, Yasunobu Hayabuchi, Sakamoto Sadaichi, Matsuoka Suguru and Yasuhiro Kuroda : Lactate-induced vascular relaxation in porcine coronary arteries is mediated by Ca2+activated K+ channels, Journal of Molecular and Cellular Cardiology, Vol.30, No.2, 349-356, 1998.
(Summary)
Under ischemic conditions and during strenuous exercise, lactate concentrations increase in coronary artery smooth muscle cells. Although lactate causes pH-independent vasorelaxation, the mechanisms responsible for this effect are unclear. We investigated the effect of lactate on K+ channels in smooth muscle cells from porcine coronary arteries. Neutralized lactate (3-100 mm) induced vasorelaxation in ring segments of porcine coronary arteries precontracted with KCl in a dose-dependent manner. One millimolar tetraethylammonium (TEA), an inhibitor of Ca2+-activated K+ channels (KCa channels), reversed the lactate-induced relaxation, while 60 microM glibenclamide, an inhibitor of ATP-sensitive K+ channels (KATP channels), did not. In both inside-out and cell-attached patch clamp technique with cultured smooth muscle cells, the KCa channels were activated by lactate. In inside-out patches, lactate activated KCa channels, even under acidic conditions. This is in contrast to the effect of H+ which inactivated KCa channels. We conclude that vasodilation of porcine coronary arteries induced by lactate is, at least in part, mediated by activation of KCa channels. This effect may be self-protective by maintaining coronary blood flow during ischemia.
Yasunobu Hayabuchi, Yutaka Nakaya, Suguru Matsuoka and Yasuhiro Kuroda : Hydrogen peroxide-induced vascular relaxtion in porcine coronary arteries is mediated by Ca2+-activated K+ channels, Heart and Vessels, Vol.13, 9-17, 1998.
212.
Masahiro Nomura, Yutaka Nakaya, 三谷 智美, 近藤 幸, 由岐中 道子 and Susumu Ito : 心磁界から求めた心室脱分極ベクトルの加齢変化, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.11, 114-115, 1998.
213.
Masahiro Nomura, 三谷 智美, 近藤 幸, 由岐中 道子, Susumu Ito and Yutaka Nakaya : 心電図波形の加齢変化, The Official Journal of Japanese Society of Laboratory Medicine, Vol.46, 761-765, 1998.
Masahiro Nomura, 由岐中 道子, 近藤 幸, 名田 智美, 遠藤 純子, 岸 史子, Ken Saito, 大木 崇, Susumu Ito and Yutaka Nakaya : Dihydropridine系Ca拮抗薬の心臓交感神経機能への影響, Heart, Vol.30, No.suppl 3, 98-100, 1998.
216.
Yoshiaki Taoka, Masahiro Nomura, Masafumi Harada, Tomomi Mitani, Junko Endo, Yuki Kondo, Michiko Yukinaka, Susumu Ito, Yutaka Nakaya and Hiromu Nishitani : Coronary-Pulmonary Artery Fistulae Depicted by Multiplanar Reconstruction Using Magnetic Resonance Imaging, Japanese Circulation Journal, Vol.62, No.6, 455-457, 1998.
217.
Masahiro Nomura, Yutaka Nakaya, T Nada, J Endo, Y Kondo, M Yukinaka, Ken Saito and Susumu Ito : Effects of intravenous administration of L-arginine on autonomic nervous activities: Analysis of heart rate variability, Japanese Heart Journal, Vol.39, 331-338, 1998.
218.
Chen Chunhe, Hitoshi Houchi, Toshiaki Tamaki and Yutaka Nakaya : Effects of cytosolic ATP and other nucleotides on Ca2+-activated K+ channels in cultures bovine adrenal chromaffin cells., European Journal of Pharmacology, Vol.350, 293-299, 1998.
219.
Hiroshi Kido, Ayako Nakano, Naoko Okishima, Hideki Wakabayashi, Fumiko Kishi, Yutaka Nakaya, Masanori Yoshizumi and Toshiaki Tamaki : Human chymase, an enzyme forming novel bioactive 31-amino acid length endothelins., The Journal of Biological Chemistry, Vol.379, 885-891, 1998.
220.
Y Kondo, Masahiro Nomura, T Nada, J Endo, M Yukinaka, Ken Saito, S Ichkawa, Susumu Ito and Yutaka Nakaya : Ischaemic electrocardiographic changes after massive blood transfusion : Findings based on myocardial scintigraphy using 99mTc-MIBI and 123I-MIBG, Acta Cardiologica, Vol.53, No.5, 279-283, 1998.
(Summary)
We performed myocardial scintigraphy on a patient with ischaemic electrocardiographic changes after massive blood transfusion. Although there was no defect by 99mTc-MIBI scintigraphy, 123I-MIBG scintigraphy was observed suggesting denervation after massive blood transfusion. Myocardial scintigraphy using 99mTc-MIBI or 123I-MIBG can be useful for the evaluation of myocardial dysfunction with reversible myocardial infarction.
Tetsuya Saijyo, Masahiro Nomura, Yutaka Nakaya, Ken Saito and Susumu Ito : Autonomic nervous system activity during infusion of L-arginine in patients with liver cirrhosis, Liver, Vol.18, 27-31, 1998.
222.
Masahiro Nomura, Yutaka Nakaya, 由岐中 道子, 近藤 幸, Ken Saito and Susumu Ito : 心磁図法によるQTc dispersion:心筋梗塞による検討, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.10, 96-97, 1997.
Masahiro Nomura, Yutaka Nakaya, F Kishi, Y Kondo, M Yukinaka, Ken Saito and Susumu Ito : Signal averaged electrocardiogram after exercise in patients with mitral valve prolapse, Journal of Medicine, Vol.28, No.1&2, 62-74, 1997.
(Summary)
While late potentials are correlated with an increased incidence of ventricular tachycardia, they are not necessarily a good predictor of ventricular electrical instability in patients with mitral valve prolapse (MVP). Our objective was to determine whether the signal averaged electrocardiogram (SAECG) after exercise can discriminate groups with a higher frequency of ventricular arrhythmia from those without. The SAECG was recorded before and after treadmill exercise in 20 normal subjects (N group), 20 patients with MVP (MVP group) and 10 patients with old myocardial infarction (MI group). Five patients (25%) in the MVP group and two patients (33%) in the MI group had late potentials before exercise. Late potentials in the MI group did not disappear with exercise, whereas they disappeared with exercise in two patients in the MVP group. The results suggest that the late potentials observed in patients with MVP differ in nature from those with old myocardial infarction and are not always related to lethal arrhythmia.
岸 史子, Masahiro Nomura, 由岐中 道子, Ken Saito, Tomotsugu Tabata, 井内 新, 福田 信夫, 大木 崇, Susumu Ito and Yutaka Nakaya : Evaluation of Myocardial Sympathetic Nerve Function in Patients With Mitral Valve Prolapse Using Iodine-123-Metaiodobenzylguanidine Myocardial Scintigraphy, Journal of Cardiology, Vol.27, No.Suppl II, 21-283, 1996.
Fumiko Kishi, Yutaka Nakaya, Akira Takahashi, Hirokazu Miyoshi, Masahiro Nomura and Ken Saito : INTRACELLULAR AND EXTRACELLULAR Ca2+REGULATE HISTAMINE-INDUCED RELEASE OF NITRIC OXIDE IN VASCULAR ENDOTHELIAL CELLS AS SHOWN WITH SENSITIVE AND SELECTIVE NITRIC OXIDE ELECTRODES, Pharmacological Research, Vol.33, No.2, 123-126, 1996.
Masahiro Nomura, Yutaka Nakaya, F Kishi, Ken Saito, A Shinohara, Susumu Ito, H Yamamoto, J Syoji, Y Ohkita and S Orino : A 90-year old patient with atrial septal defect and sinus rhythm, Acta Cardiologica, Vol.51, No.4, 377-380, 1996.
(Summary)
A 90-year old patient with an atrial septal defect (ASD) and sinus rhythm, but no history of atrial fibrillation of heart failure is presented. Literature searches revealed no similar report of such a case. In addition, this patient represents the oldest documented patients with ASD associated and sinus rhythm.
(Keyword)
Age Factors / Aged / Aged, 80 and over / Electrocardiography / Heart Rate / Heart Septal Defects, Atrial / Humans / Male
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 8888895
Yutaka Nakaya and Masahiro Nomura : 心磁図法による心筋梗塞症の心起電力の検討, Japanese journal of Electrocardiology, Vol.16, No.Suppl 1, 60-62, 1996.
229.
西條 哲也, Masahiro Nomura, 岸 史子, Susumu Ito, Yutaka Nakaya, 伊東 猛, 糸崎 秀雄, 豊田 晴久 and 賀戸 久 : 64チャンネル磁束計を用いた小腸磁界の測定, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.9, 202-203, 1996.
230.
Masahiro Nomura, 由岐中 道子, 岸 史子, Ken Saito, Susumu Ito and Yutaka Nakaya : 特発性心筋症における初期QRSベクトルの信号源, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.9, 194-195, 1996.
231.
Masahiro Nomura, Yutaka Nakaya, 渡部 克介, 岸 史子, Ken Saito, 三好 宏和, 西條 哲也, 由岐中 道子, 大木 崇 and Susumu Ito : L-アルギニン静脈注射による自律神経活動の影響:心拍変動解析による検討, Heart, Vol.28, No.Suppl 5, 31-32, 1996.
232.
Masahiro Nomura, 岸 史子, 由岐中 道子, 近藤 幸, Ken Saito, 大木 崇, Susumu Ito and Yutaka Nakaya : 長時間運動負荷後の回復過程のエネルギー代謝と自律神経活動の検討‐呼気ガス分析と心拍変動解析による検討, Heart, Vol.29, No.Suppl 4, 73-75, 1996.
233.
Masahiro Nomura, Yutaka Nakaya, Fumiko Kishi, Michiko Yukinaka, Ken Saito, Hiroshi Shibata and Susumu Ito : Heart rate variability during painful medical procedures(Percutaneous ethanol injection therapy), Electrocardiology '96 from the cell to the body surface, 395-398, 1996.
Kazushi Minami, Yasushi Hirata, Akira Tokumura, Yutaka Nakaya and Kenji Fukuzawa : Protein kinase c-independent inhibition of the Ca2+-activated K+ channel by angiotensin II and endothelin-1, Biochemical Pharmacology, Vol.49, No.8, 1051-1056, 1995.
(Summary)
We previously reported that the Ca(2+)-activated K+ channel (KCa-channel) in cultured smooth muscle cells from porcine coronary artery was inhibited by protein kinase C (C-kinase). In this study, inhibition of the KCa-channel by receptor-mediated vascular contractile agonists, such as angiotensin II (ANG II) and endothelin-1 (ET-1), was investigated by the patch-clamp technique. In cell-attached patches, addition of ANG II (500 nM) or ET-1 (50 nM) to the bath inhibited the KCa-channel activated by the calcium ionophore A23187 (10-20 microM). Phorbol 12-myristate 13-acetate (PMA, 1 microM), a C-kinase activator, also decreased the open probability of the KCa-channel. The PMA-induced decrease in the open probability was reversed by subsequent application of staurosporine (1 nM), a C-kinase inhibitor, but the ANG II- and ET-1-induced decreases were not reversed by subsequent application of staurosporine (> 30 nM). Pretreatment of smooth muscle cells with 30 nM staurosporine, a protein kinase inhibitor, or 1 mM neomycin, an inhibitor of phospholipase C, also did not abolish the inhibition of the KCa-channel by ANG II. Furthermore, ANG II inhibited the KCa-channel in cells in which C-kinase was down-regulated. These results indicate that, in porcine coronary artery smooth muscle cells, ANG II and ET-1 inhibit the KCa-channel by a C-kinase-independent mechanism.
西條 哲也, Masahiro Nomura, Susumu Ito, Yutaka Nakaya, 伊藤 猛, 糸崎 秀夫, 豊田 晴久, 春田 康博 and 賀戸 久 : 64チャンネルSQUID磁束計を用いた胃活動電流の測定‐臨床的有用性の検討‐, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.8, 318-321, 1995.
240.
Masahiro Nomura, 西條 哲也, 岸 史子, Susumu Ito, Yutaka Nakaya, 糸崎 秀夫, 豊田 晴久, 春田 康博 and 賀戸 久 : 高温超伝導SQUIDを用いた胃運動機能の評価, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.8, 322-325, 1995.
241.
Yutaka Nakaya, Masahiro Nomura, 岸 史子, 三好 宏和, Ken Saito and Susumu Ito : 前壁心筋梗塞症および健常例の初期QRSベクトルの信号源推定, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.8, 302-305, 1995.
242.
Hirokazu Miyoshi, F Kishi, K Watanabe, Masahiro Nomura, Ken Saito and Yutaka Nakaya : Nonendothelial-derived nitric oxide activates the K+ channels in cultured vascular smooth muscle cells, Heart and Vessels, Vol.9, No.suppl, 109-111, 1995.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, F Kishi, Tetsuzo Wakatsuki, Hirokazu Miyoshi, Akiyoshi Nishikado, Shigenobu Bando, Susumu Ito, Hiromu Nishitani, Masao Wada, Satoshi Fujita and Itsuro Tamura : Noninvasive localization of accessory pathways by magnetocardiographic imaging, Clinical Cardiology, Vol.17, No.5, 239-244, 1994.
(Summary)
The magnetocardiogram (MCG) is a newly developed method that helps localize a cardiac current source. To test the clinical accuracy of a 7-channel biomagnetic system in the localization of early ventricular depolarization sites, the MCGs of 14 patients with Wolff-Parkinson-White (WPW) syndrome were recorded in a radiofrequency-shielded room. The locations of early ventricular depolarization sites were classified by standard 12-lead electrocardiograms (ECGs) and body surface isopotential mapping. The accessory pathways of 3 patients with WPW syndrome were located in the right free wall and in 11 patients in the left free wall. The three-dimensional (3-D) dipole location was computed every 2 ms from the onset of the QRS complex by the least-square method. These 3-D dipole locations were projected onto a gated magnetic resonance image in order to visualize the propagation of the calculated ventricular source. The results were compared with those obtained by body surface isopotential mapping, and electrocardiographic and electrophysiologic studies. The location of the deduced current dipole at 20 ms correlated well with the location of the accessory pathway by the body surface mappings in 12 of the 14 patients with WPW syndrome. The MCG is capable of precisely determining the 3-D location of a current source in a noninvasive manner and may be of potential benefit in the treatment of WPW syndrome by catheter ablation.
(Keyword)
magnetocardiogram / Wolff-Parkinson-White syndrome / Magnetic resonance image
Yutaka Nakaya, Takahiro Katayama, Masahiro Nomura, Yasuko Ishimura, Takeshi Ohuchi, Motoo Oka, Mitsuaki Yamamoto and Shigeki Mizobuchi : Pathphysiologic significance of free and conjugated dopamines in congestive heart failure, American Heart Journal, Vol.127, No.3, 613-617, 1994.
(Summary)
sulfoconjugated dopamine constitutes the major portion of circulating or excreted dopamine, but its physiologic significance is still unknown. To test whether conjugated dopamine serves as a source of free dopamine in response to acute stress, plasma concentrations of free and conjugated dopamine were measured during an acute exacerbation of heart failure. The plasma concentration of conjugated dopamine decreased significantly during the acute phase of heart failure, whereas that of free dopamine increased. The plasma concentration of free dopamine decreased, whereas the concentration of conjugated dopamine increased as heart failure improved. An infusion of dopamine increased the plasma concentration of conjugated dopamine, suggesting that at least part of the excess active dopamine was detoxified through conjugation. The results of these tests with both conjugated and free dopamine are interconvertible and indicate that conjugated dopamine can serve as a reservoir of active dopamine.
Ken Saito, Yutaka Nakaya, Y Miyoshi, Tetsuzo Wakatsuki, M. Nomura and Masayuki Shono : Effects of vesnarinone (OPC-8212) on Ca(2+)-activated K channels and cytosolic Ca2+ in cultured smooth muscle cells from porcine coronary artery., Japanese Heart Journal, Vol.35, No.1, 61-71, 1994.
(Summary)
Vesnarinone is a new, non vasodilating cardiotonic agent. This study compared the effects of vesnarinone and amrinone, a phosphodiesterase (PDE) inhibitors with vasodilating actions, on cultured smooth muscle cells from the porcine coronary artery. Application of vesnarinone (10(-4) M) or amrinone (10(-4) M) to the bath solution in cell-attached patches activated the KCa channel having a conductance of 133 pS (bath 2.7 mM K, pipette 140 mM K). Application of vesnarinone to the cytosolic side had no direct effect on KCa channel activities in inside-out patches. Activation of the KCa channel was suppressed when the intracellular production of cAMP was suppressed by preincubation with carbachol (10(-6) M). Amrinone, but not vesnarinone, lowered [Ca2+]i in the K(+)-depolarized smooth muscle cells (K+ = 70 mM). These results suggest that vesnarinone exerts an additional effect on [Ca2+]i that is independent of PDE inhibition. The difference in the effects on [Ca2+]i in vascular smooth muscle cells may explain in part the differing actions of these agents on vascular relaxation.
(Keyword)
smooth muscle / cytosolic Ca2
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Ken Saito, Yutaka Nakaya, Yukiko Miyoshi, Tetsuzo Wakatsuki, Masahiro Nomura and M Shono : Effects of Vesnarinone(OPC-8212)on Ca2+-Activated K Channels and Cytosolic Ca2+- in Cultured Smooth Muscle Cells from Porcine Coronary Artery, Japanese Heart Journal, Vol.35, No.1, 61-71, 1994.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, H Miyoshi, F Kishi, S Hibino, T Saijyo, Susumu Ito, K Nakagawa, Hideki Nakanishi, H Nagae, N Toda, S Tanaka, H Harada, K Matsumoto and T Hasagawa : Hemopneumothorax secondary to multiple cavitary metastasis in angiosarcoma of the scalp, Respiration, Vol.61, No.2, 109-112, 1994.
(Summary)
We report a case of hemopneumothorax secondary to multiple cavitary metastasis in the angiosarcoma of the scalp in an 86-year-old woman, who died of respiratory failure. At autopsy, multiple cavities were found in both lungs. Histologic specimen of the cavitary metastasis of the lung showed that tumor cells proliferated forming several tubular spaces and these tubular spaces seemed to communicate with the central cyst. These findings suggested that imperfect vessel-like structures of the cavitary metastasis are likely to break down and finally grow up to large thin-walled cavities.
Masahiro Nomura, 西條 哲也, 岸 史子, 三好 宏和, Ken Saito, Yutaka Nakaya, 大木 崇 and Susumu Ito : 肝硬変患者における自律神経機能:体表面平均加算化心電図法を用いた検討, Journal of Cardiology, Vol.24, No.Suppl 41, 102-104, 1994.
254.
Masahiro Nomura, Yutaka Nakaya, 岸 史子, Ken Saito and Susumu Ito : 心磁図法による心房性再分極波(Ta波)の検討, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.7, 202-205, 1994.
255.
Yutaka Nakaya, Masahiro Nomura, Ken Saito, 岸 史子 and Susumu Ito : 心筋梗塞症の初期QRSベクトルと心室再分極ベクトル-心磁図法による電流源の位置, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.7, 206-209, 1994.
256.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, F Kishi, H Miyoshi, K Watanabe, Susumu Ito, M Kubo and S Matsuoka : Time- and frequency-domain analyses of signal averaged electrocardiograms in patients with diabetes mellitus, Journal of Medicine, Vol.25, No.5, 271-283, 1994.
(Summary)
We recorded the signal-averaged electrocardiography (SAECG) of patients with diabetic retinopathy in order to clarify whether a ventricular conduction disturbance can be detected by time- or frequency-domain analysis of the SAECG. Twenty-four normal subjects (N group) and 20 patients with diabetic retinopathy [diabetes mellitus (DM) group] were studied. On time-domain analysis, the duration of the filtered QRS (f-QRS), the duration of the terminal QRS below 40 microV (LAS40) and the root-mean-square amplitude of the terminal 40 msec (RMS40) were measured. The frequency-domain analysis was performed using two windows. In each window, the ratio of the area under the spectral curve from 40 to 100 Hz was compared with that from 0 to 40 Hz and the area from 20 to 50 Hz was compared with that from 0 to 20 Hz. The LAS40 of the DM group was significantly prolonged when compared with the N group. The area ratio from 40 to 100 Hz versus 0 to 40 Hz significantly increased in the DM group when compared with the N group. These results suggest that SAECG can be used to detect abnormal electrical signals due to diabetic microangiopathy. Moreover, high frequency components of 40 to 100 Hz at the terminus of the QRS wave were most sensitive for abnormalities due to diabetic microangiopathy.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, F Kishi and Susumu Ito : Circadian profile of heart rate variability in mitral valve prolapse syndrome, Japanese Heart Journal, Vol.57, No.suppl, 557-558, 1994.
258.
Tetsuya Saijo, Masahiro Nomura, Yutaka Nakaya, Ken Saito, F Kishi and Susumu Ito : Time- and frequency-domain heart rate variabilities in patients with liver cirrhosis, Japanese Heart Journal, Vol.35, No.suppl, 563-564, 1994.
259.
F Kishi, Masahiro Nomura, Yutaka Nakaya, Ken Saito and Susumu Ito : Relationship between the ischemic myocardium and focus of ventricular tachycardia in old myocardial infarction, Japanese Heart Journal, Vol.35, No.suppl, 563-564, 1994.
260.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, 岸 史子, 三好 宏和, Susumu Ito, 和田 昌夫, 藤田 智 and 田村 逸郎 : 心房興奮伝播のMRI画像上の表示‐心磁図法による電流dipoleの位置推定‐, Medical Imaging Technology, Vol.1, 551-558, 1993.
Masahiro Nomura, Yutaka Nakaya, Tetsuzo Wakatsuki, Yukiko Miyoshi, Fumiko Kishi, Ken Saito, Susumu Ito, Kimiko Nakayasu, Hiromu Nishitani, Kenji Matsuzaki, Shin-ichi Ueno, Itsuro Tamura, Masao Wada, Satoshi Fujita and Tsutomu Takae : Prediction of the site of origin of ventricular premature beat by magnetocardiogram, Heart, Vol.25, No.8, 907-913, 1993.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, 岸 史子, 三好 宏和, Akiyoshi Nishikado, 坂東 重信, Susumu Ito, 和田 昌夫, 藤田 智 and 田村 逸郎 : SQUIDを用いた心房興奮伝播のMRI画像上の表示, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.6, 214-217, 1993.
266.
Yutaka Nakaya, Masahiro Nomura, 岸 史子, Ken Saito, Akiyoshi Nishikado, 坂東 重信 and Susumu Ito : 心室性不整脈の発生源の推定-心電図と心磁図の比較, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.6, 210-213, 1993.
Masahiro Nomura, Kimiko Nakayasu, Yutaka Nakaya, Yukiko Miyoshi, Tetsuzo Wakatsuki, Ken Saito, Shigenobu Bando and Susumu Ito : Single moving dipole obtained from magnetic field of the heart in patients with left ventricular hypertrophy, Clinical Cardiology, Vol.15, No.10, 752-758, 1992.
(Summary)
Magnetocardiograms (MCGs) were recorded by means of a second-derivative SQUID (superconducting quantum interference device) magnetometer in 20 normal subjects and 28 patients with left ventricular overload to analyze the activation sequence of the heart and amplitude of estimated current source. In the normal subjects, the dipole was directed to the left and gradually superiorly 40 ms after the beginning of the QRS wave mainly due to the activation of the left ventricle. In the patients with hypertension, the direction and location of the dipoles were similar to those of the normal subjects, but their dipole moments were increased. In the patients with mitral regurgitation, the dipoles of late QRS were directed more inferiorly than in the normal subjects and their amplitude was increased. In the patients with aortic valve disease, the amplitude of the dipoles was increased markedly and their location was deviated more to the left than the dipoles of the normal subjects. We established the criterion for diagnosis of LVO from the dipole moment of 50 ms of 3.13 x 10(-3) A or more. The sensitivity of this criterion is significantly higher in the diagnosis of left ventricular overload than the electrocardiogram (ECG). The present study shows that the moving dipole method is useful to determine the increased electromotive force in patients with left ventricular overload and that sensitivity in diagnosis of left ventricular overload is increased.
(Keyword)
magnetocardiogram / left ventricular overload / single moving dipole
Yukiko Miyoshi, Yutaka Nakaya, Tetsuzo Wakatsuki, Shuichiro Nakaya, Kazuya Fujino, Ken Saito and Isao Inoue : Endothelin blocks ATP-sensitive K+ channels and depolarizes smooth muscle cells of porcine coronary artery, Circulation Research, Vol.70, No.3, 612-616, 1992.
273.
Yutaka Nakaya, Masahiro Nomura, Tetsuzo Wakatsuki, 三好 由貴子, Akiyoshi Nishikado, 坂東 重信, Susumu Ito and Kimiko Nakayasu : Single moving dipoleによる左室負荷の診断, 日本心電学会誌, Vol.12, No.Suppl 1, 85-87, 1992.
274.
Masahiro Nomura, Yutaka Nakaya, 三好 由貴子, Tetsuzo Wakatsuki, Susumu Ito, 森 博愛, 上野 慎一, 松崎 健司, Hiromu Nishitani, 田村 逸郎, 和田 昌夫, 藤田 智 and 高江 勉 : 正常例の初期QRS波のdipoleの位置推定‐心電図同期MRI画像上への表示‐, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.5, 110-113, 1992.
275.
Masahiro Nomura, Yutaka Nakaya, 三好 由貴子, Tetsuzo Wakatsuki, Susumu Ito, 森 博愛, 上野 慎一, 松崎 健司, Hiromu Nishitani, 田村 逸郎, 和田 昌夫, 藤田 智 and 高江 勉 : 心磁図法による心室最早期興奮部位の推定‐磁界分布図と体表面電位図·心表面マッピングとの対比‐, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.5, 106-109, 1992.
276.
Masanori Yoshizumi, Yutaka Nakaya, Toshiyuki Hibino, Masahiro Nomura, Kazuo Minakuchi, Tetsuya Kitagawa, Itsuo Katoh, Takeshi Ohuchi and Motoo Oka : Changes in plasma free and sulfoconjugated catecholamines before and after acute physical exercise:Experimental and clinical studies., Life Sciences, Vol.51, No.3, 227-234, 1992.
277.
Tetsuzo Wakatsuki, Yutaka Nakaya, Yukiko Miyoshi, Masahiro Nomura, Ken Saito, RX Zeng, Susumu Ito and Isao Inoue : Effects of vasopressin on K+ channels of vascular smooth muscle cells, Therap Res, Vol.13, 311-317, 1992.
278.
Yutaka Nakaya, Masahiro Nomura, Kimiko Nakayasu, S. Bandou and Susumu Ito : Diagnosis of ventricular hypertrophy by single moving dipole, International Conference on Biomagnetism., Vol.8, 439-440, 1991.
ATP sensitive K channel / Smooth music cells / Endothelin / Nicorandil
280.
Takashi Fujimoto, Koichi Kiyoshige, Yasunori Saito, Masahiro Nomura, Shigenobu Bando, Yutaka Nakaya and Hiroyoshi Mori : Vector U loop in patients with idiopathic cardiomyopathy, Journal of Electrocardiology, Vol.23, No.4, 331-339, 1990.
(Summary)
The U loops of vectorcardiograms were recorded in 50 normal subjects, 10 patients with dilated cardiomyopathy (DCM group), and 83 patients with hypertrophic cardiomyopathy (HCM group). The HCM group was divided into three subgroups: those with obstructive hypertrophic cardiomyopathy (HOCM), nonobstructive hypertrophic cardiomyopathy (HNCM), and apical hypertrophy (APH). The spatial characteristics of the U loop were examined qualitatively and quantitatively and were correlated with echocardiographic findings. The magnitude of the U loop was significantly larger in the HCM group, especially in the APH subgroup, than in the normal subjects, but it was not larger in the DCM group. The maximum U vector was significantly displaced anteriorly and to the right in the DCM and HCM groups, especially the APH and HNCM subgroups. In the HNCM and APH subgroups, the magnitude of the U loop correlated significantly with the thickness of the posterior wall of the left ventricle, but not with that of the interventricular septum. These findings suggest that the U loop is related to hypertrophy of the apex and the posterior wall of the left ventricle.
Q Yang, K Kiyoshige, T Fujimoto, M Katayama, K Fujino, Ken Saito, Yutaka Nakaya and H Mori : Signal-averaging electrocardiogram in patients with diabetes mellitus, Japanese Heart Journal, Vol.31, No.1, 25-33, 1990.
Kimiko Nakayasu, Yutaka Nakaya, S. Ishihara, Masahiro Nomura and H. Mori : Isomagnetic maps in normal subjects. Comparison with isopotential maps, CV World Report, Vol.3, No.1, 22-27, 1990.
Hideaki Nii, Yutaka Nakaya, Shuichiro Nakaya, Tetsuzo Wakatsuki, Yukiko Miyoshi, Hirohumi Yamamoto, Akiyoshi Nishikado, Kazuya Fujino, Shigenobu Bando and Hiroyoshi Mori : Alteration of Strength-Interval Relation by Class I Antiarrhythmic Drugs in Normal and K-Depolarized Cardiac Muscle Fibers, Jpn J Appl Physiol(Japanese journal of applied physiology), Vol.20, No.5, 351-358, 1990.
片山 まり子, Masahiro Nomura, 藤野 和也, Yutaka Nakaya and 森 博愛 : 心磁図法によるWPW症候群の副伝導路存在部位の推定, The Journal of Japan Biomagnetism and Bioelectromagnetics Society, Vol.3, 24-31, 1990.
290.
Kimiko Nakayasu, Yutaka Nakaya, Masahiro Nomura, S Ishihara and H Mori : Isomagnetic map of normal subjects - Comparison with isopotential map, CV. World Report, Vol.3, 22-27, 1990.
291.
K Kiyoshige, T Fujimoto, Mariko Katayama, Masahiro Nomura, H Yamamoto, Akiyoshi Nishikado, S Bando, Yutaka Nakaya and H Mori : U wave of high-speed and magnified electrocardiogram in left ventricular overloading, American Journal of Noninvasive Cardiology, Vol.4, 302-308, 1990.
292.
Yutaka Nakaya, Hideaki Nii, Masahiro Nomura, Kazuya Fujino and Hiroyoshi Mori : Effects of lidocaine and quinidine on post-repolarization refractoriness after the basic and premature action potentials: consideration of aim of antiarrhythmic drug therapy, American Heart Journal, Vol.118, No.5 Part 1, 907-912, 1989.
(Summary)
Antiarrhythmic drugs are often more effective in suppressing ventricular tachycardias than are background premature extrasystoles. The mechanism of action of these agents was examined by studies on the effects of lidocaine and quinidine on post-repolarization refractoriness of both basic and premature action potentials. In the absence of antiarrhythmic drugs, the excitability threshold was relatively constant after the end of repolarization of both basic and premature action potentials. In the presence of lidocaine or quinidine, the strength-interval curves were shifted to the right and superiorly, and the two drugs had different effects on the course of the strength-interval curve and Vmax recovery, presumably due to use-dependent V max block. Moreover, depressions of Vmax and excitability were more marked after the premature action potential than after the basic action potential. These results suggest that lidocaine and quinidine cause more depression of the excitability of second premature contractions than of first premature contractions, and also indicate that for protection against sustained ventricular tachycardias, it may not be necessary to suppress chronic premature ventricular contractions.
Q Yang, K Kiyoshige, T Fujimoto, M Katayama, K Fujino, Ken Saito, Yutaka Nakaya and H Mori : Vector U loop in patients with old myocardial infarction, Clinical Cardiology, Vol.12, No.5, 277-282, 1989.
(Summary)
The U loop of the vectorcardiogram was examined qualitatively and quantitatively in 100 normal subjects and 67 patients with old myocardial infarction, using a direct-writing vectorcardiograph with memory function. In the control group, the U loop was directed to the left, anteriorly and inferiorly, and it was inscribed counterclockwise in the horizontal plane. In patients with anterior myocardial infarction, the U loop tended to be displaced to the right, and in patients with inferior myocardial infarction to the right and superiorly. The shape of the U loop in patients was also different from that of normal subjects. The maximum U vector was significantly smaller in magnitude both in patients with anterior and inferior myocardial infarction than that of normal subjects (p less than 0.01). In patients with ventricular aneurysm, the magnitude of the maximum U vector was significantly smaller and its direction was displaced more to the right and posteriorly than those without aneurysm (p less than 0.01). In standard 12-lead electrocardiogram (ECG), observation of the U wave in patients with old myocardial infarction was difficult, especially in the limb lead, because of the small size of the U wave. Therefore, vectorcardiographic observation may be more useful than electrocardiographic observation for the analysis of the U wave in patients with old myocardial infarction.
(Keyword)
U wave / U loop / vectorcardiogram / old myocardial infarction
Kimiko Nakayasu, 大木 祐子, 中筋 恵美, Yutaka Nakaya and 森 博愛 : Importance of Long-Term Follow-UpStudies on Health Check-Up : Relation between Electrocardiogram andHypertention, Journal of health sciences, Faculty of Integrated Arts and Sciences, the University of Tokushima, Vol.1, 1-14, 1989.
Masahiro Nomura, Yutaka Nakaya, K Fujino, S Ishihara, M Katayama, A Takeuchi, K Watanabe, Y Hiasa, T Aihara and H Mori : Magnetocardiographic studies of ventricular repolarization in old inferior myocardial infarction, European Heart Journal, Vol.10, No.1, 8-15, 1989.
(Summary)
Isomagnetic maps of 50 normal subjects (control group) and 23 patients with old inferior myocardial infarction (IMI group) were recorded in order to analyse T wave abnormalities in inferior myocardial infarction. The T wave of the magnetocardiogram (MCG) in the control group showed negative deflections in the left upper portion and positive deflections in the right lower portion, thus resulting in a T vector directed leftward and inferiorly. The T wave of the IMI group was flat or positive in the left upper portion and flat or negative in the right lower portion, suggesting a T vector directed superiorly. In addition, opposing dipoles were observed in 36.4% of the IMI group; i.e. one directed superiorly, presumably due to inferior myocardial ischaemia, and the other directed inferiorly due to normal repolarization. Localized T vector abnormalities could be detected by the MCG in some cases, in which coronary T waves of the standard electrocardiogram had returned to normal. Furthermore, multiple dipoles were more frequently observed in the isomagnetic map than in the isopotential map (5 vs. 15; P less than 0.01). These results suggest that the MCG is helpful in diagnosing myocardial ischaemia when this is not detectable on the electrocardiogram.
Yutaka Nakaya, Masahiro Nomura, K Fujino, S Ishihara and H Mori : The T wave abnormality in the magnetocardiogram, Frontiers Med. Bio. Eng., Vol.1, 183-192, 1989.
302.
M Katayama, Masahiro Nomura and Yutaka Nakaya : QRS wave of the magnetocardiogram in right ventricular overloading: Correlation with right ventricular pressure, Am. J. Noninvasive Cardiol, Vol.3, 110-115, 1989.
303.
A Takeuchi, K Watanabe, M Katayama, Masahiro Nomura, Yutaka Nakaya and H Mori : Magnetic field of atrial depolarization, Medical Progress Through Technology, Vol.14, No.2, 73-80, 1989.
(Summary)
The isomagnetic maps of normal subjects and patients with right and left atrial overloading were recorded to determine the characteristic features of the magnetic field of atrial depolarization. The isomagnetic maps examined in this study indicated the instantaneous current source, which specifically localizes the current sources due to the right and left atria, respectively. The magnetic field recorded with a second derivative gradiometer clearly detected the cardiac current source from the right atrium, which is located close to the anterior chest wall, thus this method improved the diagnostic sensitivity for right atrial overloading. In patients with left atrial overloading, the isomagnetic map showed multiple dipoles due to the right and left atria, respectively, which are difficult to be detected by the electrocardiogram or isopotential map. These results suggest that the magnetocardiogram provides useful information on the current source to supplement information obtained by the conventional electrocardiogram.
Akemi Takeuchi, Katsusuke Watanabe, Masahiro Nomura, Shigeki Ishihara, Masaki Sumi, Masaru Murakami, Ken Saito, Yutaka Nakaya and Hiroyoshi Mori : The P wave in the magnetocardiogram, Journal of Electrocardiology, Vol.21, No.2, 161-167, 1988.
(Summary)
The P wave of the magnetocardiogram (MCG) was investigated in normal subjects and in patients with right and left atrial overloading. In normal subjects, the MCG P wave was positive at right lower sternal sites and negative in the other portions. The current source deduced from the MCG and the isomagnetic map was directed inferiorly and to the left throughout the entire phase of atrial activation. In patients with right atrial overloading, the direction of the current source deduced from the MCG was similar to that of normal subjects, but its amplitude was significantly greater. In left atrial overloadings, a negative-positive biphasic P wave was seen more frequently than in normal subjects at left parasternal sites. In the late phase of atrial activation, the MCG could detect the two dipoles, i.e. one directed inferiorly and other directed to the left. These dipoles might correspond to right and left atrial activities, respectively. These results show that the MCG might add useful information on current source to the conventional electrocardiogram.
Yutaka Nakaya, Akemi Takeuchi, Hideaki Nii, S Ishihara, Masahiro Nomura, Kazuya Fujino, Ken Saito and Hiroyoshi Mori : Isomagnetic maps in right ventricular overloading, Journal of Electrocardiology, Vol.21, No.2, 168-173, 1988.
(Summary)
Isomagnetic maps were recorded in normal subjects and in patients with systolic overloading of the right ventricle. The isomagnetic maps examined in this study indicated the instantaneous current source of the heart by applying the "corkscrew rule." The magnetic field recorded by a second derivative gradiometer detected clearly the cardiac current source from the right ventricle, which is located close to the anterior chest wall, and improved diagnostic sensitivity. Moreover, the isomagnetic map showed multiple dipoles, which are difficult to detect in the electrocardiogram or isopotential map. These results suggest that the magnetocardiogram provides useful information on current sources to supplement information obtained by the conventional electrocardiogram.
Masahiro Nomura, Kazuya Fujino, Mariko Katayama, Akemi Takeuchi, Yoshiharu Fukuda, Masaki Sumi, Masaru Murakami, Yutaka Nakaya and Hiroyoshi Mori : Analysis of the T wave of the magnetocardiogram in patients with essential hypertension by means of isomagnetic and vector arrow maps, Journal of Electrocardiology, Vol.21, No.2, 174-182, 1988.
T Fujimoto, K Kiyoshige, Ken Saito, Masahiro Nomura, Q Yang, Yutaka Nakaya and H Mori : Vector U loop in patients with left ventricular overloading, Am. J. Noninvasive. Cardiol, Vol.2, 224-231, 1988.
320.
Mieko Ueki, Yutaka Nakaya, Kazuya Fujino, Masahiro Nomura, Yasunori Saito, Takashi Fujimoto, Koichi Kiyoshige, Ken Saito, Yoshikazu Hiasa and Hiroyoshi Mori : Vector U loop in patients with right ventricular overloading, Journal of Electrocardiology, Vol.20, No.5, 383-390, 1987.
(Summary)
The U loop of the vectorcardiogram (VCG) was examined qualitatively and quantitatively in 126 normal subjects, 15 subjects with complete right bundle branch block (CRBBB group) and 58 patients with right ventricular overloading (RVO group), using a direct-writing vectorcardiograph with memory function. In normal subjects the U loop was directed similarly to the T loop, i.e., to the left, anteriorly and inferiorly. In the CRBBB group, maximum U vector was smaller, but its direction was not significantly different from that in normal subjects. In the RVO group, the U loop tended to be displaced posteriorly and to the left and was significantly greater in magnitude than that in normal subjects in the horizontal (P less than 0.01) and frontal (P less than 0.001) planes. In the RVO group, a good correlation was found between the direction of maximum U vector and right ventricular systolic pressure. In some cases of the RVO group, the U loop was the only abnormality suggesting right ventricular overloading. These findings suggest that abnormality of the U loop is a good indicator in a diagnosis of right ventricular overloading.
Yutaka Nakaya, Masahiro Nomura and 森 博愛 : 心磁界計測による心室再分極の検討, Japanese Journal of Medical Electronics and Biological Engineering, Vol.25, 20-21, 1987.
324.
Masaki Sumi, Akemi Takeuchi, Mariko Katayama, Yoshiharu Fukuda, Masahiro Nomura, Kazuya Fujino, Masaru Murakami, Yutaka Nakaya and Hiroyoshi Mori : Magnetocardiographic P waves in normal subjects and patients with mitral stenosis, Japanese Heart Journal, Vol.27, No.5, 621-633, 1986.
(Summary)
The P wave of the magnetocardiogram (MCG) was investigated in normal subjects and patients with mitral stenosis to determine its characteristics in normal conditions and left atrial overloading (LAO) and to analyze atrial activation by a magnetic field. In normal subjects, the MCG P wave was negative in left parasternal sites and positive in right lower sternal sites. The current source deduced from the MCG pattern and isomagnetic map was directed inferiorly and to the left through the entire phase of atrial activation, suggesting that in most normal cases the P wave reflects right atrial activity. In patients with mitral stenosis, a negative-positive biphasic P wave was seen more frequently than in normal subjects in left parasternal sites (p less than 0.005). In the late phase of atrial activation, the current source deduced from the isomagnetic map was shifted superiorly and to the left, suggesting an increased leftward force due to LAO. The MCG was similar in sensitivity to the ECG, for diagnosis of LAO, but in a few cases LAO could be detected from the MCG but not the ECG. These findings suggest that the MCG is clinically useful for diagnosis of LAO.
Masahiro Nomura, Yutaka Nakaya, Akiyoshi Nishikado, 斎藤 憲 and Susumu Ito : 心筋梗塞様心電図, 老年病診療Q&A, Vol.40, 840-841, 2003.
4.
Masahiro Nomura, Tetsuya Saijyo, Y Haruta, H Itozaki, H Toyoda, Yutaka Nakaya, Susumu Ito and H Kado : Biomagnetic measurement of gastric mechanical motility using a high-temperature SQUID imaging., In Biomag 96, Vol.IV, 624-627, 2000.
F Kishi, Masahiro Nomura, M Yukinaka, Ken Saito, Yutaka Nakaya and Susumu Ito : Source localization of initial QRS vector in patients with idiopathic cardiomyopathy : Comparison with normal subjects and patients with anterior myocardial infarction., In Biomag 96, 475-478, 2000.
Yutaka Nakaya, Nagakatsu Harada, Kazuaki Mawatari, Akira Takahashi and Toshio Hosaka : Control of hypertension in metabolic syndrome, Shikoku Acta Medica, Vol.63, No.3,4, 97-100, Aug. 2007.
(Summary)
Metabolic syndrome includes abdominal obesity, hyperlipidemia, diabetes, and hypertension. All, but hypertension, are obviously related to metabolism. However, hypertension might result from, at least in part, abdominal obesity, because adipose tissue produces bioactive mediators (adipocytokines)which increase blood pressure. In treatment of hypertension, we should concern insulin resistance, which is a major risk factor of cardiovascular events. Angiotensin converting enzyme inhibitor is known to improve insulin resistance, but results of angiotensin receptor blocker in animal studies are controversial. In clinical trial, there are many established data that ARBs prevent new onset of diabetes mellitus, suggesting that this agent also has a beneficial effect on glucose metabolism. Short acting Ca-antagonists, such as nifedipine, decrease insulin sensitivity, but long-acting Ca-antagonists increase it. βblockers decrease insulin sensitivity but those with α-blocking action improve insulin resistance. Recent study, ARB is more potent to reduce cardiovascular risk in those with obesity than in those with normal body weight, suggesting some drugs are more effective in metabolic syndrome. Thus, when we chose antihypertensive drugs in treating patients with metabolic syndrome, we have to choose proper drugs in addition to modify life-style.
Yutaka Nakaya, Kazuaki Mawatari, Akira Takahashi, Nagakatsu Harada, Hata Akiko and Yasui Sonoko : The phytoestrogen ginsensoside Re activates potassium channels of vascular smooth muscle cells through PI3K/Akt and nitric oxide pathways, The Journal of Medical Investigation : JMI, Vol.54, No.3,4, 381-384, Aug. 2007.
(Summary)
In vascular smooth muscle cells, large-conductance Ca(2+)-activated K(+) channels (K(Ca) channels) play a pivotal role in determining membrane potential, and thereby the vascular tone. Ginsenoside Re, a phytochemical from ginseng, is reported to activate this channel, but its precise mechanism is unsolved. Patch clamp studies showed that ginsenoside Re activates K(Ca) channels in the arterial smooth muscle cell line A10 in a dose-dependent manner. The channel-opening effect of ginsenoside Re was inhibited by 1 microM L-NIO, an inhibitor of eNOS, but not by 3 microM SMTC, an inhibitor of nNOS, indicating that ginsenoside Re activated K(Ca) channels through activation of eNOS. SH-6 (10 microM), an Akt inhibitor, and wortmannin, a PI3-kinase inhibitor, completely blocked activation of K(Ca) channels by ginsenoside Re, indicating that it activates eNOS via a c-Src/PI3-kinase/Akt-dependent mechanism. In addition, the ginsenoside Re-induced activation of eNOS and K(Ca) channel was blocked by 10 microM ICI 182, 780, an inhibitor of membrane estrogen receptor-alpha, suggesting that eNOS activation occurs via a non-genomic pathway of this receptor. In conclusion, ginsenoside Re releases NO via a membrane sex steroid receptors, resulting in K(Ca) channel activation in vascular smooth muscle cells, promoting vasodilation and preventing severe arterial contraction.
S Nishimoto, Daiju Fukuda, Michio Shimabukuro, Shusuke Yagi, Takeshi Soeki, Hiroshi Sakaue, Yutaka Nakaya and Masataka Sata : Macrophage Toll-like Receptor 9 Signaling Contributes to the Development of Insulin Resistance through the Promotion of Inflammation in Adipose Tissue., American Heart Association AHA 2013, Dallas, Nov. 2013.
2.
S Nishimoto, Daiju Fukuda, Michio Shimabukuro, S Matsumoto, Masayoshi Ishida, Shusuke Yagi, Takeshi Soeki, Hiroshi Sakaue, Yutaka Nakaya and Masataka Sata : Genetic ablation of TLR9 improves insulin resistance through macrophage accumulation in adipose tissue., ESC Congress 2013, Amsterdam, Aug. 2013.
3.
H. Sato, Michio Shimabukuro, Y. Hirata, Hirofumi Izaki, M. Higashida, Hirotsugu Kurobe, Hiro-omi Kanayama, Hiroshi Sakaue, Yutaka Nakaya and Masataka Sata : Region-specific regulation of the innate immune system, NLRP3 inflammasome, in human abdominal adipose tissue., ESC Congress 2012, Munich, Aug. 2012.
4.
H. Sato, Y. Hirata, Michio Shimabukuro, M. Tabata, Hirotsugu Kurobe, M. Higashida, S. Takanashi, Yutaka Nakaya, Tetsuya Kitagawa and Masataka Sata : The innate immune system, NLRP3 inflammasome, in epicardial adipose tissue intensifies human coronary atherosclerosis., ESC Congress 2012, Munich, Aug. 2012.
5.
M. Higashida, Y. Hirata, Hirotsugu Kurobe, Yutaka Nakaya, Tetsuya Kitagawa and Masataka Sata : HMGB1 Signal via TLR9 Plays Critical Role in Vascular Remodeling., AHA Scientific Sessions 2011, Orlando, Nov. 2011.
6.
M. Higashida, Y. Hirata, Hirotsugu Kurobe, Yutaka Nakaya, Tetsuya Kitagawa and Masataka Sata : HMGB1/TLR9 pathway plays a critical role in chronic inflammation and vascular remodeling after endovascular injury., ESC Congress 2011, Paris, Aug. 2011.
7.
Y. Hirata, Hirotsugu Kurobe, M. Higashida, Yutaka Nakaya, Tetsuya Kitagawa and Masataka Sata : GLP-1 receptor agonist attenuates vascular remodeling after endovascular injury., ESC Congress 2011, Paris, Aug. 2011.
8.
Rie Tsutsumi, Kazuaki Mawatari, Katayama Erika, Yutaka Nakaya and Yasuo Tsutsumi : Compound K produces cardiac protection by activating Akt phosphorylation., Experimental Biology Annual Meeting, Anaheim, California, Apr. 2010.
9.
E Katayama, Rie Tsutsumi, Yutaka Nakaya, K Hirose, K Tanaka, S Oshita and Yasuo Tsutsumi : Role of mTOR/p70S6K in amino acid-induced caediac protection., Experimental Biology 2010(American Siciety for Nutrition), Anaheim,CA, Apr. 2010.
10.
Yutaka Nakaya, Shimohata Takaaki, Haraguchi Sayaka, Nakao Toshiyuki, Minaguchi Jun, Sumitani Haruo, Nagakatsu Harada and Hiroshi Sakaue : Severe Catabolic State After An Overnight Fast In Patients With Chronic Renal Failure, 31stESPEN Congress, Wien, Aug. 2009.
11.
LI QINKAI, Toshio Hosaka, JAMBALDORJ BAYASGLAN, Yutaka Nakaya and Makoto Funaki : Extracellular Matrix with the Rigidity of Adipose Tissues Helps 3T3-L1 Adipocytes Maintain Insulin Responsiveness, The American Diabetes Association 69th Scientific Sessions, New Orleans, Jun. 2009.
12.
Emi Shuto, Yutaka Taketani, R Tanaka, Ayako Tanimura, T Uebanso, M Isshiki, Nagakatsu Harada, Hironori Yamamoto, Yutaka Nakaya and Eiji Takeda : Postprandial Hyperphosphatemia is a Novel Risk Factor for Cardiovascular Disease by Involving Endothelial Dysfunction, American Society of Bone and Mineral Research 30th ANNUAL MEETING, Montreal, Sep. 2008.
13.
Li Qinkai, Toshio Hosaka, Jambaldorj Bayasglan, Otsuka Ryo, Hirata Yohko, Teshigawara Kiyoshi, Chisato Kosugi, Yutaka Nakaya and Makoto Funaki : Serotonin Induces Insulin-Resistance in 3T3-L1 Adipocytes, 68th scientific sessions American Diabetes Association, San Francisco, Jun. 2008.
14.
Akira Takahashi, M. Nakano, Kazuaki Mawatari, Nagakatsu Harada and Yutaka Nakaya : Vibrio cholerae El tor Hemolysin Activates Cyclic AMT Dependent Cl-Secretory Pathways which Xaused Diarrhea, 108th General Meeting of the American Society for Microbiology, Boston, Jun. 2008.
15.
Hamamoto Akiko, Akira Takahashi, Nakano Masayuki, Lian Xin, Tachibana Satoko, Yagi Noriyuki, Tetutani Kayo, Masayuki Yamato, Masatake Akutagawa, Toshitaka Ikehara, Yutaka Nakaya and Yohsuke Kinouchi : Availability of UVA-light emitting diodes for disinfection system, 第22回生体・生理工学シンポジウム, Harbin, Jan. 2008.
16.
Lian Xin, Akira Takahashi, Maeda Miku, Yagi Noriyuki, Tachibana Satoko, Masayuki Yamato, Hamamoto Akiko, Masatake Akutagawa, Nakano Masayuki, Yutaka Nakaya and Yohsuke Kinouchi : New surface sterilization system using UV-LED for vegetables, Proceedings of the International Symposium on Biological and Physiological Engineering /The 22nd SICE Symposium on Biological and Physiological Engineering, 257-259, Harbin, Jan. 2008.
(Keyword)
UV-LED / surface / sterilization / 365nm
17.
Lian Xin, Akira Takahashi, Nakano Masayuki and Yutaka Nakaya : Vibrio parahaemolyticus elevates interferon alpha production in intestinal-like epithelial cells CACO-2 cells, VIBRIO 2007(The second conference on the Biology of Vibrios), Paris, Nov. 2007.
18.
Nakano Masayuki, Akira Takahashi and Yutaka Nakaya : Adrenergic regulation of Vibrio parahaemolyticus pathogenicity by the modulation of viburence-associated gene expressions, VIBRIO 2007(The second conference on the Biology of Vibrios), Paris, Nov. 2007.
19.
Yutaka Nakaya : Modulation of potassium channels in cardiovascular and neural cells by ginsenoside Re a possible mechanism for coping stress, 10th Asian Congress of Nutrition, Taipei, Sep. 2007.
20.
Morishima Masaki, Yutaka Nakaya and Ono Katsushige : High-intensity voluntary exercise attenuates cardiac sympathetic activity in SPORTS (Spontaneously-Running-Tokushima- Shikoku) rats., Internal society for Heart Research, Italy, Jun. 2007.
21.
Hamamoto Akiko, Mori Mirei, Nakano Masayuki, Wakikawa Noriko, Toshitaka Ikehara, Yohsuke Kinouchi, Masatake Akutagawa, Akira Takahashi and Yutaka Nakaya : Water disinfection system using UVA-light emitting diodes and its effects on bacterial DNA., 107th ASM general meeting, Toronto,Canada, May 2007.
22.
Akira Takahashi, Nakano Masayuki, Miyoshi Shinichi, Hamamoto Akiko and Yutaka Nakaya : Pore formation of Vibrio mimicus hemolysin in lipid bilayers., 107th ASM general meeting, Toronto, Canada, May 2007.
23.
Nhien Van Nguyen, Khan Cong Nguyen, Ninh Xuan Nguen, Yabutani Tomoki, Kassu Afework, Motonaka Junko, Fusao Ota and Yutaka Nakaya : Micronutrient deficiencies among Primary School Children in Vietnam, Consequences and Control of Micronutrient Deficiences, Istanbul, Apr. 2007.
24.
Akira Takahashi, Hamamoto Akiko, Wakikawa Noriko, Mori Mirei, Nakano Masayuki, Masatake Akutagawa, Yohsuke Kinouchi and Yutaka Nakaya : New water sterilization system used by UVA-LED., The 41st Joint Conference US-Japan Cooperative Medical Science Program Cholera Panel, Gifu, Japan, Nov. 2006.
25.
Nakano Masayuki, Akira Takahashi and Yutaka Nakaya : Norepinephrine modulates the pathogencity of Vibrio parahaemolyticus., The 41st Joint Conference US-Japan Cooperative Medical Science Program Cholera Panel, Gifu, Japan, Nov. 2006.
26.
Sachiko Chikahisa, Hiroyoshi Sei, Masaki Morishima, Atsuko Sano, Kazuyoshi Kitaoka, Yutaka Nakaya and Yusuke Morita : Exposure to music in the perinatal period enhances learning performance and alters BDNF/TrkB signaling in mice as adults, Neuroscience 2006, Atlanta, USA, Oct. 2006.
27.
Morishima Masaki, Akira Takahashi and Yutaka Nakaya : Transthyretin and serotonin levels in the hippocampus are decreased in SPORTS rats., 36th Society for Neuroscience, Atlanta, USA, Oct. 2006.
28.
Morishima Masaki, Nagakatsu Harada, Hara Sayuri, Akira Takahashi and Yutaka Nakaya : Hippocampal norepinephrine (NE) level and exercise behavior in SPORTS rats., 15th Annual Meeting of the International Behavioral Neuroscience Society, Briitish Columbia, Canada, May 2006.
29.
Akiko Hamamoto, Masayuki Nakano, Toshitaka Ikehara, Masatake Akutagawa, Yohsuke Kinouchi, Yutaka Nakaya and Akira Takahashi : A new water sterilization system which use UVA-light emitting diode (Q-401)., 106th ASM general meeting, Florida, USA, May 2006.
30.
Nakano Masayuki, Akira Takahashi, Sakai Yuko and Yutaka Nakaya : Response of Vibrio parahaemolytiocus to neuroendcrine hormone norepinephrine (D-026)., 106th ASM general meeting, Florida,USA, May 2006.
31.
Nakano Masayuki, Akira Takahashi, Sakai Yuko and Yutaka Nakaya : Norepinephrine modulates the pathogenicity of Vibrio parahameolyticus., 11th Asian conference on diarrhoeal diseases and nutrition, Bangkok, Mar. 2006.
32.
Yutaka Nakaya, Okita Kiwamu, Kato Akinobu, Miwa Toshiyuki, Suzuki Kazuyuki and Moriwaki Hisataka : Randamized trial of branched chain amino acid rich supplement against carbohydrate rich snaks as a late evening snack in patients with liver cirrhosis., TheLiver Meeting-AASLD's 56th Annual Meeting, San Francisco, Nov. 2005.
33.
Hiroyuki Sakakibara, Kaori Ishida, Yuki Izawa, Yuko Minami, Satomi Saito, Yoshichika Kawai, Butterweck Veronika, Toshiaki Tamaki, Yutaka Nakaya and Junji Terao : Effects of Ginkgo biloba Extract on Rat brain Function, 2nd International Conference on Polyphenols and Health, California Davis, Davis, Oct. 2005.
34.
Yutaka Nakaya, Okita Kiwamu, Kato Akinobu, Miwa Toshiyuki, Suzuki Kazuyuki and Moriwaki Hisataka : Hisataka Moriwaki Branched chain amino acid-mixture as a late evening snack but not carbohydrate-rich snack improved nutrutional states, The 11th congress of parenteral and enteral nutrition society of Asia, Seoul, Oct. 2005.
35.
Yutaka Nakaya : Diabetes, insulin resistance and cardiovascular disease, The 8th Iranian Congress of Biochemistry and the First International Congress of Biochemistry and Molecular Biology, Tehran, Iran, Sep. 2005.
36.
Hiroyuki Sakakibara, Kaori Ishida, Yuki Izawa, Yuko Minami, Saito Saromi, Yoshichika Kawai, Butterweck Veronika, Toshiaki Tamaki, Yutaka Nakaya and Junji Terao : Effects of forced swimming stress on rat brain function, 2005 COE International Conference ''Biological Mechanism for Stress Control'', Tokushima, Aug. 2005.
37.
Nakano Masayuki, Akira Takahashi, Sakai Yuko and Yutaka Nakaya : Response of enteropathogen to neuroendocrine hormone ., COE international conference on biological mechanism for stress control, Tokushima, Japan, Aug. 2005.
38.
Akira Takahashi, Nakano Masayuki, Miyoshi Shinichi, Nagakatsu Harada and Yutaka Nakaya : (B-053) Hemolysin produced by Vibrio mimicus activates two Cl- secretory pathways in cultured intestinal-like cells., 105th American society for microbiology general meeting, Atlanta, Georgia, USA, Jun. 2005.
39.
Masahiro Nomura, Yutaka Nakaya, Susumu Ito and Hideo Itozaki : Visualization of cardiac electrical current using 32-channel high temperature superconducting quantum interference device, Biomag2004, 632-633, Boston, Aug. 2004.
40.
Masahiro Nomura, Yutaka Nakaya, Akiyoshi Nishikado, Kunihiko Koshiba, Kouji Yamaguchi, Tomohito Kawano and Susumu Ito : Autonomic nervous activity and QT dispersion common bile duct treatment during endoscopic retrograde cholangiopancreaticography: correlation with cardiac accidents, The 31th International Congress on Electrocardiology, Kyoto, Jun. 2004.
41.
Masahiro Nomura, Yutaka Nakaya, Hitoshi Miyajima, Akiyoshi Nishikado, Kunihiko Koshiba, Koji Yamaguchi, Tomohito Kawano and Susumu Ito : Autonomic nervous activity and QT dispersion at common bile duct treatment during endoscopic retrograde cholangiopancreaticography: correlation with cardiac accidents, The 31th International Congress on Electrocardiology, Kyoto, Jun. 2004.
42.
Maki Toda, Hideki Nakanishi, Yutaka Nakaya, Hiroshi Harada, Ichiro Hashimoto, Hiromichi Sedo and Ikuno Kanda : Antithorombotic Effectireness of S.H. in Iniured Microvessels of Rabbit Ear, The 13th International Congress of the International Confederation for plastic, Reconstructive and Aesthetic Surgery, Sydney, Aug. 2003.
43.
Masahiro Nomura, Kohzou Uehara, Kenji Harada, Eiko Uemura, Akiko Iga, Akiyoshi Nishikado, Ken Saito, Yutaka Nakaya and Susumu Ito : Impairment of gastrointestinal motility by nitrate administration: Evaluation based on electrogastrographic changes and autonomic nervous activities, 10th Taisyo international symposium on gastroenterology, Shimoda, Apr. 2003.
44.
U Eiko, Masahiro Nomura, Kohzou Uehara, Naoki Muguruma, Seisuke Okamura, Yutaka Nakaya and Susumu Ito : , Influence in gastrointestinal endoscopy on circulatory dynamics: Relation with pulse wave velocity, The 7th Asia/Oceania Regional Congress of Gerontology, Tokyo, 2003.
45.
Masahiro Nomura, Yutaka Nakaya, Hitoshi Miyajima, Tomomi Nada, Yoshie Ochi, Ritsuko Kawaguchi, S Morishita, Akiyoshi Nishikado, Hiroshi Shibata, Hirohito Honda, Ken Saito and Susumu Ito : Detection of myocardial damage caused by hepatitis C virus using signal averaged electrocardiogram and 123I-BMIPP myocardial scintigraphy, The XXVIII International congress on electrocardiology, Sao Paulo,Brazil, 2001.
46.
Yoko Sakai, Hiroshi Kitahata, Yutaka Nakaya and Shuzo Oshita : Propofol-induced relaxation of rat aorta is altered by aging., The Annual Meeting of the American Society of Anesthesiologists, Vol.A-75, San Francisco, Oct. 2000.
47.
Hideki Matoba, Daisuke Sato, Sadaichi Sakamoto, Yasuharu Niwa and Yutaka Nakaya : Metabolic properties and capillarity of the skeletal muscle in Otsuka Long-Evans Tokushima Fatty rat, --- Metabolic properties and capillarity of the skeletal muscle in Otsuka Long-Evans Tokushima Fatty rat ---, Physiologist, Vol.43, 326, Portland, Jan. 2000.
48.
Yasuo Tsutsumi, Shuzo Oshita, Hiroshi Kitahata and Yutaka Nakaya : Effects of thiamylal on adenosine triphosphate-sensitive potassium (KATP) channels in single rat ventricular myocytes., The Annual Meeting of the American Society of Anesthesiologists, Dallas, Oct. 1999.
49.
Yuki Kondo, Masahiro Nomura, Hitoshi Miyajima, Tomomi Nada, Michiko Yukinaka, Susumu Ito and Yutaka Nakaya : Magnatic resonance coronary angiography in patients with ST-T changes during exercise, XXXIst Congress of the European Society of Cardiology, Barcelona, 1999.
50.
Hitoshi Miyajima, Masahiro Nomura, Yuki Kondo, Susumu Ito, Yutaka Nakaya, Masafumi Harada and Hiromu Nishitani : Coronary artery hemodynamics using FCARD PC method in patients with essential hypertension, The 72th Sicentific sessions of American Heart Association, Atlanta, 1999.
51.
Hitoshi Miyajima, Masahiro Nomura, Tomomi Nada, Naoki Muguruma, Toshiya Okahisa, Hiroshi Shibata, Seisuke Okamura, Hirohito Honda, Ichiro Shimizu, Susumu Ito and Yutaka Nakaya : Abnormal gastric motility in liver cirrhosis: Effect of autonomic nervous function and volume of portal blood flow, The 7th United European Gastroenterology Week, Roma,Italy, 1999.
52.
Yasuo Tsutsumi, Shuzo Oshita, Hiroshi Kitahata and Yutaka Nakaya : Effects of thiamylal on ATP-sensitive potassium channels in single rat ventricular myocytes., 5th America-Japan Anesthesia Congress, Matsuyama, Oct. 1998.
53.
Tomoko Wada, Hiroshi Kitahata, Hideyuki Kimura, Yutaka Nakaya and Shuzo Oshita : Effects of endothelin (1-31) on tracheal and aortic smooth muscles in rat., The Annual Meeting of the American Society of Anesthesiologists, Orlando, Oct. 1998.
54.
Michiko Yukinaka, Masahiro Nomura, Tomomi Mitani, Yuki Kondo, Takashi Oki, Susumu Ito and Yutaka Nakaya : Examination of the coronary artery flow velocity by magnetic resonance coronary angiography (MRCA) before and after PTCA -Prediction for restenosis-, XXth Congress of the European Society of Cardiology, Wien, 1998.
55.
Michiko Yukinaka, Masahiro Nomura, Tomomi Nada, Yuki Kondo, Ken Saito, Susumu Ito and Yutaka Nakaya : QTc Dispersion using magnetocardiogram: Analysis in patients with myocardial infarction, The 11th International Conference on Biomagnetism, Sendai, 1998.
56.
Yuki Kondo, Masahiro Nomura, Yutaka Nakaya, Tomomi Nada, Michiko Yukinaka, Susumu Ito, Hideo Itozaki and R Nagaishi : Magnetocardiographic measurement using a high-temperature SQUID in healthy subjects: comparison with conventional low-temperature SQUID system, The 11th International Conference on Biomagnetism, Sendai, 1998.
57.
Yuki Kondo, Masahiro Nomura, Tomomi Nada, Michiko Yukinaka, Ken Saito, Susumu Ito and Yutaka Nakaya : Biomagnetic measurement of small intestine electrical activity by 64-channel magnetographic imaging, The 11th International Conference on Biomagnetism, Sendai, 1998.
58.
Michiko Yukinaka, K Tezuka, Masahiro Nomura, Toru Hayashi, T Torisu, Y Takeuchi, Yuki Kondo, Ken Saito, Susumu Ito and Yutaka Nakaya : 1/f fluctuation of heart rate during colon fiberscopy, World Congresses of Gastroenterology, Wien, 1998.
59.
Yuki Kondo, Masahiro Nomura, Michiko Yukinaka, Tomomi Mitani, Ken Saito, Hirohito Honda, Ichiro Shimizu, Susumu Ito and Yutaka Nakaya : Myocardial injury on injections of interferon in patients with chronic hepatitis: assessment by myocardial scintigraphy, World Congresses of Gastroenterology, Wien, 1998.
60.
Yuki Kondo, Masahiro Nomura, Tomomi Mitani, Michiko Yukinaka, Ken Saito, Hirohito Honda, Ichiro Shimizu, Yutaka Nakaya and Susumu Ito : Clinical significance of 1/f fluctuation of 24-hour heart rate variability: studies in liver cirrhosis, The 11th Biannual scientific meeting Asian Pacific association for the study of liver, Perth, 1998.
61.
Michiko Yukinaka, Masahiro Nomura, Tomomi Mitani, Yuki Kondo, Ken Saito, Hirohito Honda, Ichiro Shimizu, Yutaka Nakaya and Susumu Ito : Production of nitric oxide and sympathetic nervous dysfunction in patients with liver cirrhosis, The 11th Biannual scientific meeting Asian Pacific association for the study of liver, Perth, 1998.
62.
Tomomi Mitani, Masahiro Nomura, Yuki Kondo, Michiko Yukinaka, Ken Saito, Hirohito Honda, Ichiro Shimizu, Yutaka Nakaya and Susumu Ito : Assessment of autonomic nervous activity in liver cirrhosis using blood pressure variability by tonometry, The 11th Biannual scientific meeting Asian Pacific association for the study of liver, Perth, 1998.
63.
Masahiro Nomura, Yuki Kondo, Tomomi Nada, Michiko Yukinaka, Ken Saito, Susumu Ito and Yutaka Nakaya : Biomagnetic measurement of small intestinal electrical activity by 64-channel magnetographic imaging, The 11th International Conference on Biomagnetism, Sendai, 1998.
64.
Yuki Kondo, Yutaka Nakaya, Masahiro Nomura, Michiko Yukinaka, Ken Saito and Susumu Ito : Clinical significance of 1/f fluctuation of 24-hour heart rate variability: studies in gastroenterological disease, The 6th United European Gastroenterology week, Birmingham, UK, 1997.
65.
Michiko Yukinaka, Masahiro Nomura, Yuki Kondo, Ken Saito, Yutaka Nakaya and Susumu Ito : Detection of sympathetic nervous dysfunction in patients with liver cirrhosis using 123I-metaiodobenzylguandine myocardial scintigraphy, The 6th United European Gastroenterology week, Birmingham, UK, 1997.
66.
Masahiro Nomura, Tetsuya Saijyo, Yasuhiro Haruta, Hideo Itozaki, Haruhisa Toyoda, Yutaka Nakaya, Susumu Ito and H Kado : Biomagnetic measurement of gastric mechanical motility using a high-temperature SQUID imaging, The 10th International Conference on Biomagnetism, Santa Fe, New Mexico, USA, 1996.
67.
Tetsuya Saijyo, Masahiro Nomura, Yasuhiro Haruta, Hideo Itozaki, Haruhisa Toyoda, Takeshi Ito, Yutaka Nakaya, Susumu Ito and H Kado : Magnetogastrograms using 64-channel SQUID system: study on clinical usefulness, The 10th International Conference on Biomagnetism, Santa Fe, New Mexico, USA, 1996.
68.
Fumiko Kishi, Masahiro Nomura, Yutaka Nakaya, Ken Saito and Susumu Ito : Source localization of initial QRS vector in patients with idiopathic cardiomyopathy: comparison with normal subjects and patients with anterior myocardial infarction, The 10th International Conference on Biomagnetism, Santa Fe, New Mexico, USA, 1996.
69.
Michiko Yukinaka, Yutaka Nakaya, Masahiro Nomura and Ken Saito : Analysis of electromotive force by magnatocardiogram - Is the origin of initial QRS force (septal vector) intraventricular septum?, The 10th International Conference on Biomagnetism, Santa Fe, New Mexico, USA, 1996.
70.
Masahiro Nomura, Yutaka Nakaya, Fumiko Kishi, Michiko Yukinaka, Ken Saito, Hiroshi Shibata and Susumu Ito : Heart rate variability during painful medical procedures (percutaneous ethanol injection therapy), The XXIIIrd International congress on Electrocardiology, Cleveland, USA, 1996.
71.
Tetsuya Saijo, Masahiro Nomura, Fumiko Kishi, Yasuhiro Haruta, Takeshi Ito, T Yoshida, Hideo Itozaki, H Toyoda, Yutaka Nakaya, Susumu Ito and Hisashi Kado : Biomagnetic measurement of small intestinal electrical activity by 64-channel magnetogastrographic imaging, Annual Meetings of the American Gastroenterological Association and American Association for the Study Liver Diseases at Digestive Disease Week, San Francisco, 1996.
72.
Tetsuya Saijo, Masahiro Nomura, Yutaka Nakaya, Ken Saito, Fumiko Kishi, Ichiro Shimizu, Susumu Ito, H Moritoki, Y Shiraishi, H Mima, Takashi Yamamoto, Hirofumi Yamamoto and Shunsuke Orino : Circadian rhythm of autonomic nervous function in patients with hepatic encephalopathy, Annual Meetings of the American Gastroenterological Association and American Association for the Study Liver Diseases at Digestive Disease Week, San Francisco, 1996.
73.
Hideki Matoba, Noriaki Miyagawa, Kimiko Nakayasu, Yutaka Nakaya, Masaharu Ohnaka, Masako Iwamoto and Kenji Shima : Influence of exercise and food intake on post-exercise carbohydrate and fat metabolism, FISU/CESU Conference The 18th Universiade 1995 Fukuoka ABSTRACT, p97, 1995.
74.
Tetsuya Saijo, Masahiro Nomura, Yasuhiro Haruta, Hideo Itozaki, Haruhisa Toyoda, Yutaka Nakaya, Susumu Ito and H Kado : Biomagnetic measurement of gastric electrical activity by 64-channel magnetocardiographic imaging, The 95th Annual meeting of the American Gastroenterological Asociation, San Diego, 1995.
75.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, Fumiko Kishi and Susumu Ito : Circadian profile of heart rate variability in mitral valve prolapse syndrome, XXI Internal Congress on Electrocardiology, Yokohama, 1994.
76.
Fumiko Kishi, Masahiro Nomura, Yutaka Nakaya, Ken Saito and Susumu Ito : Relationship between the ischemic myocardium and focus of ventricular tachycardia in old myocardial infarction, XXI Internal Congress on Electrocardiology, Yokohama, 1994.
77.
Tetsuya Saijyo, Masahiro Nomura, Yutaka Nakaya, Ken Saito, Fumiko Kishi and Susumu Ito : Time- and frequency-domain heart rate variability in patients with liver cirrhosis, XXI Internal Congress on Electrocardiology, Yokohama, 1994.
78.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, Fumiko Kishi, Susumu Ito, M Yoshizui, Itsuo Katoh, T Ohuchi and M Oka : Free and conjugated catecholamines before and after exercise in mitral valve prolapse, First World Congress on Stress, Bethesda, USA, 1994.
79.
Tetsuya Saijyo, Masahiro Nomura, Yutaka Nakaya, Ken Saito, Fumiko Kishi, Hirohito Honda, Ichiro Shimizu and Susumu Ito : Autonomic function during upper gastrointestinal endoscopy using blood pressure measurement by tonometry, First World Congress on Stress, Bethesda, USA, 1994.
80.
Hirokazu Miyoshi, Fumiko Kishi, K Watanabe, Masahiro Nomura, Ken Saito and Yutaka Nakaya : Nonendothelial-derived nitric oxide activates the K+ channels in cultured vascular smooth muscle cells, Tokyo Women's Medical international Symposium '94, Tokyo, 1994.
81.
Hirokazu Miyoshi, Fumiko Kishi, Masahiro Nomura, Ken Saito and Yutaka Nakaya : Muscle-derived nitric oxide produced greater vasodilative action than nitrovasolators, XIth Scientific Sessions of International Society for Heart Research Japanese Section, Tokyo, 1994.
82.
Tetsuya Saijo, Susumu Ito, Masahiro Nomura, Yutaka Nakaya, Ken Saito, Fumiko Kishi, H Fujikawa, W Shinohara, S Ohkita and Shunsuke Orino : Heart rate variability in peptic ulcer, The 95th Annual Meetings of the American Gastroenterological Association, New Orleans, 1994.
83.
Masahiro Nomura, Tetsuya Saijyo, Yutaka Nakaya, Ken Saito, Fumiko Kishi and Susumu Ito : Autonomic imbalance in liver cirrhosis, The 95th Annual Meetings of the American Gastroenterological Association, New Orleans, 1994.
84.
Tetsuya Saijo, Masahiro Nomura, Yutaka Nakaya, Fumiko Kishi, Ken Saito and Susumu Ito : Decreased variability of arterial blood pressure in patients with liver cirrhosis, The 10th World Congress of Gastroenterology, Los Angeles, 1994.
85.
Tetsuya Saijo, Masahiro Nomura, Yutaka Nakaya, Ken Saito, Fumiko Kishi, Susumu Ito, H Shinohara, H Yamamoto and Shunsuke Orino : Autonomic nervous imbalance during colon fiberscopy, 10th World Congress of Gastroenterology, Los Angeles, 1994.
86.
Masahiro Nomura, Tetsuya Saijyo, Yutaka Nakaya, Ken Saito, Shunsuke Orino and Susumu Ito : The autonomic factor in occurence of peptic ulcer associated with essential hypertension, The 10th World Congress of Gastroenterology, Los Angeles, 1994.
87.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, Fumiko Kishi, Hirokazu Miyoshi, Susumu Ito, Masao Wada, Satoshi Fujita, Tsutomu Takae and Itsuro Tamura : Atrial excitation onto the MRI using magnetocardiogram, The 9th International Conference on Biomagnetism, Wien, 1993.
88.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, Fumiko Kishi, Hirokazu Miyoshi, Susumu Ito, Masao Wada, Satoshi Fujita, Tsutomu Takae and Itsuro Tamura : Localization of the focus in ventricular tachycardia by magnetocardiogram, The 9th International Conference on Biomagnetism, Wien, 1993.
89.
Yutaka Nakaya, Masahiro Nomura, Ken Saito, F Kishi, Hirokazu Miyoshi, Akiyoshi Nishikado, Shigenobu Bando and Hiromu Nishitani : Comparative studies of magnetocardiographic and electrocardiographic mappings for localization of accessory pathway in WPW syndrome, The 9th International Conference on Biomagnetism, Wien, 1993.
90.
Ken Saito, Yutaka Nakaya, Masahiro Nomura, N Takeuchi, Naoki Muguruma, Fumiko Kishi, Hirokazu Miyoshi and Hiromu Nishitani : Study on the excitation process during ventricular depolarization in normal subjects by magnetocardiogram, The 9th International Conference on Biomagnetism, Wien, 1993.
91.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, I Tamura, M Wada, S Fujita and T Takae : Localization of early ventricular depolarization by magnetocardiogram in patients with WPW syndrome and ventricular tachycardia, American College of Cardiology 42nd Annual Scientific Session, Anaheim, 1993.
92.
Masahiro Nomura, Yutaka Nakaya, Ken Saito, Fumiko Kishi, Masao Wada, S Fujita, T Takae and I Tamura : Source localization of atrial excitation by three-dimensional magnetocardiographic imaging, American Heart Association 66th Scientific Sessions, Atlanta, 1993.
93.
Masahiro Nomura and Yutaka Nakaya : Fundamental of the cardiac arrhythmia, The 9th International Conference on Biomagnetism, Wien, 1993.
94.
Tetsuzo Wakatsuki, Yutaka Nakaya, Yukiko Miyoshi, XR Zeng, Masahiro Nomura, Ken Saito and Isao Inoue : Effect of vasopressin ATP-sensitive and Ca2+-activated K+ channels of coronary arterial smooth muscle cell, International Symposium "smooth muscle" -Assessment of current knowledges-, Fukuoka, 1992.
95.
Yukiko Miyoshi, Tetsuzo Wakatsuki, Masahiro Nomura, Ken Saito, Yutaka Nakaya and Isao Inoue : Endothelin blocks ATP-sensitive K+ channels and depolarizes smooth muscle cells of porcine artery, International Symposium "smooth muscle" -Assessment of current knowledges-, Fukuoka, 1992.
96.
Yutaka Nakaya, Masahiro Nomura, Kimiko Nakayasu, S. Bandou and Susumu Ito : Diagnosis of ventricular hypertrophy by single moving dipole, 8th International Conference on Biomagnetism., Munister,Germany, Aug. 1991.
Yutaka Nakaya, Masahiro Nomura, Kimiko Nakayasu, Tetsuzo Wakatsuki, Yukiko Miyoshi, Shigenobu Bando and Susumu Ito : Diagnosis of left ventricular hypertrophy by single moving dipole, The 8th International Conference on Biomagnetism, Münster, Germany, 1991.
98.
Masahiro Nomura, Kazuya Fujino and Yutaka Nakaya : The magnetocardiograms of left ventricular overloading, The 16th International congress on medical physicsand biomedical engineering, Kyoto, 1991.
99.
Masahiro Nomura, K Watanabe, Mariko Katayama, Akemi Takeuchi, Kazuya Fujino, Yutaka Nakaya and H Mori : Detection of the abnormal repolarization vector in diabetes mellitus by means of the isomagnetic map, The 7th International Conference on Biomagnetism, New York, 1989.
100.
Mariko Katayama, Masahiro Nomura, K Watanabe, Akemi Takeuchi, Kazuya Fujino, Yutaka Nakaya and H Mori : The magnetocardiogram in patients with systolic and diastolic overloadof the right ventricle, The 7th International Conference on Biomagnetism, New York, 1989.
101.
Masahiro Nomura, Yutaka Nakaya, K Watanabe, Mariko Katayama, Akemi Takeuchi, Kazuya Fujino and H Mori : Detection of accessory pathway in patients with WPW syndrome by means of the isomagnetic and MRI, The 7th International Conference on Biomagnetism, New York, 1989.
102.
Yutaka Nakaya, Masahiro Nomura and H Mori : Clinical value of magnetocardiographic mapping, The 7th International Conference on Biomagnetism, New York, 1989.
103.
Yutaka Nakaya, Hideaki Nii, Masahiro Nomura, Shuichiro Nakaya and H Mori : Effect of class I antiarrhythmic drugs on relation between excitability and recovery from use-dependent Vmax block, International symposium on basic mechanisms of arrhythmias, Tokyo, 1988.
104.
Yutaka Nakaya, Akemi Takeuchi, K Watanabe, Mariko Katayama, Yoshiharu Fukuda, Kazuya Fujino, Masahiro Nomura, M Sumi, M Murakami and H Mori : Magnetocardiogram of the P wave in right and left atrial overloading, The 6th International Conference on Biomagnetism, Tokyo, 1987.
105.
Masahiro Nomura, Kazuya Fujino, K Watanabe, Mariko Katayama, Akemi Takeuchi, Yoshiharu Fukuda, M Sumi, M Murakami, Yutaka Nakaya and H Mori : Studies on the repolarization abnormality in systolic overloading of the left ventricle by means of the magnetocardiography, The 6th International Conference on Biomagnetism, Tokyo, 1987.
106.
M Sumi, K Watanabe, Akemi Takeuchi, Shuichiro Nakaya, Yoshiharu Fukuda, Masahiro Nomura, Kazuya Fujino, M Murakami, Yutaka Nakaya and H Mori : Isomagnetic map in right ventricular overloading, The 6th International Conference on Biomagnetism, Tokyo, 1987.
107.
M Murakami, K Watanabe, Akemi Takeuchi, Mariko Katayama, Masahiro Nomura, Yoshiharu Fukuda, M Sumi, Yutaka Nakaya and H Mori : The QRS wave of the magnetocardiogram in myocardial infarction, The 6th International Conference on Biomagnetism, Tokyo, 1987.
108.
K Watanabe, Masahiro Nomura, M Sumi, M Murakami, Yutaka Nakaya and H Mori : Analysis of activation sequence by isomagnetic and vector arrow maps, The 6th International Conference on Biomagnetism, Tokyo, 1987.
Proceeding of Domestic Conference:
1.
瀬部 真由, Rie Tsutsumi, 瀬野浦 聖佳, Jun Kishi, Masashi Kuroda, 木下 成三, Yutaka Nakaya, Yasuo Tsutsumi, Yasuhiko Nishioka and Hiroshi Sakaue : 脂質の過剰摂取は関節リウマチ病態の増悪・骨格筋量の減少を引き起こす, Online Journal of JSPEN, Vol.2, No.Suppl.1, 824, Nov. 2020.
瀬部 真由, Rie Tsutsumi, 瀬野浦 聖佳, Jun Kishi, Masashi Kuroda, 木下 成三, Yutaka Nakaya, Yasuo Tsutsumi, Yasuhiko Nishioka and Hiroshi Sakaue : 飽和脂肪酸の過剰摂取は関節リウマチ病態の増悪・骨格筋量の減少を引き起こす, Journal of the The Japan Diabetes Society, Vol.63, No.Suppl.1, S-329, Aug. 2020.
H Sato, Y Hirata, Michio Shimabukuro, Daiju Fukuda, M Tabata, Hirotsugu Kurobe, S Takanashi, Tetsuya Kitagawa, Yutaka Nakaya and Masataka Sata : ヒト脂肪組織における炎症性シグナルとNLRP3インフラマソームの関与, 第33回日本肥満学会, Oct. 2012.
11.
H Sato, Michio Shimabukuro, Y Hirata, M Tabata, M Dagvasumberel, S Bando, Hirotsugu Kurobe, Daiju Fukuda, Takeshi Soeki, S Takanashi, Tetsuya Kitagawa, Yutaka Nakaya and Masataka Sata : 心臓周囲脂肪酸NLRP3インフラマゾームのヒト冠動脈硬化症における役割, 第60回日本心臓病学会学術集会, Sep. 2012.
12.
Hiroshi Sakaue, 福田 亜希子, 阪上 浩, 黒田 雅士 and Yutaka Nakaya : 培養脂肪細胞でのレプチン発現はDNA脱メチル化と転写因子による活性化の2つのステップで制御されている, 日本栄養・食糧学会大会講演要旨集, Vol.66, 185, May 2012.
13.
H Sato, Y Hirata, Michio Shimabukuro, M Tabata, Hirotsugu Kurobe, M Higashida, Asuka Shiota, Hirofumi Izaki, Hiro-omi Kanayama, S Takanashi, Tetsuya Kitagawa, Yutaka Nakaya and Masataka Sata : 心臓周囲脂肪NLRP3インフラマゾームのヒト冠動脈硬化症における役割, 第55回日本糖尿病学会年次学術集会, May 2012.
14.
二見 明香里, Hiroshi Sakaue, Nagakatsu Harada, Tetsuya Shiuchi and Yutaka Nakaya : 中枢神経系におけるグレリンの摂食と運動調節経路の解析, Journal of the The Japan Diabetes Society, Vol.55, No.Suppl.1, S-300, May 2012.
富永 彩子, Hiroshi Sakaue, 福田 亜希子, 黒田 雅士, Nagakatsu Harada and Yutaka Nakaya : 3T3-L1培養脂肪細胞でのレプチン発現はDNAメチル化と転写因子による活性化の2つのステップで制御されている, 第16回アディポサイエンス研究会シンポジウム, Aug. 2011.
24.
富永 彩子, Hiroshi Sakaue, 福田 亜希子, 黒田 雅士, Nagakatsu Harada and Yutaka Nakaya : 3T3-L1培養脂肪細胞でのレプチン発現はDNAメチル化と転写因子による活性化の2つのステップで制御されている, 第16回アディポサイエンス研究会シンポジウム, Aug. 2011.
25.
C. Nishio, M. Higashida, Y. Hirata, Hirotsugu Kurobe, Masashi Akaike, Yutaka Nakaya, Tetsuya Kitagawa and Masataka Sata : GLP-1 Receptor Agonist Attenuates Vascular Remodeling after Endovascular Injury., 第75回日本循環器学会総会・学術集会, Aug. 2011.
26.
M. Higashida, C. Nishio, Y. Hirata, Hirotsugu Kurobe, Masashi Akaike, Yutaka Nakaya, Tetsuya Kitagawa and Masataka Sata : HMGB1 Plays a Critical Role in Chronic Inflammation and Vascular Remodeling after Endovascular Injury., 第75回日本循環器学会総会・学術集会, Aug. 2011.
27.
Higashida Mayuko, Hirata Yoichiro, Hirotsugu Kurobe, Yutaka Nakaya, Tetsuya Kitagawa and Masataka Sata : Toll-like receptor 9 plays a critical role in vascular remodeling., 第43回 日本動脈硬化学会総会・学術集会, Jul. 2011.
28.
東田 真由子, Hirotsugu Kurobe, 松岡 裕貴, 平田 陽一郎, Yutaka Nakaya, Tetsuya Kitagawa and Masataka Sata : 血管リモデリングにおけるHMGB1の果たす役割, 第98回 日本循環器学会 中国・四国合同地方会, May 2011.
谷口 康子, Hiroshi Sakaue, Nagakatsu Harada and Yutaka Nakaya : 中枢神経系におけるアディポネクチンの自発運動制御作用の検討, Journal of the The Japan Diabetes Society, Vol.54, No.Suppl.1, S-257, Apr. 2011.
C. Nishio, M. Higashida, Y. Hirata, Hirotsugu Kurobe, Masashi Akaike, Yutaka Nakaya, Tetsuya Kitagawa and Masataka Sata : GLP-1 Receptor Agonist Attenuates Vascular Remodeling after Endovascular Injury., 第75回日本循環器学会総会・学術集会, Mar. 2011.
34.
M. Higashida, C. Nishio, Y. Hirata, Hirotsugu Kurobe, Masashi Akaike, Yutaka Nakaya, Tetsuya Kitagawa and Masataka Sata : HMGB1 Plays a Critical Role in Chronic Inflammation and Vascular Remodeling after Endovascular Injury., 第75回日本循環器学会総会・学術集会, Mar. 2011.
Bayasgalan Jambaldorji and Yutaka Nakaya : CSP1 invold in insulin resistance by attenuation Glut4 vesicle docking with plasma membrane, 第53回日本糖尿病学会総会年次学術集会, May 2010.
田中 佑佳 and Yutaka Nakaya : 褥瘡治療におけるアルギニン強化栄養剤の有効性について, 第13回日本病態栄養学会年次学術集会, Jan. 2010.
59.
大橋 希江 and Yutaka Nakaya : 透析患者の味覚異常における血清亜鉛値の意義についての検討, 第13回日本病態栄養学会年次学術集会, Jan. 2010.
60.
木内 香奈 and Yutaka Nakaya : 頭頸部がん患者の化学療法後にみられた高カリウム血症, 第13回日本病態栄養学会年次学術集会, Jan. 2010.
61.
LI QINKAI, Toshio Hosaka, Jambaldorj Bayasglan, Fukunaga Keiko, Nishiwak Yuka, Yutaka Nakaya and Makoto Funaki : Extracellular matrix with the rigidity of adipose tissues helps 3T3-L1 adipocytes maintain insulin responsiveness, 第52回日本糖尿病学会年次学術集会, May 2009.
62.
Le Thi Kim Chung, Toshio Hosaka, Jambaldorj Bayasglan, Fukunaga Keiko, Nishiwak Yuka, Yutaka Nakaya and Makoto Funaki : Myosin A enhances membrane fusion of GLUT4-containing vesicles, but not recycling endosomes, with the plasma membrane., 第52回日本糖尿病学会年次学術集会, May 2009.
63.
Qinkai Li, Kazuaki Mawatari, Nagakatsu Harada, 中野 政之, Akira Takahashi, Yutaka Nakaya, Toshio Hosaka, Bayasgalan Jambaldorj, 大塚 良 and Makoto Funaki : Chronic 5-Hydroxytryptamine Treatment Induces Insulin Resistance in 3T3-L1 Adipocytes by mTOR-dependent modification of IRS-1, 第238回徳島医学会学術集会, Feb. 2009.
森島 真幸, Yutaka Nakaya and 小野 克重 : :自発的高運動性ラットSPORTSの海馬ノルエピネフリン神経伝達と運動制御, 第10回活性アミンに関するワークショップ, Aug. 2006.
81.
Yutaka Nakaya : Rondomized trial of branched chain amino acid-rich supplement agaisnt carbohydrate-rich snacks as a late evening snack in patients with liver cirrhosis, The 4th Forum of Hepatic Encephalopathy, Aug. 2006.
森島 真幸, 原 小由合, Nagakatsu Harada, Atsuko Sano, Hiromasa Seno, Akira Takahashi and Yutaka Nakaya : 高運動性モデルラットSPORTSにおける海馬ノルエピネフリン動態は運動習性を調節する., 第82回日本生理学会, May 2005.
87.
森島 真幸, Nagakatsu Harada, 原 小由合, Atsuko Sano, Hiromasa Seno, Akira Takahashi and Yutaka Nakaya : 高運動性モデルラットSPORTSにおける運動習性と脳内モノアミン制御., 第59回日本栄養食糧学会, May 2005.
88.
T Watanabe, Masahiro Nomura, E Kimura, K Yamaguchi, K Koshiba, Tomohito Kawano, Hirotsugu Yamada, Tetsuzo Wakatsuki, Tomotsugu Tabata, Akiyoshi Nishikado, Yutaka Nakaya and Susumu Ito : Antioxydative Effect and Atrial Electrophysiological Improvement by Candesartan in Hypertensive Patients., 69th Annual scientific meeting of the Japanese circulation society, Mar. 2005.
89.
K Yamaguchi, Masahiro Nomura, E Kimura, T Watanabe, K Koshiba, Tomohito Kawano, Hirotsugu Yamada, Tetsuzo Wakatsuki, Tomotsugu Tabata, Akiyoshi Nishikado, Susumu Ito and Yutaka Nakaya : Dose Obstructive Sleep Apnea Syndrome (OSAS) Cause the Myocardial Injury? Examination by 99mTc-MIBI Scintigraphy., 69th Annual scientific meeting of the Japanese circulation sciety, Mar. 2005.
90.
K Yamaguchi, Masahiro Nomura, E Kimura, T Watanabe, K Koshiba, Tomohito Kawano, Hirotsugu Yamada, Tetsuzo Wakatsuki, Tomotsugu Tabata, Akiyoshi Nishikado, Susumu Ito and Yutaka Nakaya : Effect of Carvedilol on Autonomic Nerves Function and Oxidative Stress in the Essential Hypertensive Patients with Obstructive Sleep Apnea Syndrome., 69th Annual scientific meeting of the Japanese circulation society, Mar. 2005.
91.
K Yamaguchi, Masahiro Nomura, E Kimura, T Watanabe, K Koshiba, Tomohito Kawano, Hirotsugu Yamada, Tetsuzo Wakatsuki, Tomotsugu Tabata, Akiyoshi Nishikado, Susumu Ito and Yutaka Nakaya : Atherosclerosis Suppression Effect of Estrogen: Is the Chronic Liver Disease Atherogenic?, 69th Annual scientific meeting of the Japanese circulation society, Mar. 2005.
92.
Masahiro Nomura, E Kimura, T Watanabe, K Yamaguchi, K Koshiba, Tomohito Kawano, Hirotsugu Yamada, Tetsuzo Wakatsuki, Tomotsugu Tabata, Akiyoshi Nishikado, Susumu Ito and Yutaka Nakaya : Current Density Map at Ventricular Repolarization Phase in Myocardial Infarction., 69th Annual scientific meeting of the Japanese circulation society, Mar. 2005.
K Uehara, Masahiro Nomura, T Nakayama, M Yukinaka, Y Ozaki, S Morishita, H Ikefuji, H Fujinaka, M Kimura, K Tikamori, Yutaka Nakaya and Susumu Ito : Clinical significance of high sensitivity CRP as risk factor for LV remodeling in patients with acute myocardial infarction treated by reperfusion therapy, 66th annual scientific meeting of the Japanese Circulation society, Apr. 2004.
Masahiro Nomura, Akiko Iga, Akiyoshi Nishikado, Ken Saito, Takashi Oki, Susumu Ito and Yutaka Nakaya : Evaluation of coronary microvascular disorder using 99mTc-MIBI myocardial SPECT, 66th annual scientific meeting of the Japanese Circulation society, Apr. 2004.
Masahiro Nomura, Yutaka Nakaya, Akiko Iga, Akiyoshi Nishikado, Ken Saito, Takashi Oki and Susumu Ito : Detection of electrical conduction velocity using 32-channel high temperature superconducting quantum interference device, 66th annual scientific meeting of the Japanese Circulation society, Apr. 2004.
Masahiro Nomura, Akiko Iga, Akiyoshi Nishikado, Ken Saito, Takashi Oki, Susumu Ito and Yutaka Nakaya : Relation between insulin resistance and 123I-BMIPP myocardial scintigraphy, 66th annual scientific meeting of the Japanese Circulation society, Apr. 2004.
Tomohito Kawano, Masahiro Nomura, Akiyoshi Nishikado, Tomotsugu Tabata, Tetsuzo Wakatsuki, H Tanaka, Kanji Kusunoki, Norihito Kageyama, Eriko Kimura, Shinichiro Miyazaki, Junji Yamashita, Eiko Uemura, Susumu Ito, Yutaka Nakaya and Ken Saito : The anti-atherosclerosis effect of glimepiride: Examination by inflammatory cytokines, pulse wave velocity (baPWV) and agumentation index (AI), The 68th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2004.
Tomohito Kawano, Masahiro Nomura, Akiyoshi Nishikado, Tomotsugu Tabata, Tetsuzo Wakatsuki, H Tanaka, Kanji Kusunoki, Norihito Kageyama, Eriko Kimura, Shinichiro Miyazaki, Junji Yamashita, Eiko Uemura, Susumu Ito, Yutaka Nakaya and Ken Saito : Electrophysiological improvement of the atrium by losartan potassium (Nu-Lotan®) in hypertensive patients., The 68th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2004.
Junji Yamashita, Masahiro Nomura, Akiyoshi Nishikado, Tomotsugu Tabata, Tetsuzo Wakatsuki, H Tanaka, Kanji Kusunoki, Tomohito Kawano, Kouji Yamaguchi, Norihito Kageyama, Eriko Kimura, Shinichiro Miyazaki, Eiko Uemura, Susumu Ito, Yutaka Nakaya and Ken Saito : Mechanism of ST segment depression during exercise test in patients with liver cirrhosis., The 68th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2004.
Masahiro Nomura, Akiyoshi Nishikado, Tomotsugu Tabata, Tetsuzo Wakatsuki, H Tanaka, Kanji Kusunoki, Tomohito Kawano, Norihito Kageyama, Eriko Kimura, Shinichiro Miyazaki, Junji Yamashita, Eiko Uemura, Susumu Ito, Yutaka Nakaya and Ken Saito : Current density map in ventricular repolarization phase in diabetic patients., The 68th Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2004.
(Summary)
糖尿病例の心室再分極異常について検討した．Current density mapにより，心電図で検出される前の異常を早期に検出できると思われた．
心磁図により糖尿病性心筋障害の早期診断が可能かどうか，current density mapにより検討した．異常電流が心電図で捉えられる以前に早期に検出できた．
27.
Kanji Kusunoki, Kohzou Uehara, Masahiro Nomura, Akiyoshi Nishikado, K Harada, N Kageyama, Yutaka Nakaya, Ken Saito, Tetsuzo Wakatsuki, Tomotsugu Tabata and Susumu Ito : Detection of myocardial microvasular disorders using dynamic 99mTc-MIBI SPECT., 67th annual scientific meeting of the Japanese Circulation society, Mar. 2003.
Kenji Harada, Masahiro Nomura, Akiyoshi Nishikado, Kouzoh Uehara, Kanji Kusunoki, A Saito, N Kageyama, Eriko Kimura, E Tanaka, Tetsuzo Wakatsuki, Tomotsugu Tabata, Yutaka Nakaya and Susumu Ito : Effect of glimepiride on coronary blood flow reserve: evaluation by % uptake increases during exercise myocardial scintigraphy, 67th annual scientific meeting of the Japanese Circulation society, Mar. 2003.
Kozo Uehara, Masahiro Nomura, Akiyoshi Nishikado, Kenji Harada, Kanji Kusunoki, N Kageyama, Yutaka Nakaya, Ken Saito, Tetsuzo Wakatsuki, Tomotsugu Tabata and Susumu Ito : Relationship among high-sensitive CRP, maximum oxygen uptake and insulin resistance., 67th annual scientific meeting of the Japanese Circulation society, Mar. 2003.
Tomohito Kawano, Masahiro Nomura, Yutaka Nakaya and Susumu Ito : Can supplementation of L-arginine improves insulin resistance and lipid metabolism in diabetic rat?, 67th annual scientific meeting of the Japanese Circulation society, Mar. 2003.
N Kageyama, Kohzou Uehara, Masahiro Nomura, Akiyoshi Nishikado, K Harada, K Kusunoki, Tetsuzo Wakatsuki, Tomotsugu Tabata, Ken Saito, Yutaka Nakaya and Susumu Ito : Influence of sleep apnea on autonomic nervous activity in patients with essential hypertension, 67th annual scientific meeting of the Japanese Circulation society, Mar. 2003.
T Toyoshima, Masahiro Nomura, Tomohito Kawano, S Hashizume, M Murakami, K Kawahara, I Hayashi, T Niki, S Morishita, Takashi Oki, Susumu Ito and Yutaka Nakaya : Is left ventricular wall motion detected correctly using QGS method in infarcted myocardium?, The 65th Anniversary Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2001.
S Morishita, Masahiro Nomura, Akiyoshi Nishikado, Ken Saito, Takashi Oki, Susumu Ito and Yutaka Nakaya : Evaluation of fatty acid metabolism in the left ventricular myocardium by 123I-BMIPP myocardial scintigraphy in patients with right ventricular overload, The 65th Anniversary Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2001.
Masahiro Nomura, Yutaka Nakaya, S Morishita, Tomomi Nada, Hitoshi Miyajima, Ken Saito, Akiyoshi Nishikado, Takashi Oki and Susumu Ito : Visualization of cardiac electrical current using 32-channel high temperature superconducting quantum interference device, The 65th Anniversary Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2001.
(Summary)
高温超伝導量子干渉計を用いて心臓磁界を測定し，current density mapを作成した．心房脱分極相，心室脱分極相で良好に心起電力を検出できた．
50.
Masahiro Nomura, Yutaka Nakaya, S Morishita, Tomomi Nada, Hitoshi Miyajima, Ken Saito, Akiyoshi Nishikado, Takashi Oki and Susumu Ito : Relationship between insulin resistance and various parameters in total health promotion planning, The 65th Anniversary Annual Scientific Meeting of the Japanese Circulation Society, Mar. 2001.
岸 史子, Masahiro Nomura, 由岐中 道子, 近藤 幸, Ken Saito, 大木 崇, Susumu Ito and Yutaka Nakaya : Human chymaseによるbig endothelinのprocessing-endothelin (1-31)の生成とその生理活性についての検討, 第62回日本循環器学会学術集会, Mar. 1998.
(Summary)
Human chymaseはbig endothelin (ET)に作用し新規化合物ET (1-31)を生成した．ET (1-31)は，ET (1-21)とは異なった経路を介し心肥大·動脈硬化に関与している．
由岐中 道子, Masahiro Nomura, 近藤 幸, Ken Saito, 大木 崇, Susumu Ito and Yutaka Nakaya : 右室負荷疾患において99mTc-Tetrofosmin心筋シンチにおける洗い出し率による検討, 第62回日本循環器学会学術集会, Mar. 1998.
Masahiro Nomura, Ken Saito, 岸 史子, 大木 崇, Susumu Ito and Yutaka Nakaya : 心電図検診における右脚ブロックパターン例の自律神経活動の検討ー心拍変動スペクトル解析および123I-MIBG心筋シンチによる検討ー, 第60回日本循環器学会総会, Mar. 1996.
Ayaka Kobayashi, Masahiro Nomura, Yuko Tomokane, Takashi Kawaguchi, Kunihiko Koshiba, Koji Yamaguchi, Tomohito Kawano, Tetsuzo Wakatsuki, Tomotsugu Tabata, Akiyoshi Nishikado, Susumu Ito and Yutaka Nakaya : A Patient with sustained ventricular tachycardia:identification of a responder to aminodarone using signal-averaged electrocardiogram, The Journal of Medical Investigation : JMI, Vol.51, No.3-4, 247-253, Aug. 2004.
(Summary)
A 75-year-old man suffered sustained ventricular tachycardia with syncopal attack. Ventricular tachycardias appeared repeatedly, and an electrical defibrillator was used after an anti-arrhythmic drug, such as lidocaine or mexiletine, proved ineffective. The tachycardias had multiple origins, and the signal-averaged electrocardiogram (SAECG) showed ventricular late potential before the administration of amiodarone. After administration, the filtered QRS and duration of the late potential increased, but the recurrence of tachycardias was suppressed. The reason for this is thought to be that amiodarone blocked the sodium channel and delayed conduction, consequently blocking reentry, because amiodaron has antiarrhymic properties with a prolongation of refractoriness and minimal effect on conduction velocity in ventricular myocardium, and inhibits sympathetic activity, and blocks L-type calcium channel besides the depression of the fast sodium channel. In this case, SAECG predicted to some degree whether or not this patient's ventricular tachycardia would respond to amiodarone.
(Keyword)
Aged / Amiodarone / Anti-Arrhythmia Agents / Electrocardiography / Humans / Male / Signal Processing, Computer-Assisted / Tachycardia, Ventricular
Molecular genetic analysis of atherosclerosis and atrial thrombosis rat model spontaneously induced by hypoactivity (Project/Area Number: 25560368 )
Rapid screening of gene(s) related to the phenotype of model rats with high levels of voluntarily wheel running activity (Project/Area Number: 23650406 )
Research for the regulation of voluntary exercise and energy metabolism by appetite-regulating factors (Project/Area Number: 22700693 )
Establishment of molecular mechanism of exercise motivation using a novel rat-strain featured by high levels of wheel-running activity (Project/Area Number: 21700696 )
Finding the novel anti-metabolic syndrome treatment by examining the mechanism of improvement for lipid metabolism with hyperbaric oxygen. (Project/Area Number: 21500685 )
Molecular mechanisms of muscle mass regulation : Identification of a novel protease involved in myostatin activation. (Project/Area Number: 21500632 )
Investigation in the mechanism of regulation of voluntary exercise and abdominal visceral fat accumulation by monoamines. (Project/Area Number: 20700551 )
Study on the development of exercise applied Awa-Dance to and function and effect of it. (Project/Area Number: 20500597 )
Molecular meohanisms of mechanosensing inskeletal muscles : Based on regulation system of atrogen expression (Project/Area Number: 19500564 )
Mechanism of increase inphysical activity using a novel animal model of high wheel running (Project/Area Number: 19300222 )
Research on hypoglycemia caused by inhibition of orexin expression (Project/Area Number: 18590991 )
Characterization of a cerebellar ubiquitin ligase, which mediates effects of training to nerve (Project/Area Number: 17500430 )
Monoamine dynamics in control of spontaneous physical activity in rats (Project/Area Number: 17500429 )
Study of the skin microcirculation in the rabbit ear suffering from hyperlipidemia or hypergricemia (Project/Area Number: 16390510 )
Interaction of sarcolemmal and mitochondrial ATP-sensitive K channel on cardioprotection (Project/Area Number: 15591636 )
Study of hair growth mechanism through ABS transporter and adenosine (Project/Area Number: 15591179 )
Molecular mechanism of unloading-mediated insulin resistance (Project/Area Number: 15500449 )
Mechanism of voluntary exercise and effect of exercise training on life-style related disease studied using a line of rats for high levels of voluntary wheel running (Project/Area Number: 15500448 )
Physiological study about skin microcirculation on diabetes mellitus (Project/Area Number: 14571714 )
Molecular Pathogenesis of Hereditary Glomerulosclerosis. (Project/Area Number: 14571026 )
Versatile Study about Skin Microcirculatory Failures on Rabbit Diabetes Mellitus Model (Project/Area Number: 13671880 )
The role of mitochondrial ATP sensitive potassium channel on cardioprotection of ischemic preconditioning and anesthetics (Project/Area Number: 13671586 )
The role of K_<ATP> channel activities on the ischemic preconditioning and the influence of anesthetics on K_<ATP> channel activities. (Project/Area Number: 11671501 )
A novel vasoactive peptide, 31-amino acid length endothelin, by human chymase and its relation to atherosclerosis (Project/Area Number: 11670685 )
Experimental studies on circulatory disturbances in the spinal cord after traumatic spinal cord injury. (Project/Area Number: 11470311 )
Combined Effects of Acidosis, Hypoxia, and Anesthetics on the K_<ATP> Channels in Isolated Rat Myocytes. (Project/Area Number: 09671568 )