Shinji Yasuda

Publications (22)59.39 Total impact

• Article: Both stimulation of GLP-1 receptors and inhibition of glycogenolysis additively contribute to a protective effect of oral miglitol against ischaemia-reperfusion injury in rabbits.

  Masamitsu Iwasa, Yoshihisa Yamada, Hiroyuki Kobayashi, Shinji Yasuda, Itta Kawamura, Shohei Sumi, Takeru Shiraki, Takahiko Yamaki, Hiroaki Ushikoshi, Arihiro Hattori, Takuma Aoyama, Kazuhiko Nishigaki, Genzou Takemura, Hisayoshi Fujiwara, Shinya Minatoguchi
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  ABSTRACT: We previously reported that pre-ischaemic i.v. miglitol reduces myocardial infarct size through the inhibition of glycogenolysis during ischaemia. Oral administration of miglitol has been reported to produce glucagon-like peptide 1 (GLP-1). We hypothesized that p.o. administration of miglitol, an absorbable antidiabetic drug, reduces myocardial infarct size by stimulating GLP-1 receptors and inhibiting glycogenolysis in the myocardium. The effects of p.o. and i.v. administration of miglitol on myocardial infarct size were compared in a rabbit model of ischaemia induced by 30 min of coronary occlusion and 48 h of reperfusion. The levels of phospho(p)-PI3kinase and p-Akt were measured in cardiac tissue by use of Western blot analysis. Both p.o. and i.v. administration of miglitol reduced the infarct size, and this effect was greater after p.o. than after i.v. administration under similar plasma miglitol concentrations. The reduction in infarct size induced by p.o. miglitol but not that induced by i.v. miglitol was partially inhibited by treatment with exendin(9-39), a GLP-1 receptor blocker. Both p.o. and i.v. miglitol improved ejection fraction and ±dP/dt after myocardial infarction. Miglitol administered p.o. but not i.v. up-regulated the myocardial expression of phospho(p)-PI3kinase and p-Akt following myocardial infarction; an effect that was inhibited by exendin(9-39). Administration of miglitol p.o. reduces myocardial infarct size through stimulation of GLP-1 receptors and activation of PI3kinase-Akt pathway in addition to the inhibition of glycogenolysis. These findings may have clinical implications for the p.o. administration of miglitol for the treatment of patients with diabetes mellitus combined with coronary artery disease.
  British Journal of Pharmacology 03/2011; 164(1):119-31. · 4.41 Impact Factor
• Article: Postconditioning effect of granulocyte colony-stimulating factor is mediated through activation of risk pathway and opening of the mitochondrial KATP channels.

  Shohei Sumi, Hiroyuki Kobayashi, Shinji Yasuda, Masamitsu Iwasa, Takahiko Yamaki, Yoshihisa Yamada, Hiroaki Ushikoshi, Arihiro Hattori, Takuma Aoyama, Kazuhiko Nishigaki, Genzou Takemura, Shinya Minatoguchi
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  ABSTRACT: Granulocyte colony-stimulating factor (G-CSF) has been reported to improve cardiac function after myocardial infarction. However, whether postinfarct acute effect of G-CSF is mediated through the same signaling pathways as those of ischemic postconditioning is still unclear. We examined the postinfarct acute effect of G-CSF on myocardial infarct size and its precise molecular mechanism. Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Rabbits were intravenously injected 10 μg/kg of G-CSF (G-CSF group) or saline (control group) immediately after reperfusion. The wortmannin + G-CSF, PD-98059 + G-CSF, N(ω)-nitro-L-arginine methyl ester (l-NAME) + G-CSF, and 5-hydroxydecanoic acid sodium salt (5-HD) + G-CSF groups were respectively injected with wortmannin (0.6 mg/kg), PD-98059 (0.3 mg/kg), L-NAME (10 mg/kg), and 5-HD (5 mg/kg) 5 min before G-CSF administration. Myocardial infarct size was calculated as a percentage of the risk area of the left ventricle. Western blot analysis was performed to examine the signals such as protein kinase B (Akt), extracellular signal-regulated protein kinase (ERK), eNOS, p70S6 kinase (p70S6K), and glycogen synthase kinase-3β (GSK3β) in the ischemic myocardium after 48 h of reperfusion. The infarct size was significantly smaller in the G-CSF group (26.7 ± 2.7%) than in the control group (42.3 ± 4.6%). The infarct size-reducing effect of G-CSF was completely blocked by wortmannin (44.7 ± 4.8%), PD-98059 (38.3 ± 3.9%), L-NAME (42.1 ± 4.2%), and 5-HD (42.5 ± 1.7%). Wortmannin, PD-98059, L-NAME, or 5-HD alone did not affect the infarct size. Western blotting showed higher myocardial expression of phospho-Akt, phospho-ERK, phosho-eNOS, phosho-p70S6K, and phosho-GSK3β at 10 min and 48 h after reperfusion in the G-CSF group than in the control group. In conclusion, postreperfusion G-CSF administration reduces myocardial infarct size via activation of phosphatidylinositol 3-kinase-Akt and ERK prosurvival signaling pathways and their downstream targets eNOS, p70S6 kinase, GSK3β, and mitochondrial ATP-dependent K(+) channel.
  AJP Heart and Circulatory Physiology 10/2010; 299(4):H1174-82. · 3.71 Impact Factor
• Article: Antidiabetic drug voglibose is protective against ischemia-reperfusion injury through glucagon-like peptide 1 receptors and the phosphoinositide 3-kinase-Akt-endothelial nitric oxide synthase pathway in rabbits.

  Masamitsu Iwasa, Hiroyuki Kobayashi, Shinji Yasuda, Itta Kawamura, Shohei Sumi, Yoshihisa Yamada, Takeru Shiraki, Takahiko Yamaki, Hiroaki Ushikoshi, Takuma Aoyama, Kazuhiko Nishigaki, Genzou Takemura, Takako Fujiwara, Hisayoshi Fujiwara, Shinya Minatoguchi
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  ABSTRACT: Glucagon-like peptide 1 (GLP-1) reportedly exerts a protective effect against cardiac ischemia. We hypothesized that the alpha-glucosidase inhibitor voglibose, an unabsorbable antidiabetic drug with cardioprotective effects, may act through stimulation of GLP-1 receptors. The results of the present study suggest oral administration of voglibose reduces myocardial infarct size and mitigates cardiac dysfunction in rabbits after 30 minutes of coronary occlusion and 48 hours of reperfusion. Voglibose increased basal and postprandial plasma GLP-1 levels and reduced postprandial plasma glucose levels. The infarct size-reducing effect of voglibose was abolished by treatment with exendin(9-39), wortmannin, Nomega-nitro-L-arginine methylester, or 5-hydroxydecanoate), which inhibit GLP-1 receptors, phosphoinositide 3-kinase, nitric oxide synthase, and K(ATP) channels, respectively. Western blot analysis showed that treatment with voglibose upregulated myocardial levels of phospho-Akt, phosphoendothelial nitric oxide synthase after myocardial infarction. The upregulation of phospho-Akt was inhibited by exendin(9-39) and wortmannin. These findings suggest that voglibose reduces myocardial infarct size through stimulation of GLP-1 receptors, activation of the phosphoinositide 3-kinase-Akt-endothelial nitric oxide synthase pathways, and the opening of mitochondrial K(ATP) channels. These findings may provide new insight into therapeutic strategies for the treatment of patients with coronary artery disease.
  Journal of cardiovascular pharmacology 03/2010; 55(6):625-34. · 2.83 Impact Factor
• Article: Postinfarct treatment with oxytocin improves cardiac function and remodeling via activating cell-survival signals and angiogenesis.

  Hiroyuki Kobayashi, Shinji Yasuda, Narentuoya Bao, Masamitsu Iwasa, Itta Kawamura, Yoshihisa Yamada, Takahiko Yamaki, Syohei Sumi, Hiroaki Ushikoshi, Kazuhiko Nishigaki, Genzou Takemura, Takako Fujiwara, Hisayoshi Fujiwara, Shinya Minatoguchi
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  ABSTRACT: We investigated whether postinfarct treatment with oxytocin (OT) improves left ventricular (LV) function and remodeling via cardiac repair of myocardial ischemia-reperfusion injury. Experiments were performed with 30 minutes of coronary occlusion and 2 or 14 days of reperfusion rabbit model of myocardial infarction. LV function and remodeling were significantly improved in the OT group. The infarct size was significantly reduced in the OT group. The number of CD31-positive microvessels was increased significantly in the OT group. There were no Ki67-positive myocytes in either group. The expression of the OT receptor, phosphorylated (p)-Akt protein kinase, p-extracellular signal-regulated protein kinase, p-enodthelial NO synthase, p-signal transducer and activator of transcription 3, vascular endothelial growth factor, B-cell lymphoma 2, and matrix metalloproteinase-1 (MMP-1) were markedly increased in the OT group days 2 and 14 post myocardial infarction. Postinfarct treatment with OT reduces myocardial infarct size and improves LV function and remodeling by activating OT receptors and prosurvival signals and by exerting antifibrotic and angiogenic effects through activation of MMP-1, endothelial NO synthase, and vascular endothelial growth factor. These findings provide new insight into therapeutic strategies for ischemic heart disease.
  Journal of cardiovascular pharmacology 09/2009; 54(6):510-9. · 2.83 Impact Factor
• Article: Acarbose reduces myocardial infarct size by preventing postprandial hyperglycemia and hydroxyl radical production and opening mitochondrial KATP channels in rabbits.

  Shinya Minatoguchi, Zengi Zhang, Narentuoya Bao, Hiroyuki Kobayashi, Shinji Yasuda, Masamitsu Iwasa, Syouhei Sumi, Itta Kawamura, Yoshihisa Yamada, Kazuhiko Nishigaki, Genzou Takemura, Takako Fujiwara, Hisayoshi Fujiwara
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  ABSTRACT: Acarbose, an antidiabetic drug, is an alpha-glucosidase inhibitor that can inhibit glucose absorption in the intestine. A recent large-scale clinical trial, STOP-NIDDM, showed that acarbose reduces the risk of myocardial infarction. We examined whether acarbose reduces myocardial infarct size and investigated its mechanisms. Rabbits were fed with 1 of 2 diets in this study: normal chow, 30 mg acarbose per 100 g chow for 7 days. Rabbits were assigned randomly to 1 of 4 groups: control (n = 10), acarbose (n = 10), acarbose + 5HD (n = 10, intravenous 5 mg/kg of 5-hydroxydecanoate), and 5HD (n = 10, intravenous 5 mg/kg of 5HD). Rabbits then underwent 30 minutes of coronary occlusion followed by 48-hour reperfusion. Postprandial blood glucose levels were higher in the control group than in the acarbose group. The infarct size as a percentage of the left ventricular area at risk was reduced significantly in the acarbose (19.4% +/- 2.3%) compared with the control groups (42.8% +/- 5.4%). The infarct size-reducing effect of acarbose was abolished by 5HD (43.4% +/- 4.7%). Myocardial interstitial 2,5-dihydroxybenzoic acid levels, an indicator of hydroxyl radicals, increased during reperfusion after 30 minutes of ischemia, but this increase was inhibited in the acarbose group. This was reversed by 5HD. Acarbose reduces myocardial infarct size by opening mitochondrial KATP channels, which may be related to the prevention of postprandial hyperglycemia and hydroxyl radical production.
  Journal of cardiovascular pharmacology 06/2009; 54(1):25-30. · 2.83 Impact Factor
• Article: Antidiabetic drug pioglitazone protects the heart via activation of PPAR-gamma receptors, PI3-kinase, Akt, and eNOS pathway in a rabbit model of myocardial infarction.

  Shinji Yasuda, Hiroyuki Kobayashi, Masamitsu Iwasa, Itta Kawamura, Shouhei Sumi, Bao Narentuoya, Takahiko Yamaki, Hiroaki Ushikoshi, Kazuhiko Nishigaki, Kenshi Nagashima, Genzou Takemura, Takako Fujiwara, Hisayoshi Fujiwara, Shinya Minatoguchi
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  ABSTRACT: The insulin-sensitizing drug pioglitazone has been reported to be protective against myocardial infarction. However, its precise mechanism is unclear. Rabbits underwent 30 min of coronary occlusion followed by 48 h of reperfusion. Rabbits were assigned randomly to nine groups (n = 10 in each): the control group (fed a normal diet), pioglitazone group (fed diets containing 1 mg.kg(-1).day(-1) pioglitazone), pioglitazone + 5-hydroxydecanoic acid (HD) group [fed the pioglitazone diet + 5 mg/kg iv 5-HD, a mitochondrial ATP-sensitive K(+) (K(ATP)) channel blocker], pioglitazone + GW9662 group [fed the pioglitazone diet + 2 mg/kg iv GW9662, a peroxisome proliferator activated receptor (PPAR)-gamma antagonist], GW9662 group (fed a normal diet + iv GW9662), pioglitazone + wortmannin group [fed the pioglitazone diet + 0.6 mg/kg iv wortmannin, a phosphatidylinositol (PI)3-kinase inhibitor], wortmannin group (fed a normal diet + iv wortmannin), pioglitazone + nitro-l-arginine methyl ester (l-NAME) group [fed the pioglitazone diet + 10 mg/kg iv l-NAME, a nitric oxide synthase (NOS) inhibitor], and l-NAME group (fed a normal diet + iv l-NAME). All groups were fed the diets for 7 days. The risk area and nonrisk area of the left ventricle (LV) were separated by Evans blue dye, and the infarct area was determined by triphenyltetrazolium chloride staining. The infarct size was calculated as a percentage of the LV risk area. Western blotting was performed to assess levels of Akt and phospho-Akt and phospho-endothelial NOS (eNOS) in the myocardium following reperfusion. The infarct size was significantly smaller in the pioglitazone group (21 +/- 2%) than in the control group (43 +/- 3%). This effect was abolished by GW9662 (42 +/- 3%), wortmannin (40 +/- 3%), or l-NAME (42 +/- 7%) but not by 5-HD (24 +/- 5%). Western blotting showed higher levels of phospho-Akt and phospho-eNOS in the pioglitazone group. Pioglitazone reduces the myocardial infarct size via activation of PPAR-gamma, PI3-kinase, Akt, and eNOS pathways, but not via opening the mitochondrial K(ATP) channel. Pioglitazone may be a novel strategy for the treatment of diabetes mellitus with coronary artery disease.
  AJP Heart and Circulatory Physiology 04/2009; 296(5):H1558-65. · 3.71 Impact Factor
• Article: Simvastatin reduces myocardial infarct size via increased nitric oxide production in normocholesterolemic rabbits.

  Narentuoya Bao, Hiroaki Ushikoshi, Hiroyuki Kobayashi, Shinji Yasuda, Itta Kawamura, Masamitsu Iwasa, Takahiko Yamaki, Shohei Sumi, Kenshi Nagashima, Takuma Aoyama, Masanori Kawasaki, Kazuhiko Nishigaki, Genzou Takemura, Shinya Minatoguchi
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  ABSTRACT: Statins have been reported to be protective against myocardial infarction (MI). Moreover, statin drugs upregulate nitric oxide (NO) in coronary artery independent of lipid-lowering effects. However their precise mechanism for MI-protection is unclear. We investigated the effect of lipophilic statin administration in a normocholesterolemic rabbit MI model. Nω-nitro-L-arginine methylester (L-NAME, 10 mg/kg) or vehicle alone was intravenously administered 20 min before inducing ischemia, followed by intravenous administration of simvastatin (5 mg/kg) or saline 10 min before ischemia. Rabbits then underwent 30 min of coronary occlusion followed by 48 h of reperfusion. The at-risk and infarct areas were calculated as a percentage of the total left ventricular slice area. Determination of infarct size revealed that pre-ischemic treatment with simvastatin reduced infarct size (30.5 ± 4%) in comparison to controls (45.0 ± 3%) (P < 0.05). This infarct size-reducing effect of simvastatin could be completely abrogated by pretreatment with L-NAME (42.0 ± 4%). Pre-ischemic treatment with simvastatin reduces MI size via NO production. Simvastatin could be a useful drug for coronary artery disease patients without dyslipidemia as it has direct protective effects.
  Journal of Cardiology 02/2009; 53(1):102-7. · 1.28 Impact Factor
• Article: Transcatheter embolization by autologous blood clot is useful management for small side branch perforation due to percutaneous coronary intervention guide wire.

  Shinichiro Tanaka, Kazuhiko Nishigaki, Shinsuke Ojio, Shinji Yasuda, Munenori Okubo, Takahiko Yamaki, Tomoki Kubota, Nobuhiro Takasugi, Yoshiyuki Ishihara, Masanori Kawasaki, Shinya Minatoguchi
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  ABSTRACT: A 75-year-old man underwent PCI for a bifurcation lesion with 90% stenosis in segment 6 and 75% proximal stenosis in segment 9 of the left coronary artery. We implanted a Duraflex coronary stent into segment 6 and kissing balloon inflation for segments 6 and 9. Although these 2 lesions were adequately dilated, we noticed coronary perforation caused by the guide wire in a small branch of segment 9. We tried to repair the perforation using a small balloon and long inflation, but unfortunately the perforation was not improved. We attempted to occlude the small branch including the perforation site with an autologous blood clot via a wire microcatheter inserted into the small branch. The autologous blood clot was suspended in contrast media and saline. Using this procedure, the small branch of segment 9 was occluded completely and the perforated site was repaired. After the procedure, no significant CPK elevation was detected, and 6 months later, we confirmed that small branch embolization was improved and coronary flow was good. Autologous blood clot is useful to occlude and repair perforations in small side branches of the coronary artery without myocardial damage.
  Journal of Cardiology 01/2009; 52(3):285-9. · 1.28 Impact Factor
• Article: Tissue characterization of coronary plaques: comparison of integrated backscatter intravascular ultrasound with virtual histology intravascular ultrasound.

  Munenori Okubo, Masanori Kawasaki, Yoshiyuki Ishihara, Urara Takeyama, Shinji Yasuda, Tomoki Kubota, Shinichiro Tanaka, Takahiko Yamaki, Shinsuke Ojio, Kazuhiko Nishigaki, Genzou Takemura, Masanao Saio, Tsuyoshi Takami, Hisayoshi Fujiwara, Shinya Minatoguchi
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  ABSTRACT: Integrated backscatter (IB) intravascular ultrasound (IVUS) and IVUS Virtual Histology (VH) have been developed for tissue characterization, but have never been compared directly. The purpose of this study was to compare the overall agreement between IB-IVUS and IVUS-VH in the tissue characterization of plaques from the same coronary arterial cross-section. Images were acquired from 46 coronary arteries from 25 cadavers. Of a total of 392 histology/IVUS image pairs, 152 pairs were diagnosed as Stary's type III, IV, Va, Vb and Vc, and compared for IB-IVUS, IVUS-VH and histology. In the qualitative comparison, the overall agreement between histological and IB-IVUS diagnoses was higher (kappa = 0.81, 95% confidence interval (CI): 0.74-0.89) than that of the IVUS-VH diagnoses (kappa = 0.66, 95%CI: 0.56-0.75). The % fibrosis area determined by IB-IVUS was significantly correlated with the relative area of fibrosis based on histology (r = 0.67, p < 0.001). In the quantitative comparison, the overall agreement between the histological and IB-IVUS diagnoses was higher (kappa = 0.83, 95% CI: 0.75-0.91) than that of the IVUS-VH diagnoses (kappa = 0.73, 95% CI: 0.63-0.83). Based on histology as the gold standard, IB-IVUS provided higher diagnostic accuracy than IVUS-VH for tissue characterization of coronary plaques.
  Circulation Journal 09/2008; 72(10):1631-9. · 3.77 Impact Factor
• Article: Can negative cardiac effect of proton pump inhibitor and high-dose H2-blocker have clinical influence on patients with stable angina?

  Shinichiro Tanaka, Kazuhiko Nishigaki, Shinsuke Ojio, Munenori Okubo, Shinji Yasuda, Yoshiyuki Ishihara, Tomoki Kubota, Nobuhiro Takasugi, Itta Kawamura, Takahiko Yamaki, Hiroaki Ushikoshi, Takuma Aoyama, Masanori Kawasaki, Genzou Takemura, Shinya Minatoguchi
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  ABSTRACT: Aspirin and anti-platelet drugs are used commonly for patients with coronary heart disease. Proton pump inhibitor (PPI) and high-dose H2-blocker were recommended for preventing NSAIDs-related ulcer. Previously H2-blocker reported to have some negative cardiovascular effects. Additionally, a recent in vitro study showed that PPI reduced cardiac contractility. In this study, we evaluated whether chronic administration of PPI and high-dose H2-blocker affects left ventricular function. Fifty-two stable angina patients were enrolled and classified into PPI group ([P]; lansoprazole: 15 mg/day, n=28), H2-blocker group ([H]; famotidine: 40 mg/day, n=8), and control ([C]; none or mucosal-defense drug, n=16). Eligible patients showed normal cardiac function in initial catheterization without administrated PPI or H2-blocker. They received percutaneous coronary intervention and follow-up catheterization. We compared changes in ejection fraction (EF: %), end diastolic/systolic volume index (EDVI/ESVI: ml/m(2)), and peak positive/negative dp/dt (+/-dp/dt: mmHg/s) in left ventricular angiography series. There were no significant differences among three groups regarding patient characteristics, backgrounds of angiographic and intervention, except for fewer smokers in [C]. Other drugs such as beta- and Ca-blocker did not have effects on cardiac function except for aspirin during 255+/-115 days follow-up. Rate of EF changes significantly decreased in [P], and tended to decrease in [H] (C: 3.8+/-9.8%, H: -1.6+/-7.6%, P: -2.1+/-5.9%; p<0.05 for [C] vs. [P]). Those of ESVI changes were significantly greater in [P], and tended to be greater in [H] (C: -4.5+/-16.2%, H: 4.9+/-15.5%, P: 7.3+/-16.2%; p<0.05 for [C] vs. [P]), though, EDVI changes' were similar (C: 2.5+/-8.9%, H: 2.6+/-3.6%, P: 1.6+/-6.1%; p=ns). Rate of +/-dp/dt-changes tended to decrease in [H] (+dp/dt: C: 3.9+/-15.5%, H: -10.0+/-25.2%, P: 0.3+/-19.6%; p=ns, -dp/dt: C: -0.1+/-19.5%, H: -8.5+/-20.4%, P: 5.7+/-27.7%; p=ns). In this study, PPI and high-dose H2-blocker have EF-reducing tendency. However, these changes were small and these drugs seemed to exhibit little influence clinically.
  Journal of Cardiology 08/2008; 52(1):39-48. · 1.28 Impact Factor
• Article: Post-infarct treatment with an erythropoietin-gelatin hydrogel drug delivery system for cardiac repair.

  Hiroyuki Kobayashi, Shinya Minatoguchi, Shinji Yasuda, Narentuoya Bao, Itta Kawamura, Masamitsu Iwasa, Takahiko Yamaki, Syohei Sumi, Yu Misao, Hiroaki Ushikoshi, Kazuhiko Nishigaki, Genzou Takemura, Takako Fujiwara, Yasuhiko Tabata, Hisayoshi Fujiwara
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  ABSTRACT: We investigated the effect of an erythropoietin (EPO)-gelatin hydrogel drug delivery system (DDS) applied to the heart on myocardial infarct (MI) size, left ventricular (LV) remodelling and function. Experiments were performed in a rabbit model of MI. The infarct size was reduced, and LV remodelling and function were improved 14 days and 2 months after MI but not at 2 days after MI in the EPO-DDS group. The number of cluster of differentiation 31(CD31)-positive microvessels and the expression of erythropoietin receptor (EPO-R), phosphorylated-Akt (p-Akt), phosphorylated glycogen synthase kinase 3beta (p-GSK-3beta), phosphorylated extracellular signal-regulated protein kinase (p-ERK), phosphorylated signal transducer and activator of transcription 3 (p-Stat3), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-1 (MMP-1) were significantly increased in the myocardium of the EPO-DDS group. Post-MI treatment with an EPO-DDS improves LV remodelling and function by activating prosurvival signalling, antifibrosis, and angiogenesis without causing any side effect.
  Cardiovascular Research 07/2008; 79(4):611-20. · 6.06 Impact Factor
• Article: In vivo hepatocyte growth factor gene transfer reduces myocardial ischemia-reperfusion injury through its multiple actions.

  Xue-Hai Chen, Shinya Minatoguchi, Kenichiro Kosai, Kentaro Yuge, Tomoyuki Takahashi, Masazumi Arai, Ningyuan Wang, Yu Misao, Chuanjiang Lu, Hirohito Onogi, Hiroyuki Kobayashi, Shinji Yasuda, Masayasu Ezaki, Hiroaki Ushikoshi, Genzou Takemura, Takako Fujiwara, Hisayoshi Fujiwara
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  ABSTRACT: Hepatocyte growth factor (HGF) is reported to protect the heart against ischemia-reperfusion injury. However, whether in vivo adenovirus-mediated HGF gene transfer before ischemia is protective against ischemia-reperfusion and its precise mechanisms are still unknown. By using a rabbit model of ischemia-reperfusion injury, we demonstrate that HGF gene transfer is cardioprotective through its multiple beneficial actions, such as angiogenesis, Bcl-2 overexpression, and decreasing hydroxyl radicals, deoxyuride-5'-triphosphate biotin nick end labeling (TUNEL)-positive myocytes, and fibrotic area. After HGF gene transfer, the rabbits underwent 30 minutes of coronary occlusion and 30 minutes, 4 hours, 48 hours, and 14 days of reperfusion. The infarct size at 48 hours of reperfusion was significantly reduced in the HGF group (13.4% +/- 2.3%) compared with that in the LacZ group (36.5% +/- 2.0%) and saline group (40.3% +/- 3.2%). At 14 days of reperfusion, HGF gene transfer improved left ventricular ejection fraction and fractional shortening, reduced the fibrotic area, and increased the capillary density in the risk area. At 4 hours of reperfusion, Bcl-2 protein was overexpressed and the incidence of TUNEL-positive myocytes was significantly decreased in the risk area in the HGF group compared with the LacZ and saline groups. The myocardial interstitial 2,5-dihydroxybenzoic acid level, an indicator of hydroxyl radical, increased during 30 minutes of ischemia and 30 minutes of reperfusion in the LacZ and saline groups, and was significantly inhibited in the HGF group. HGF gene therapy may be a novel therapeutic strategy against unstable angina pectoris or severe angina pectoris, which may progress to acute myocardial infarction.
  Journal of cardiac failure 01/2008; 13(10):874-83. · 3.25 Impact Factor
• Article: Pravastatin reduces myocardial infarct size via increasing protein kinase C-dependent nitric oxide, decreasing oxyradicals and opening the mitochondrial adenosine triphosphate-sensitive potassium channels in rabbits.

  Narentuoya Bao, Shinya Minatoguchi, Hiroyuki Kobayashi, Shinji Yasuda, Itta Kawamura, Masamitsu Iwasa, Takahiko Yamaki, Syohei Sumi, Yu Misao, Masazumi Arai, Kazuhiko Nishigaki, Genzou Takemura, Takako Fujiwara, Hisayoshi Fujiwara
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  ABSTRACT: Statins reportedly protect against myocardial infarction, but the precise mechanism is unclear. Rabbits underwent 30 min of coronary occlusion followed by 48 h of reperfusion. Pravastatin (1 or 5 mg/kg) or saline was intravenously administered 10 min before ischemia. Pravastatin (5 mg/kg) was also administered 10 min before reperfusion. N(omega)-nitro-L-arginine methylester (L-NAME, 10 mg/kg), chelerythrine (5 mg/kg) or 5-hydroxydecanoic acid sodium salt (5-HD, 5 mg/kg) was intravenously administered 10 min before pravastatin injection. The infarct size was determined. The myocardial interstitial levels of 2,5-dihydroxybenzoic acid (DHBA) and nitrogen oxide (NOx), and the intensity of myocardial dihydroethidium staining were measured. Pre-ischemic treatment with pravastatin reduced the infarct size (34+/-5% and 24+/-4%, 1 and 5 mg/kg, respectively), but not pre-reperfusion treatment (42.1+/-3.7%), compared with the control (45+/-3%). This effect was blocked by L-NAME (42.6+/-4%), chelerythrine (50.9+/-3%) and 5-HD (52.7+/-2%). Pre-ischemic treatment with pravastatin increased myocardial NOx levels, and attenuated both the 2,5-DHBA level and the intensity of dihydroethidium staining during reperfusion. Chelerythrine abolished the increase in NOx levels by pravastatin. Pre-ischemic treatment with pravastatin reduces the myocardial infarct size via protein kinase C-dependent nitric oxide production, decreasing hydroxyl radicals and superoxide, and opening the mitochondrial adenosine triphosphate-sensitive potassium channels.
  Circulation Journal 11/2007; 71(10):1622-8. · 3.77 Impact Factor
• Article: Nicorandil improves post-ischemic myocardial dysfunction in association with opening the mitochondrial K(ATP) channels and decreasing hydroxyl radicals in isolated rat hearts.

  Chuanjiang Lu, Shinya Minatoguchi, Masazumi Arai, Ningyuan Wang, Xue-Hai Chen, Narentuoya Bao, Itta Kawamura, Shinji Yasuda, Hiroyuki Kobayashi, Der-Jinn Wu, Genzou Takemura, Hisayoshi Fujiwara
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  ABSTRACT: Nicorandil has been reported to induce cardioprotection by opening the mitochondrial K(ATP) channels. However, whether nicorandil affects reactive oxygen species is unclear. The hearts of male Sprague-Dawley rats were excised and perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O(2) and 5% CO(2). 1 mmol/L of nicorandil was given 10 min before ischemia. Left ventricular developed pressure (LVDP, mmHg), +/-dP/dt (mmHg/s) and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 min consisting of a 30 min pre-ischemic period, followed by a 30 min global ischemia and 60 min reperfusion with and without 5-hydroxydecanoic acid sodium salt (5-HD), a mitochondrial K(ATP) channel blocker. The concentrations of 2,3-dihydroxybenzoic acid (2,3-DHBA), an indicator of hydroxyl radicals, in the perfusate during reperfusion period were also measured. Nicorandil significantly improved LVDP and +/-dP/dt, and increased coronary flow during reperfusion. Pretreatment with 5-HD abolished the improvement of LVDP and +/-dP/dt, and the increase in coronary flow induced by nicorandil. Nicorandil significantly attenuated the concentrations of 2,3-DHBA during reperfusion, which were restored by 5-HD. Nicorandil is protective against post-ischemic left ventricular dysfunction in association with opening the mitochondrial K(ATP) channels, decreasing hydroxyl radicals and increasing coronary flow in the isolated rat heart.
  Circulation Journal 01/2007; 70(12):1650-4. · 3.77 Impact Factor
• Article: Edaravone reduces myocardial infarct size and improves cardiac function and remodelling in rabbits.

  Hirohito Onogi, Shinya Minatoguchi, Xue-Hai Chen, Narentuoya Bao, Hiroyuki Kobayashi, Yu Misao, Shinji Yasuda, Takahiko Yamaki, Rumi Maruyama, Yoshihiro Uno, Masazumi Arai, Genzou Takemura, Hisayoshi Fujiwara
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  ABSTRACT: 1. In the present study, we investigated the effect of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), a free radical scavenger, on myocardial infarct (MI) size and cardiac function in an in vivo model of MI in rabbits. We further investigated the contribution of hydroxyl radicals, superoxide and nitric oxide (NO) to its effects. 2. Anaesthetized open-chest Japanese white male rabbits were subjected to 30 min coronary occlusion and 48 h reperfusion. The control group (n = 10) was injected with saline 10 min before reperfusion. The edaravone group (n = 10) was injected with a bolus of 3 mg/kg edaravone 10 min before reperfusion. The edaravone + N(G)-nitro-L-arginine methyl ester (L-NAME) group (n = 5) was given 10 mg/kg, i.v., L-NAME 10 min before the administration of 3 mg/kg edaravone. The L-NAME group (n = 5) was given 10 mg/kg, i.v., L-NAME 20 min before reperfusion. Infarct size was measured using the triphenyl tetrazolium chloride method and is expressed as a percentage of area at risk. Cardiac function was assessed by echocardiography 14 days after infarction. 3. In another series of experiments, rabbits were subjected to 30 min coronary occlusion and 30 min reperfusion and myocardial interstitial 2,3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA levels, indicators of hydroxyl radical, were measured using a microdialysis technique. 4. Infarct size in the edaravone group was significantly reduced compared with that in the control group (27.4 +/- 6.8 vs 43.4 +/- 6.8%, respectively; P < 0.05). The edaravone-induced reduction of infarct size was abolished by pretreatment with L-NAME. Myocardial interstitial levels of 2,3-DHBA and 2,5-DHBA increased 20 and 30 min after ischaemia and peaked at 10 min reperfusion in the control group. Edaravone significantly inhibited the increase in 2,3-DHBA and 2,5-DHBA levels seen during reperfusion. Dihydroethidium staining showing in situ detection of superoxide was less intense in ischaemic myocardium in the edaravone-treated group compared with the control group. Edaravone improved cardiac function and left ventricular remodelling 14 days after infarction. 5. In conclusion, edaravone significantly reduces MI size and improves cardiac function and LV remodelling by decreasing hydroxyl radicals and superoxide in the myocardium and increasing the production of NO during reperfusion in rabbits.
  Clinical and Experimental Pharmacology and Physiology 12/2006; 33(11):1035-41. · 1.85 Impact Factor
• Article: Myocardial perfusion during transient slow-flow in the patient with old vein graft intervention: assessment by serial measurement of pressure-derived fractional flow reserve and thermodilution-derived coronary flow reserve.

  Hitoshi Matsuo, Sachiro Watanabe, Shinji Yasuda, Takeshi Hirose, Makoto Iwama, Shinichiro Tanaka, Takahiko Yamaki, Kouji Ono, Haruki Takahashi, Tomonori Segawa, Yukihiko Matsuno, Shinya Minatoguchi, Hisayoshi Fujiwara
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  ABSTRACT: A patient with distal slow-flow after stenting in the old vein graft intervention was reported. This case is a first in whom guidewire-based serial measurement of pressure-derived fractional flow reserve (FFR(myo)) and thermodilution-based coronary flow reserve (CFR(thermo)) clearly demonstrated the serial change of microvascular circulation. During slow-flow, CFR(thermo) remained in low value despite significant improvement of FFR(myo) from 0.61 to 0.90. After thrombus aspiration and nicorandil injection, coronary flow reestablished immediately. CFR(thermo) improved significantly from 1.3 during slow-flow to 3.6 after restoration of flow.
  Catheterization and Cardiovascular Interventions 12/2003; 60(3):392-8. · 2.29 Impact Factor
• Article: Evidence of pharmacologic preconditioning during PTCA by intravenous pretreatment with ATP-sensitive K+ channel opener nicorandil.

  Hitoshi Matsuo, Sachiro Watanabe, Tomonori Segawa, Shinji Yasuda, Takeshi Hirose, Makoto Iwama, Shinichiro Tanaka, Takahiko Yamaki, Yukihiko Matsuno, Masaaki Tomita, Shinya Minatoguchi, Hisayoshi Fujiwara
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  ABSTRACT: It is not known whether pretreatment with nicorandil, an ATP-sensitive K+ channel (K(ATP)channel) opener, induces a preconditioning effect independent of increased collateral recruitment. Forty-four patients with angina who underwent percutaneous transluminal coronary angioplasty (PTCA) to proximal left anterior descending artery (LAD) stenosis were randomly allocated for pretreatment with an intravenous injection of 80 g/kg nicorandil 5 min before initial ballooning (n=22) or saline (n=22). 99mTc tetrofosmin was injected during balloon inflation, quantitative analysis of occlusion images by SPECT was conducted, and the defect severity score (SS) was calculated. An ECG was recorded during the 2-min inflation to calculate the sum of ST elevation (sigmaST). SigmaST levels were significantly reduced in patients with nicorandil pretreatment compared with control patients (control:1.89+/-0.85 mV nicorandil:1.24+/-0.57 mV, p=0.0052). However, no difference was observed in defect severity (control: 79.0+/-32.5, nicorandil: 98.7+/-48.9 ns). A close correlation was observed between SS and sigmaST in both groups (nicorandil group R(2)=0.505, control group R(2)=0.599). A multivariate regression model demonstrated that both defect severity (p<0.0001) and pretreatment with nicorandil (p<0.001) were significantly related to the level of sigmaST, suggesting a cellular protective effect against ischaemia by nicorandil, independent of myocardial blood flow. Nicorandil pretreatment resulted in the induction of myocardial preconditioning independent of the severity of ischaemia.
  European Heart Journal 07/2003; 24(14):1296-303. · 10.48 Impact Factor
• Article: FRS-043 Voglibose Reduces Myocardial Infarct Size via Stimulation of GLP-1 Receptors and PI3 kinase-Akt-eNOS Pathway in Rabbits

  Masamitsu Iwasa, Hiroyuki Kobayashi, Shinji Yasuda, Naren two ya BAO, Takahiko Yamaki, Shohei Sumi, Hiroaki Ushikoshi, Kazuhiko Nishigaki, Genzou Takemura, Takako Fujiwara, Hisayoshi Fujiwara, Shinya Minatoguchi
• Article: OE-423 Relation between Various Risk Factors and Tissue Characterization of Atherosclerosis in Coronary Arteries (An Integrated Backscatter Intravascular Ultrasound Study)

  Munenori Okubo, Masanori Kawasaki, Keiji Sano, Yoko ITOH, Haruko Yokoyama, Tomoki Kubota, Shinji Yasuda, Shinichiro Tanaka, Tomohisa HIRANO, Kunihiko Tsuchiya, Shinsuke Ojio, Genzou Takemura, Kazuhiko Nishigaki, Shinya Minatoguchi, Hisayoshi Fujiwara
• Article: FRS-092 A New Real-time System for Tissue Characterization of Coronary Plaques Using Integrated Backscatter Intravascular Ultrasound

  Munenori Okubo, Masanori Kawasaki, Keiji Sano, Yoshiyuki Ishihara, Urara MORI, Kenji SOH, Masamitsu Iwasa, Shinji Yasuda, Tomoki Kubota, Shinichiro Tanaka, Takahiko Yamaki, Shinsuke Ojio, Kunihiko Tsuchiya, Masazumi Arai, Genzou Takemura, Masanao Saio, Kazuhiko Nishigaki, Shinya Minatoguchi, Tsuyoshi Takami, Hisayoshi Fujiwara