2003 Fiscal Year Annual Research Report

虚血心筋細胞死と新しい心筋保護薬

Research Project

Project/Area Number	14572168
Research Institution	Aichi Medical University School of Medicine
Principal Investigator	堀田芳弘愛知医科大学, 医学部, 教授 (40109757)
Co-Investigator(Kenkyū-buntansha)	矢島道夫愛知医科大学, 医学部, 講師 (50065596) 伊藤元愛知医科大学, 医学部, 教授 (10022823) 石川直久愛知医科大学, 医学部, 教授 (80109321) 川井範夫愛知医科大学, 医学部, 助教授 (50095535) 村上英嗣愛知医科大学, 医学部, 講師 (80131225)
Keywords	guinea-pig Langendorff hearts / ischemia-reperfused injury / ^<31>P-NMR / ESR / LVDP / apoptosis / Tunel / MPTP
Research Abstract	1.虚血再灌流細胞死であるTunelアポトーシス細胞(apo)はLangendorff心の灌流液のglucoseと酸素との両方を減少させると急激なATP、pHの低下を伴うミトコンドリアMit機能の低下を示し、認められた(Tong et al.,2001)。 2.Mit膜電位に関与しCa流入を伴うapoを生じ、Na-H交換阻害薬(NHEI)がこの作用を抑制したNHEIが心筋障害に有効との成績が得られ、構造中に塩素Cl(CL)とフッ素F(FL)をもち90%以上のLVDP回復を示す2つの化合物が合成された。活性酸素消去能を持つFLの方が、apo生成阻止作用はCLに比べ大きかった。活性酸素消去能を持たないCLは長時間の虚血再灌流ではFLよりも高いLVDPの回復を示した(Eur J Pharmacol in press 2004)。 3.また、5HT_<2A>拮抗薬(Mol Cell Biochem投稿中)および新たに合成された5HT_<1A>拮抗薬も抗虚血作用を示し、活性酸素消去、apo細胞、関係するcaspase3の生成阻止を示した(第77回薬理年会発表)。 4.酒類に含まれる環状ジペプチドも高い抗虚血作用を示し、MitへのCa^<2+>の取り込みの抑制、活性酸素消去、apo細胞、関係するcaspase3の生成阻止を示した(第77回薬理年会発表)。 5.灌流Mit標本での灌流液のpH, Ca濃度の変化による急激なMitへのCa取り込みは、Mit permeability transition pore(MPTP)のopener, atractylosideで同様にMitへCa^<2+>は取り込まれ、MTPTのblocker, cyclosporin Aにより抑制された(第77回薬理年会発表)。これらのことから、虚血再灌流障害はMitのPTPを生じチトクロームCが放出され、アポトーシス細胞の発生に関与するcaspace3を活性化する経路の関与が考えられる。

Research Products

(10 results)

All Other

All Publications (10 results)

[Publications] Yoshihiro Hotta et al.: "Protective effects of antioxidative serotonin derivatives isolated from safflower against postischemic myocardial dysfunction."Mol Cell Biochem. 238. 151-162 (2002)
[Publications] Yamada Jun et al.: "(±)-pyrapyridolol, a new pyrazolo [1, 5-a]pyridirie derivative, inhibits 5-HT_<1A> receptor-mediated behavior in mice."Pharmacol Rev Commun. 12. 197-203 (2002)
[Publications] Yoshihiro Hotta et al.: "Different effects of NHEI inhibitors on cardiac function and cardiomyocyte apoptosis in guinea pig ischemia-reperfused hearts."J Pharmacol Sci. 91・Suppl. I. 139 (2003)
[Publications] Tatsuya Muto et al.: "Protective effects of 5-HT antagonists, against postischemic myocardial dysfunction in guinea pig hearts."J Pharmacol Sci. 91・Suppl. I. 143 (2003)
[Publications] Michio Yajima et al.: "Protective effects of antioxidative radical scavenger edaravone against postischemic myocardial dysfunction in quinea-pig hearts:^<31>P-NMR and ESR measurements of cellular energy and free radical."J Pharmacol Sci. 91・Suppl. I. 152 (2003)
[Publications] 芥川隆, 古川忠志, 高谷芳明, 丹羽正武, 堀田芳弘, 石川直久: "環状ジペプチドの合成と抗酸化活性"日本薬学会東海支部例会要旨集. 31 (2003)
[Publications] Yoshihiro Hotta et al.: "Differences in the effects of Na^+_H^+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts."Eur J Pharmacol. 12(in press). (2004)
[Publications] Yoshihiro Hotta et al.: "The permeability transition pores (MPTP) against post-ischemic myocardial dysfunction."J Pharmacol Sci. 94・Suppl. I. 159 (2004)
[Publications] Lei Huang et al.: "Different effects on optical isomers of the 5-HT1A antagonist pyrapyridolol against postischemic myocardial dysfunction in guinea-pig hearts."J Pharmacol Sci. 94・Suppl. I. 159 (2004)
[Publications] Takashi Akutagawa et al.: "Protective effects of the cyclic dipeptides in alcohol beverages against ischemia/reperfusion injury in guinea-pig hearts."J Pharmacol Sci. 94・Suppl. I. 159 (2004)

2003 Fiscal Year Annual Research Report

虚血心筋細胞死と新しい心筋保護薬

Principal Investigator

堀田 芳弘 愛知医科大学, 医学部, 教授 (40109757)

Research Products

[Publications] Yoshihiro Hotta et al.: "Protective effects of antioxidative serotonin derivatives isolated from safflower against postischemic myocardial dysfunction."Mol Cell Biochem. 238. 151-162 (2002)

[Publications] Yamada Jun et al.: "(±)-pyrapyridolol, a new pyrazolo [1, 5-a]pyridirie derivative, inhibits 5-HT_<1A> receptor-mediated behavior in mice."Pharmacol Rev Commun. 12. 197-203 (2002)

[Publications] Yoshihiro Hotta et al.: "Different effects of NHEI inhibitors on cardiac function and cardiomyocyte apoptosis in guinea pig ischemia-reperfused hearts."J Pharmacol Sci. 91・Suppl. I. 139 (2003)

[Publications] Tatsuya Muto et al.: "Protective effects of 5-HT antagonists, against postischemic myocardial dysfunction in guinea pig hearts."J Pharmacol Sci. 91・Suppl. I. 143 (2003)

[Publications] Michio Yajima et al.: "Protective effects of antioxidative radical scavenger edaravone against postischemic myocardial dysfunction in quinea-pig hearts:^<31>P-NMR and ESR measurements of cellular energy and free radical."J Pharmacol Sci. 91・Suppl. I. 152 (2003)

[Publications] 芥川隆, 古川忠志, 高谷芳明, 丹羽正武, 堀田芳弘, 石川直久: "環状ジペプチドの合成と抗酸化活性"日本薬学会東海支部例会 要旨集. 31 (2003)

[Publications] Yoshihiro Hotta et al.: "Differences in the effects of Na^+_H^+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts."Eur J Pharmacol. 12(in press). (2004)

[Publications] Yoshihiro Hotta et al.: "The permeability transition pores (MPTP) against post-ischemic myocardial dysfunction."J Pharmacol Sci. 94・Suppl. I. 159 (2004)

[Publications] Lei Huang et al.: "Different effects on optical isomers of the 5-HT1A antagonist pyrapyridolol against postischemic myocardial dysfunction in guinea-pig hearts."J Pharmacol Sci. 94・Suppl. I. 159 (2004)

[Publications] Takashi Akutagawa et al.: "Protective effects of the cyclic dipeptides in alcohol beverages against ischemia/reperfusion injury in guinea-pig hearts."J Pharmacol Sci. 94・Suppl. I. 159 (2004)

堀田芳弘愛知医科大学, 医学部, 教授 (40109757)

[Publications] 芥川隆, 古川忠志, 高谷芳明, 丹羽正武, 堀田芳弘, 石川直久: "環状ジペプチドの合成と抗酸化活性"日本薬学会東海支部例会要旨集. 31 (2003)