2001 年度実績報告書

心臓突然死の発生機序と心筋保護薬による予防法の研究

研究課題

研究課題/領域番号	11357020
研究機関	山梨医科大学
研究代表者	橋本敬太郎山梨医科大学, 医学部, 教授 (10004665)
研究分担者	西勝英熊本大学, 医学部, 教授 (00040220) 木村純子福島県立医科大学, 医学部, 教授 (10186322) 中谷晴昭千葉大学, 医学部, 教授 (60113594) 辻本豪三国立成育医療センター研究所, 薬剤治療研究部, 部長(研究職) (80172013)
キーワード	不整脈 / 心臓突然死 / 心臓保護薬 / Na / H交換 / Na / Ca交換 / AVブロック
研究概要	心筋梗塞や、急性虚血再潅流などによる心室細動、また交感神経緊張モデルとしてアドレナリン不整脈をイヌ、ラット、モルモットなどで作成し突然死モデルとした。その予防にNa/H交換機構、Na/Ca交換機構、心筋細胞膜のK_<ATP>チャネルに作用点を持つ心筋保護薬の作用を検討した。本年度はNa/H交換抑制薬としてFR168888のラット心室細動モデルに対する作用を検討し、一般的にNa/H交換阻害薬が虚血再潅流に伴う急性死を抑制出来る可能性を示した。同様に新規の大阪大学薬学部で開発されたNa/Ca交換抑制薬についても検討したが、虚血再潅流やジギタリスによる不整脈に無効であった。またK_<ATP>チャネル抑制薬はイヌ虚血中の不整脈は抑制したが、再潅流不整脈には有効とは言えなかった。さらに遺伝子を改変してα受容体やチャネル異常を持つマウスも開発も試みているが、受容体欠損ラットが早期死亡が多い可能性があり、不整脈によるものかを検討している。心筋保領薬の心臓突然死の予防作用や循環動態に対する作用、電気生理学的作用を検討したが、イヌ不整脈モデルの開発および循環動態の解析は橋本、西が行った。遺伝子改変動物の作成実験は中各、辻本が行い、電気生理学的実験は木村、中谷が行った。薬物標的受容体やトランスポーター蛋白などの解析は辻本が行った。

研究成果

(23件)

すべてその他

すべて文献書誌 (23件)

[文献書誌] Takahara A. et al.: "Cardiovascular action of a cardioselective Ca^<2+> channel blocker AH-1058 in conscious dogs assessed by telemetry"Euro. J. Pharmacol. 413. 101-108 (2001)
[文献書誌] Takahara A. et al.: "Utilization of telemetry system to assess the cardiovascular profile of AH-1058, a new cardioselective Ca^<2+> channel blocker, in conscious dogs"Jpn. J. Pharmacol. 85. 331-334 (2001)
[文献書誌] Homma N, et al.: "Electrophysiologic effects of an antiarrhythmic agent, bidisomide, on sodium current in isolated rat ventricular myocytes : Comparison with mexiletine and disopyramide"Jpn. J. Pharmacol. 86. 23-31 (2001)
[文献書誌] Miyamoto S, et al.: "Slowing Na^+ channel inactivation prolongs QT interval and aggravates adrenaline-induced arrhythmias"Jpn. J. Pharmacol. 86. 114-119 (2001)
[文献書誌] Sugiyama A. et al.: "Electropharmacologic effects of a new phosphodiesterase III inhibitor, toborinone(OPC-18790), assessed in an in vivo canine model"J. Cardiovasc. Pharmacol. 38. 268-277 (2001)
[文献書誌] Takahara A. et al.: "In vivo antiarrhythmic profile of AP-792 assessed in different canine arrhythmia models"Jpn. J. Pharmacol. 87. 21-26 (2001)
[文献書誌] Sugiyama A. et al.: "Acute electropharmacological effects of intravenously administered amiodarone assessed in the in vivo canine model"Jpn. J. Pharmacol. 87. 74-82 (2001)
[文献書誌] Noguchi K, et al.: "Effects of HNS-32, a novel antiarrhythmic agent, on guinea-pig myocardium"Pharmacology. 64. 36-42 (2002)
[文献書誌] Zhu BM et al.: "Inhibitory effects of pre-ischemic and post-ischemic treatment with FR 168888, a new Na^+/H^+ eschange inhibitor, on reperfusion-induced ventricular arrhythmias in anesthetized rat"Jpn. J. Pharmacol. 88. 93-99 (2002)
[文献書誌] Watanabe Yasuhide, et al.: "Inhibitory effect of 2, 3-butanedione monoxime(BDM)on Na^+-Ca^<2+> exchange current in guinea-pig cardiac ventricular myocytes"Br. J. Pharmacol. 132. 1317-1325 (2001)
[文献書誌] Watanabe Yasuhide, et al.: "Blocking effect of bepridil on Na^+-Ca^<2+> exchange current in guinea pig cardiac ventricular myocytes"Jpn. J. Pharmacol. 85. 370-375 (2001)
[文献書誌] Takano Shizuko, et al.: "Inhibition of aggregation of rabbit and human platelets induced by adrenaline and 5-hydroxytryptamine by KB-R7943, a Na^+-Ca^<2+> exchange inhibitor"Br. J. Pharmacol. 132. 1383-1388 (2001)
[文献書誌] Ishida H, et al.: "Opening of mitochondrial K_<ATP> channels attenuates the ouabain-induced calcium overload in mitochondria"Cir. Res. 89. 856-858 (2001)
[文献書誌] Kobayashi S, et al.: "Inhibitory effect of bepridil on hKv 1.5 channel current : comparison with amidarone and E-4031"Eur. J. Pharmacol. 430. 149-157 (2001)
[文献書誌] Suzuki M. et al.: "Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice"Circ. Res. 88. 570-577 (2001)
[文献書誌] Tanito Y. et al.: "Interaction of edrophonium with muscarinic acetylcholine M2 and M3 receptors"Anesthesiology. 94. 804-814 (2001)
[文献書誌] Suzuki T., et al.: "Beneficial effects of nitric oxide synthase Inhibition on the recovery of neurological function after spinal cord Injury In rats"Naunyn-Schmiedeberg's Arch Pharmacol. 363. 94-100 (2001)
[文献書誌] Suzuki M. et al.: "Role of sarcolemmal KATP channels In cardioprotection against Ischemia/reperfusion injury in mice"J. Clin Invest. 109. 509-516 (2001)
[文献書誌] Hirasawa Akira, et al.: "Regulation of subcellular localization of α 1-adrenoceptor subtypes"Life Sciences. 68. 2259-2267 (2001)
[文献書誌] Katsuma Susumu, et al.: "Molecular monitorin of bleomycin-Induced pulmonary fibrosis by cDNA microarray-based gene expression profiling"Biochemical and Biophysical Research Communications. 288. 747-751 (2001)
[文献書誌] Katsuma Susumu, et al.: "Genome medicine promised by microarray technology"Expert Rev. Mol. Diagn. 1(4). 377-382 (2001)
[文献書誌] Katsuma Susumu. et al.: "Genomic analysis of a mouse model of Immunoglobulin A nephropathy reveals and enhanced PDGF-EDG5 cascade"The Pharmacogenomics Journal. 1. 211-217 (2001)
[文献書誌] Yamauchi Junji. et al.: "Parallel regulation of Mitogen-activated protein kinase kinase 3(MKK3)and MKK6 In Gq-signaling cascade"The Journal of Biological Chemistry. 276(26). 233262-23372 (2001)

2001 年度 実績報告書

心臓突然死の発生機序と心筋保護薬による予防法の研究

研究代表者

橋本 敬太郎 山梨医科大学, 医学部, 教授 (10004665)

研究成果

[文献書誌] Takahara A. et al.: "Cardiovascular action of a cardioselective Ca^<2+> channel blocker AH-1058 in conscious dogs assessed by telemetry"Euro. J. Pharmacol. 413. 101-108 (2001)

[文献書誌] Takahara A. et al.: "Utilization of telemetry system to assess the cardiovascular profile of AH-1058, a new cardioselective Ca^<2+> channel blocker, in conscious dogs"Jpn. J. Pharmacol. 85. 331-334 (2001)

[文献書誌] Homma N, et al.: "Electrophysiologic effects of an antiarrhythmic agent, bidisomide, on sodium current in isolated rat ventricular myocytes : Comparison with mexiletine and disopyramide"Jpn. J. Pharmacol. 86. 23-31 (2001)

[文献書誌] Miyamoto S, et al.: "Slowing Na^+ channel inactivation prolongs QT interval and aggravates adrenaline-induced arrhythmias"Jpn. J. Pharmacol. 86. 114-119 (2001)

[文献書誌] Sugiyama A. et al.: "Electropharmacologic effects of a new phosphodiesterase III inhibitor, toborinone(OPC-18790), assessed in an in vivo canine model"J. Cardiovasc. Pharmacol. 38. 268-277 (2001)

[文献書誌] Takahara A. et al.: "In vivo antiarrhythmic profile of AP-792 assessed in different canine arrhythmia models"Jpn. J. Pharmacol. 87. 21-26 (2001)

[文献書誌] Sugiyama A. et al.: "Acute electropharmacological effects of intravenously administered amiodarone assessed in the in vivo canine model"Jpn. J. Pharmacol. 87. 74-82 (2001)

[文献書誌] Noguchi K, et al.: "Effects of HNS-32, a novel antiarrhythmic agent, on guinea-pig myocardium"Pharmacology. 64. 36-42 (2002)

[文献書誌] Zhu BM et al.: "Inhibitory effects of pre-ischemic and post-ischemic treatment with FR 168888, a new Na^+/H^+ eschange inhibitor, on reperfusion-induced ventricular arrhythmias in anesthetized rat"Jpn. J. Pharmacol. 88. 93-99 (2002)

[文献書誌] Watanabe Yasuhide, et al.: "Inhibitory effect of 2, 3-butanedione monoxime(BDM)on Na^+-Ca^<2+> exchange current in guinea-pig cardiac ventricular myocytes"Br. J. Pharmacol. 132. 1317-1325 (2001)

[文献書誌] Watanabe Yasuhide, et al.: "Blocking effect of bepridil on Na^+-Ca^<2+> exchange current in guinea pig cardiac ventricular myocytes"Jpn. J. Pharmacol. 85. 370-375 (2001)

[文献書誌] Takano Shizuko, et al.: "Inhibition of aggregation of rabbit and human platelets induced by adrenaline and 5-hydroxytryptamine by KB-R7943, a Na^+-Ca^<2+> exchange inhibitor"Br. J. Pharmacol. 132. 1383-1388 (2001)

[文献書誌] Ishida H, et al.: "Opening of mitochondrial K_<ATP> channels attenuates the ouabain-induced calcium overload in mitochondria"Cir. Res. 89. 856-858 (2001)

[文献書誌] Kobayashi S, et al.: "Inhibitory effect of bepridil on hKv 1.5 channel current : comparison with amidarone and E-4031"Eur. J. Pharmacol. 430. 149-157 (2001)

[文献書誌] Suzuki M. et al.: "Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice"Circ. Res. 88. 570-577 (2001)

[文献書誌] Tanito Y. et al.: "Interaction of edrophonium with muscarinic acetylcholine M2 and M3 receptors"Anesthesiology. 94. 804-814 (2001)

[文献書誌] Suzuki T., et al.: "Beneficial effects of nitric oxide synthase Inhibition on the recovery of neurological function after spinal cord Injury In rats"Naunyn-Schmiedeberg's Arch Pharmacol. 363. 94-100 (2001)

[文献書誌] Suzuki M. et al.: "Role of sarcolemmal KATP channels In cardioprotection against Ischemia/reperfusion injury in mice"J. Clin Invest. 109. 509-516 (2001)

[文献書誌] Hirasawa Akira, et al.: "Regulation of subcellular localization of α 1-adrenoceptor subtypes"Life Sciences. 68. 2259-2267 (2001)

[文献書誌] Katsuma Susumu, et al.: "Molecular monitorin of bleomycin-Induced pulmonary fibrosis by cDNA microarray-based gene expression profiling"Biochemical and Biophysical Research Communications. 288. 747-751 (2001)

[文献書誌] Katsuma Susumu, et al.: "Genome medicine promised by microarray technology"Expert Rev. Mol. Diagn. 1(4). 377-382 (2001)

[文献書誌] Katsuma Susumu. et al.: "Genomic analysis of a mouse model of Immunoglobulin A nephropathy reveals and enhanced PDGF-EDG5 cascade"The Pharmacogenomics Journal. 1. 211-217 (2001)

[文献書誌] Yamauchi Junji. et al.: "Parallel regulation of Mitogen-activated protein kinase kinase 3(MKK3)and MKK6 In Gq-signaling cascade"The Journal of Biological Chemistry. 276(26). 233262-23372 (2001)

2001 年度実績報告書

橋本敬太郎山梨医科大学, 医学部, 教授 (10004665)