1999 Fiscal Year Annual Research Report

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

Research Project

Project/Area Number	11357020
Research Category	Grant-in-Aid for Scientific Research (A)
Research Institution	山梨医科大学
Principal Investigator	橋本敬太郎山梨医科大学, 医学部, 教授 (10004665)
Co-Investigator(Kenkyū-buntansha)	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, 助教授 (10186322) 中谷晴昭千葉大学, 医学部, 教授 (60113594) 辻本豪三国立小児病院, 小児医療研究センター, 部長 (80172013)
Keywords	心筋梗塞 / イヌ / 心室性不整脈 / Na / H交換 / Na / Ca交換 / AVブロック
Research Abstract	心筋梗塞モデルや、慢性房室ブロック犬に交感神経亢進とを組み合わせることにより、イヌで不整脈による突然死が起こるモデルをいくつか作り、その予防にNa/H交換やNa/Ca交換などの心筋トランスポーターを抑制する薬物や、その他の心筋保護薬の作用を検討した。動物の不整脈モデルは、従来実験室で急性麻酔下に作製し、薬物の急性効果を検討するのに適したものが多かったが、臨床でみられる様な長い時間のうちで突然発生する不整脈のモデルとして慢性動物モデルでの突然死を起こすものの開発を行った。ホルター心電計により、無麻酔下での長時間記録が行なえる様になり、Kチャネル抑制クラスIII抗不整脈薬について無麻酔実験を行なったが、正常犬では重症な不整脈を誘発することは出来なかった。房室ブロック犬と高頻度刺激心不全犬モデルを用い突然死が交感神経作用薬との併用で起こり易くなること、Kチャネル抑制薬で心室細動死を起こし易くなることを証明できた。さらに遺伝子を改変してチャネル異常を持つマウスも開発も試みているが、現段階では成功していない。心筋保護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谷、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。

Research Products
(17 results)

All Other

All Publications (17 results)

[Publications] Sugiyama, A: "Cariporide, a highly selective Na^+/H^+ exchange inhibitor, suppresses the reperfusion-induced lethal arrhythmias and "overshoot" phenomenon of creatine phosphate in situ rat heart."J. Cardiovasc. Pharmacol.. 33. 116-121 (1999)
[Publications] Aye, N.N.: "Effects and interaction, of cariporide and preconditioning on cardiac arrhythmias and infarction in rat in vivo."Brit. J. Pharmacol.. 127. 1048-1055 (1999)
[Publications] Xue, Y.X.: "Effects of azimilide, a K_<V(r)> and K_<V(s)> blocker, on canine ventricular arrhythmia models."Europ. J. Pharmacol.. 376. 27-35 (1999)
[Publications] Hashimoto, K.: "Antiarrhythmic effects of Na^+/H^+ exchange inhibitors."European Heart J. Supplements. 1(Suppl K). K31-K37 (1999)
[Publications] Arita, J.: "Rapid pacing-induced heart failure aggravates reperfusion arrhythmias in dogs"Asia Pacific J. Pharmacol.. 13. 137-144 (1998)
[Publications] Ohmoto-Sekine Y: "Inhibitory effects of aprindine on the delayed rectifier K+ current and the muscarinic acetylcholine receptor-operated K+ current in guinea-pig atrial cells."Br J Pharmacol. 126・2. 751-761 (1999)
[Publications] Takahara A: "Effect of AH-1058, a new antiarrhythmic drug, on experimental arrhythmias and cardiac membrane currents."J Cardiovasc Pharmacol. 33. 625-632 (1999)
[Publications] Matumoto Y: "Histamine H1-receptor-mediated modulation of the delayed rectifier K+ current in guinea-pig atrial cells: opposite effects on IKs and IKr."Br J Pharmacol. 128. 1545-1553 (1999)
[Publications] 中谷晴昭: "K+チャネル遮断薬の展望 -IKr遮断薬から次世代へ-."循環器. 45. 227-232 (1999)
[Publications] 中谷晴昭: "不整脈を起こす心臓病の分子生物学的背景."Therapeutic Research. 20. 9-14 (1999)
[Publications] Torihashi S: "Blockade of Kit signaling induced transdifferentiation of interstitial cells of Cajal to a smooth muscle phenotipe."Gastroenterology. 117. 140-148 (1999)
[Publications] Liu J: "Differential roles of Ca2+/calmodulin-dependent proteinkinase II and mitogen-activated proteinkinase activation in Hippocampal long-term potentiation."J. Neuroscience. 19. 8292-8299 (1999)
[Publications] Kimura, J.: "Effects of novel cardioprotective drug, JTV-519, on membrane currents of guinea pig ventricular myocytes."Jpn. J. Pharmacol.. 79. 275-281 (1999)
[Publications] Kimura, J.: "Direction-independent block of bi-directional Na+/Ca2+ exchange current by KB-R7943 in guinea-pig cardiac myocytes."Br. J. Pharmacol.. 128. 969-974 (1999)
[Publications] Takei, R.: "A novel α 1-adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human α 1-adrenoceptors."Jpn. J. Pharmacol.. 79. 447-454 (1999)
[Publications] Ohmi, K.: "Characterization of α 1-adrenoceptors expressed in a novel vascular smooth muscle cell line cloned from p53 knock out mice, P53LMAC01(AC01) cells."Br. J. Pharmacol.. 127. 756-762 (1999)
[Publications] Moriyama, N.: "Semiquantitative evaluation of α 1a-adrenoceptor subtype mRNA in human hypertrophied prostate and non-hypertrophied prostate: regional comparison."Life Sciences. 64・3. 201-210 (1999)

1999 Fiscal Year Annual Research Report

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

Principal Investigator

橋本 敬太郎 山梨医科大学, 医学部, 教授 (10004665)

Research Products

[Publications] Sugiyama, A: "Cariporide, a highly selective Na^+/H^+ exchange inhibitor, suppresses the reperfusion-induced lethal arrhythmias and "overshoot" phenomenon of creatine phosphate in situ rat heart."J. Cardiovasc. Pharmacol.. 33. 116-121 (1999)

[Publications] Aye, N.N.: "Effects and interaction, of cariporide and preconditioning on cardiac arrhythmias and infarction in rat in vivo."Brit. J. Pharmacol.. 127. 1048-1055 (1999)

[Publications] Xue, Y.X.: "Effects of azimilide, a K_<V(r)> and K_<V(s)> blocker, on canine ventricular arrhythmia models."Europ. J. Pharmacol.. 376. 27-35 (1999)

[Publications] Hashimoto, K.: "Antiarrhythmic effects of Na^+/H^+ exchange inhibitors."European Heart J. Supplements. 1(Suppl K). K31-K37 (1999)

[Publications] Arita, J.: "Rapid pacing-induced heart failure aggravates reperfusion arrhythmias in dogs"Asia Pacific J. Pharmacol.. 13. 137-144 (1998)

[Publications] Ohmoto-Sekine Y: "Inhibitory effects of aprindine on the delayed rectifier K+ current and the muscarinic acetylcholine receptor-operated K+ current in guinea-pig atrial cells."Br J Pharmacol. 126・2. 751-761 (1999)

[Publications] Takahara A: "Effect of AH-1058, a new antiarrhythmic drug, on experimental arrhythmias and cardiac membrane currents."J Cardiovasc Pharmacol. 33. 625-632 (1999)

[Publications] Matumoto Y: "Histamine H1-receptor-mediated modulation of the delayed rectifier K+ current in guinea-pig atrial cells: opposite effects on IKs and IKr."Br J Pharmacol. 128. 1545-1553 (1999)

[Publications] 中谷晴昭: "K+チャネル遮断薬の展望 -IKr遮断薬から次世代へ-."循環器. 45. 227-232 (1999)

[Publications] 中谷晴昭: "不整脈を起こす心臓病の分子生物学的背景."Therapeutic Research. 20. 9-14 (1999)

[Publications] Torihashi S: "Blockade of Kit signaling induced transdifferentiation of interstitial cells of Cajal to a smooth muscle phenotipe."Gastroenterology. 117. 140-148 (1999)

[Publications] Liu J: "Differential roles of Ca2+/calmodulin-dependent proteinkinase II and mitogen-activated proteinkinase activation in Hippocampal long-term potentiation."J. Neuroscience. 19. 8292-8299 (1999)

[Publications] Kimura, J.: "Effects of novel cardioprotective drug, JTV-519, on membrane currents of guinea pig ventricular myocytes."Jpn. J. Pharmacol.. 79. 275-281 (1999)

[Publications] Kimura, J.: "Direction-independent block of bi-directional Na+/Ca2+ exchange current by KB-R7943 in guinea-pig cardiac myocytes."Br. J. Pharmacol.. 128. 969-974 (1999)

[Publications] Takei, R.: "A novel α 1-adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human α 1-adrenoceptors."Jpn. J. Pharmacol.. 79. 447-454 (1999)

[Publications] Ohmi, K.: "Characterization of α 1-adrenoceptors expressed in a novel vascular smooth muscle cell line cloned from p53 knock out mice, P53LMAC01(AC01) cells."Br. J. Pharmacol.. 127. 756-762 (1999)

[Publications] Moriyama, N.: "Semiquantitative evaluation of α 1a-adrenoceptor subtype mRNA in human hypertrophied prostate and non-hypertrophied prostate: regional comparison."Life Sciences. 64・3. 201-210 (1999)

橋本敬太郎山梨医科大学, 医学部, 教授 (10004665)