2000 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) 辻本豪三国立小児病院, 小児医療研究センター, 部長 (80172013)
キーワード	心室細動 / Na / H交換 / Kチャネル / イオンチャネル / 不整脈モデル / トランスポーター
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、またアドレナリンなどによりイヌやラット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、その他のものとして心筋細胞膜のKATPチャネルの抑制薬などを含む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SMP-300とFR168888のラットとイヌの心室細動モデルに対する作用を検討し、両者とも有効であり、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Na/Ca交換抑制薬KBR7039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KATPチャネル抑制薬も理論上の推定と反して有効とは言えなかった。またQT延長を起こして催不整脈作用を示す薬物に関して、従来実験室で急性麻酔下に作製したハロセン・アドレナリン不整脈の悪化は、Kチャネル抑制薬では認められるが、同時にNaチャネルも抑制薬では悪化しないが、Naチャネルを不活性化してQTを延長させる薬物では悪化させることも示し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

(26件)

すべてその他

すべて文献書誌 (26件)

[文献書誌] Naito H: "Effects of zatebradine and propranolol on canine ischemia and reperfusion-induced arrhythmias."Europ.J.Pharmacol.. 388・2. 171-176 (2000)
[文献書誌] Saitoh M.: "Effects of HNS-32,a novel antiarrhythmic drug,on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats."Molecular and Cellular Biochemistry. 205・1-2. 133-140 (2000)
[文献書誌] Homma N.: "Both α_<1A>-and α_<1B>-adrenergic receptor subtypes couple to the transient outward curent (I_<to>) in rat ventricular myocytes."Brit.J.Pharmacol.. 129・6. 1113-1120 (2000)
[文献書誌] Satoh Y.: "Effect of magnesium sulfate on the haloperidol-induced QT prolongation assessed in the canine in vivo model under the monitoring of monophasic action potential."Jap.Circulation J.. 64・6. 445-451 (2000)
[文献書誌] Miyamoto S.: "QT-prolonging class I drug,disopyramide,does not aggravate but suppresses adrenaline-induced arrhythmias.Comparison with cibenzoline and pilsicainide."Europ.J.Pharmacol.. 400. 263-269 (2000)
[文献書誌] Aye N.N.: "Effects of MET-88,a γ-butyrobetaine hydroxylase inhibitor,on ischemia/reperfusion ventricular arrhythmias in anaesthetized animals in vivo."Asia Pacific J.Pharmacol.. 14. 93-99 (2000)
[文献書誌] Akie Y.: "Proarrhythmic effects of four class III antiarrhythmic drugs,MS-551,sematilide,dofetilide and KCB328,examined using ambulatory ECG."Asia Pacific J.Pharmacol.. 14. 101-109 (2000)
[文献書誌] Chiba K.: "Proarrhythmic effects of fluoroquinolone antibacterial agents : In ivo effects as physiologic substrate for torsades."Toxicol.Appl.Pharmacol.. 169. 8-16 (2000)
[文献書誌] Moriyama N: "Distribution of al-adrenoceptor subtype mRNA and identification of subtype responsible for renovascular contraction in human renal artery."Life Sciences. 66. 915-926 (2000)
[文献書誌] Shinoura H.: "Key amino acids of vasopressin V1a receptor responsible for the species difference in the affinity of OPC-21268."FEBS Letters. 466. 255-258 (2000)
[文献書誌] Irie T.: "Automated DNA fragment collection by capillary array gel electrophoresis in search of differentially expressed genes."Electrophoresis. 21. 367-374 (2000)
[文献書誌] Nakamura S.: "Characterization of a novel nonpeptide vasopressin V2-agonist, OPC-51803, in cells transfected human vasopressin receptor subtypes."Br.J.Pharmacol.. 129. 1700-1706 (2000)
[文献書誌] Shimoyama Y.: "Identification of three human type II classic cadherins and frequent heterophilic interactions between different subclasses of type II classic cadherins."Biochem.J.. 349. 159-167 (2000)
[文献書誌] Goda N.: "Structural organization and promoter analysis of the murine cytohesin-1 gene."Biochim.Biophys.Acta.. 1493. 195-199 (2000)
[文献書誌] Koshimizu T.: "Characterization of calcium signaling by purinergic receptor-channels expressed in excitable cells."Mol.Pharmacol.. 58. 936-945 (2000)
[文献書誌] Katoh Y.: "Inhibitory action of troglitazone, an insulin-sensitizing agent on the calcium current in cardiac ventricular cells of guinea pig."Jap.J.Pharmacol.. 82. 162-169 (2000)
[文献書誌] Hattori Y.: "Diminished function and expression of the cardiac Na+-Ca2+exchanger in diabetic rats : implication in Ca2+ overload."J.Physiol.. 82. 85-94 (2000)
[文献書誌] Watanabe Y.: "Inhibitory effect of amiodarone on Na+/Ca2+ exchange current in guinea-pig cardiac myocytes."Brit.J.Pharmacol.. 131. 80-84 (2000)
[文献書誌] Suzuki T.: "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] Nakaya H.: "Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea-pig hearts."Br.J.Pharmacol.. 131. 1363-1372 (2000)
[文献書誌] Sakurada K.: "cis-9,10-Metylenehexadecanoic acid inhibits contractility and actomyosin ATPase activity of guinea pig myocardium."Biochem.Biophys.Res.Communications.. 274. 533-536 (2000)
[文献書誌] Nakaya H.: "Sarcolemmal ATP-sensitive K+ channels and cardiovascular function."Jpn.J.Electrocardiol.. 20 Suppl3. S3-113-S3-116 (2000)
[文献書誌] Hirota M.: "Influence of extracellular K+ concentrations on quinidine-induced K+ current inhibition in rat ventricular myocytes."J.Pharm.Pharmacol.. 52. 99-105 (2000)
[文献書誌] Tokutomi N.: "The Effects of Mexiletine on the Activity of Neuronal Voltage-gated Na^+ channels."Jpn.Pharmacol & Therapeutics. 28. 133-141 (2000)
[文献書誌] Lai ZF: "Enhancement of Intracellular Cl^- Concentrations Induced by Extracellular ATP in Guinea Pig Ventricurar Muscle."Jpn.J.Phamacol. 84. 438-448 (2000)
[文献書誌] Kimura J.: "Heart physiology and pathophysiology.4th ed"Academic Press (Sperelais N. et al. Eds.). 417-425 (2000)

2000 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] Naito H: "Effects of zatebradine and propranolol on canine ischemia and reperfusion-induced arrhythmias."Europ.J.Pharmacol.. 388・2. 171-176 (2000)

[文献書誌] Saitoh M.: "Effects of HNS-32,a novel antiarrhythmic drug,on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats."Molecular and Cellular Biochemistry. 205・1-2. 133-140 (2000)

[文献書誌] Homma N.: "Both α_<1A>-and α_<1B>-adrenergic receptor subtypes couple to the transient outward curent (I_<to>) in rat ventricular myocytes."Brit.J.Pharmacol.. 129・6. 1113-1120 (2000)

[文献書誌] Satoh Y.: "Effect of magnesium sulfate on the haloperidol-induced QT prolongation assessed in the canine in vivo model under the monitoring of monophasic action potential."Jap.Circulation J.. 64・6. 445-451 (2000)

[文献書誌] Miyamoto S.: "QT-prolonging class I drug,disopyramide,does not aggravate but suppresses adrenaline-induced arrhythmias.Comparison with cibenzoline and pilsicainide."Europ.J.Pharmacol.. 400. 263-269 (2000)

[文献書誌] Aye N.N.: "Effects of MET-88,a γ-butyrobetaine hydroxylase inhibitor,on ischemia/reperfusion ventricular arrhythmias in anaesthetized animals in vivo."Asia Pacific J.Pharmacol.. 14. 93-99 (2000)

[文献書誌] Akie Y.: "Proarrhythmic effects of four class III antiarrhythmic drugs,MS-551,sematilide,dofetilide and KCB328,examined using ambulatory ECG."Asia Pacific J.Pharmacol.. 14. 101-109 (2000)

[文献書誌] Chiba K.: "Proarrhythmic effects of fluoroquinolone antibacterial agents : In ivo effects as physiologic substrate for torsades."Toxicol.Appl.Pharmacol.. 169. 8-16 (2000)

[文献書誌] Moriyama N: "Distribution of al-adrenoceptor subtype mRNA and identification of subtype responsible for renovascular contraction in human renal artery."Life Sciences. 66. 915-926 (2000)

[文献書誌] Shinoura H.: "Key amino acids of vasopressin V1a receptor responsible for the species difference in the affinity of OPC-21268."FEBS Letters. 466. 255-258 (2000)

[文献書誌] Irie T.: "Automated DNA fragment collection by capillary array gel electrophoresis in search of differentially expressed genes."Electrophoresis. 21. 367-374 (2000)

[文献書誌] Nakamura S.: "Characterization of a novel nonpeptide vasopressin V2-agonist, OPC-51803, in cells transfected human vasopressin receptor subtypes."Br.J.Pharmacol.. 129. 1700-1706 (2000)

[文献書誌] Shimoyama Y.: "Identification of three human type II classic cadherins and frequent heterophilic interactions between different subclasses of type II classic cadherins."Biochem.J.. 349. 159-167 (2000)

[文献書誌] Goda N.: "Structural organization and promoter analysis of the murine cytohesin-1 gene."Biochim.Biophys.Acta.. 1493. 195-199 (2000)

[文献書誌] Koshimizu T.: "Characterization of calcium signaling by purinergic receptor-channels expressed in excitable cells."Mol.Pharmacol.. 58. 936-945 (2000)

[文献書誌] Katoh Y.: "Inhibitory action of troglitazone, an insulin-sensitizing agent on the calcium current in cardiac ventricular cells of guinea pig."Jap.J.Pharmacol.. 82. 162-169 (2000)

[文献書誌] Hattori Y.: "Diminished function and expression of the cardiac Na+-Ca2+exchanger in diabetic rats : implication in Ca2+ overload."J.Physiol.. 82. 85-94 (2000)

[文献書誌] Watanabe Y.: "Inhibitory effect of amiodarone on Na+/Ca2+ exchange current in guinea-pig cardiac myocytes."Brit.J.Pharmacol.. 131. 80-84 (2000)

[文献書誌] Suzuki T.: "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] Nakaya H.: "Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea-pig hearts."Br.J.Pharmacol.. 131. 1363-1372 (2000)

[文献書誌] Sakurada K.: "cis-9,10-Metylenehexadecanoic acid inhibits contractility and actomyosin ATPase activity of guinea pig myocardium."Biochem.Biophys.Res.Communications.. 274. 533-536 (2000)

[文献書誌] Nakaya H.: "Sarcolemmal ATP-sensitive K+ channels and cardiovascular function."Jpn.J.Electrocardiol.. 20 Suppl3. S3-113-S3-116 (2000)

[文献書誌] Hirota M.: "Influence of extracellular K+ concentrations on quinidine-induced K+ current inhibition in rat ventricular myocytes."J.Pharm.Pharmacol.. 52. 99-105 (2000)

[文献書誌] Tokutomi N.: "The Effects of Mexiletine on the Activity of Neuronal Voltage-gated Na^+ channels."Jpn.Pharmacol & Therapeutics. 28. 133-141 (2000)

[文献書誌] Lai ZF: "Enhancement of Intracellular Cl^- Concentrations Induced by Extracellular ATP in Guinea Pig Ventricurar Muscle."Jpn.J.Phamacol. 84. 438-448 (2000)

[文献書誌] Kimura J.: "Heart physiology and pathophysiology.4th ed"Academic Press (Sperelais N. et al. Eds.). 417-425 (2000)

2000 年度実績報告書

橋本敬太郎山梨医科大学, 医学部, 教授 (10004665)