2000 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 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, 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
Research Abstract	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。

Research Products

(26 results)

All Other

All Publications (26 results)

[Publications] Naito H: "Effects of zatebradine and propranolol on canine ischemia and reperfusion-induced arrhythmias."Europ.J.Pharmacol.. 388・2. 171-176 (2000)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] Chiba K.: "Proarrhythmic effects of fluoroquinolone antibacterial agents : In ivo effects as physiologic substrate for torsades."Toxicol.Appl.Pharmacol.. 169. 8-16 (2000)
[Publications] 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)
[Publications] 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)
[Publications] Irie T.: "Automated DNA fragment collection by capillary array gel electrophoresis in search of differentially expressed genes."Electrophoresis. 21. 367-374 (2000)
[Publications] 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)
[Publications] 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)
[Publications] Goda N.: "Structural organization and promoter analysis of the murine cytohesin-1 gene."Biochim.Biophys.Acta.. 1493. 195-199 (2000)
[Publications] Koshimizu T.: "Characterization of calcium signaling by purinergic receptor-channels expressed in excitable cells."Mol.Pharmacol.. 58. 936-945 (2000)
[Publications] 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)
[Publications] 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)
[Publications] Watanabe Y.: "Inhibitory effect of amiodarone on Na+/Ca2+ exchange current in guinea-pig cardiac myocytes."Brit.J.Pharmacol.. 131. 80-84 (2000)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] Nakaya H.: "Sarcolemmal ATP-sensitive K+ channels and cardiovascular function."Jpn.J.Electrocardiol.. 20 Suppl3. S3-113-S3-116 (2000)
[Publications] Hirota M.: "Influence of extracellular K+ concentrations on quinidine-induced K+ current inhibition in rat ventricular myocytes."J.Pharm.Pharmacol.. 52. 99-105 (2000)
[Publications] Tokutomi N.: "The Effects of Mexiletine on the Activity of Neuronal Voltage-gated Na^+ channels."Jpn.Pharmacol & Therapeutics. 28. 133-141 (2000)
[Publications] Lai ZF: "Enhancement of Intracellular Cl^- Concentrations Induced by Extracellular ATP in Guinea Pig Ventricurar Muscle."Jpn.J.Phamacol. 84. 438-448 (2000)
[Publications] Kimura J.: "Heart physiology and pathophysiology.4th ed"Academic Press (Sperelais N. et al. Eds.). 417-425 (2000)

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

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

[Publications] 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)

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

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

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

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

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

橋本敬太郎山梨医科大学, 医学部, 教授 (10004665)