心筋細胞機能障害と心作動物質

1989 Fiscal Year Annual Research Report

• Project/Area Number: 01624001
• Research Institution: The University of Tokyo
• Principal Investigator: 杉本 恒明 東京大学, 医学部, 教授 (60019883)
• Co-Investigator(Kenkyū-buntansha): 西 勝英 熊本大学, 医学部, 教授 (00040220) ; 平 則夫 東北大学, 医学部, 教授 (60004553) ; 栗原 敏 慈恵会医科大学, 医学部, 教授 (90057026) ; 中村 隆雄 大阪大学, 理学部, 教授 (30028112) ; 栗山 ひろし 九州大学, 医学部, 教授 (40037495)
• Keywords: プロスタグランジン / Gタンパク / GTP / Ca^<2+>トランジエント / 強心薬 / 抗不整脈薬 / 内因性ジギタリス様物質 / エンドセリン

Research Abstract

1.心筋の興奮・収縮に対する心作動物質の作用:べーター活性薬作用、cAMP、タンパク燐酸化、Ca動態の関連が拍動能を保持した単離心室筋細胞を用いた実験系において明らかになった(中村)。他方、乳頭筋標本を用いた実験において、これらの点についての再検討が必要であることが見出された(栗原)。選択的ベーター部分活性薬の薬理学的作用の相異の機序が受容体理論解析から検討され、高親和性選択刺激の重要性が示された(平)。2.心筋細胞膜イオン流の解析:心筋細胞内のイオン活性をイオン選択性電極法を用いて測定し、細胞内Na、Ca、K、そしてHイオンの動きが直接に観察された(西)。心房筋電流系においてアラキドン酸の5ーリポキシゲナーゼ代謝物がGタンパクを活性化し、Kチャネル電流系を開くことが知られた(杉本)。3.病的状態の心筋における検討:低酸素状態で流出する脂肪酸結合タンパクは心筋障害のマーカーになり得ることが見られた(安田)。虚血、再潅流時の心室筋標本のアセチルコリン、ノルエピネフリン量、cAMP量の変動とこれを修飾する要因の関与が検討され(小川)、また、この状況を想定した状態では活動電位立ち上り速度の使用依存性抑制への効果から抗不整脈薬の分類が試みられた(外山)。4.心作動物質:内因性ジギタリス様物質はほぼ精製され、その血管収縮性と細胞内機構の解明が進んだ(杉本)。本物質は糖尿病性心筋症発症に関与することも推測された(竹田)。内因性プロスタサイクリンは血管平滑筋細胞増殖の自己調節作用に関係する(杉本)。エンドセリンは心室筋陽性変力作用をもつが、これは加令にともない減弱する(真崎)。硝酸薬、Kチャネルオープナーの血管平滑筋作用におけるcGMPの関与が検討された(栗山)。

Research Products

• [Publications] Yoshida A.et al.: "Bi-directional regulation of dephosphorylation of cAMP-dependent phosphorylated proteins by cAMP and calcium in permeabilized rat heart cells" J Biochem. (1989)
• [Publications] Yano T,et al.: "Acidosis depresses delayed afterdepolarization in guinea-pig myocardium" Am J Physiol. 26. (1989)
• [Publications] Kurihara S,et al.: "Modulation of Ca transients and tension by beta-adrenergic and muscarinic receptor stimulation in mammalian ventricular muscles" Proc IUPS. 17. 193 (1989)
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• [Publications] Yokoyama H,et al.: "An explanation of bell-shaped,dose-positive inotropic effect curves for dopamine in canine right ventricular muscle" J Cardiovasc Pharmacol. (1989)
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• [Publications] Morise T,et al.: "Biological activity of partially purified digitalis-like substance and Na-K-ATPase inhibitor in rats" Jpn Circ J. 32. 405-411 (1989)
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• [Publications] Kodama I,et al.: "Electrophysiological effects of TYB-3823,a new antiarrhythmic agent,on isolated guinea pig ventricular muscles" J Cardiovasc Pharmacol. 13. 616-623 (1989)
• [Publications] Honjo H,et al.: "Effects of propafenone on electrical and mechanical activities of single ventricular myocytes isolated from guinea pig hearts" Br J Pharmacol. (1989)
• [Publications] Goto A,et al.: "The effects of urinary digitalis-like factor on factor on cultured vascular smooth muscle cells" Hypertension. 11. 645-650 (1988)
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• [Publications] Kurachi Y,et al.: "Arachidonic acid metabolites as intracellular modulators of G protein-gated cardiac K^+ channel" Nature. 337. 555-557 (1989)
• [Publications] Nakajima T,et al.: "Anticholinergic effects of quinidine,disopyramide,and procainamide in isolated atrial myocytes:Mediation by different molecular mechanisms" Circ Res. 64. 297-303 (1989)
• [Publications] Kurachi Y,et al.: "Activation of atrial muscarinic K^+ channels by low concentrations of beta:gamma subunits of rat brain G protein" Pfluegers Archiv(Eur J Physiol). 413. 325-327 (1989)
• [Publications] Fu-iwara T,et al.: "Actions of a phorbol ester on factors regulating contraction in rabbit mesenteric artery" Circ Res. 63. 893-902 (1988)
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• [Publications] Ishikawa T,et al.: "Positive inotropic action of novel vasoconstrictor peptide on guinea pig atria" Am J Physiol. 255. H970-H973 (1988)
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• [Publications] Okamoto H,et al.: "Lipid alterations in renal membrane of stroke-prone spontaneously hypertensive rats" Hypertension. 13. 456-462 (1989)
• [Publications] Okumura K,et al.: "Alteration of 1,2-diacylglycerol content in myocardium from diabetic rats" Diabetes. 37. 1168-1172 (1988)
• [Publications] Okumura K,et al.: "Increased 1,2-diacylglycerol content in myopathic hamster hearts at a prenecrotic stage" Life Sci. 43. 1371-1377 (1988)
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• [Publications] Watanabe Y,et al.: "Effects of digoxin on acetylcholine and norepinephrine concentrations in rat myocardium" J Cardiovasc Pharmacol. 13. 702-708 (1989)
• [Publications] Kurihara S,et al.: "eds Segawa T,Endo M,Ui M,Kurihara K Physiology and Pharmacology of Transmembrane Signalling" Elsevier science Pub, (1989)
• [Publications] Ikeda M,et al.: "eds Lee TH,Huh KB Recent Advances in Insulin Therapy" Elsevier Science Pub, (1989)