1989 Fiscal Year Annual Research Report

心筋細胞障害の成因と防御に関する基礎的研究

Research Project

Project/Area Number	01624003
Research Institution	Osaka University
Principal Investigator	多田道彦大阪大学, 医学部, 教授 (90093434)
Co-Investigator(Kenkyū-buntansha)	外山淳治名古屋大学, 環境医学研究所, 教授 (20023658) 河合忠一京都大学, 医学部, 教授 (70025659) 杉本恒明東京大学, 医学部, 教授 (60019883) 戸嶋裕徳久留米大学, 医学部, 教授 (00080664) 中村元臣九州大学, 医学部, 教授 (60037322)
Keywords	心筋細胞障害 / 心筋興奮収縮連関 / イオンチャンネル / 収縮蛋白質 / 細胞情報伝達機構 / 心筋肥大 / 酸素ラジカル / ミトコンドリア遺伝子異常症
Research Abstract	心臓病における心筋細胞障害の成因を明確にし適切な防御を講じる上には、心臓機能の基本的原理並びにその調節・適応機構の生物学的基盤を究めることは必須である。かかる研究立脚点を基本として、重点領域研究「心筋細胞障害の成因と防御に関する基礎的研究」を推進し、以下の成果が得られている。心筋機能を司る興奮収縮連関の物質論的基盤を明らかにする立場から心筋の各種イオンチャネル、イオンポンプ、受容体、収縮蛋白質の基本的性質の解明を進めた。心筋では、特にこの基本機構への調節系が重要であり、例えば、心筋小胞体のCa能動輸送ではサイクリックAMPによる調節系の実体が分子レベルで明らかにされた。心筋負荷に対する応答機構では、交感神経系作動亢進、心筋肥大という観点から研究が進んだ。その結果、交感神経亢進を各種受容体レベルでとらえられた。心肥大では、収縮蛋白質ミオシン分子の形質が遺伝子レベルで変換されることにより肥大心筋の機能的代償機構が働くことが明らかにされた。細胞機能の破綻では、細胞内Ca過剰負荷とオキシラジカル産生が重要な細胞内過程であると認識されつつある。特に後者では、アラキドン酸遊離、それに引き続くリポキシゲネース系が関与することを明らかにした。遺伝性心筋障害ではミトコンドリア遺伝子異常によるミトコンドリアサイトパチーに新しい展開があり、その本体の解明が進んでいる。新たな治療法の開発は、上述の各機構あるいはその異常の解明と表裏一体の関係にあり、それぞれのレベルでの研究が著しく進展した。

Research Products
(31 results)

All Other

All Publications (31 results)

[Publications] Fujii J.et al.: "Expression and siteーspecific mutagenesis of phospholamban." J.Biol.Chem.264. 12950-12955 (1989)
[Publications] James P.et al.: "The nature and site of regulation of the calcium pump of sarcoplasmic reticulum by phospholamban." Nature. 324. 90-92 (1989)
[Publications] Kuzuya T.et al.: "Role of free radicals and neutrohils in canine myocardial reperfusion injury:myocardial salvage by a novel free radical scavenger,2ーoctadecylascorbic acid." Cardiovasc.Res.23. 323-330 (1989)
[Publications] Nishida M.et al.: "Polymorphonuclear leukocytes induced vasoconstriction in isolated canine coronary arteries" Circ.Res.66. 253-258 (1990)
[Publications] Kuzuya T.et al.: "Detection of oxygenーderived free radical generation in the canine postischemic heart during late phase of reperfusion." Circ.Res.
[Publications] Honjo H.et al.: "Fluctuations of membrane potential in isolated single ventricular myocytes of guineaーpig upon resumption of oxidative phosphorylation." J.Mol.Cell.Cardiol.21. 241-252 (1989)
[Publications] Suzuki S.et al.: "Evidence against the central nervous system being involved in altered reflex control of sympathtic nerve activity by atrial natriuretic peptide." Brain Res.485. 109-114 (1989)
[Publications] Suzuki S.et al.: "Central nervous system mechanisms involved in ihibition of renal sympathetic nerve activity induced by arginine vasopressin" Circ.Res.65. 1390-1399 (1989)
[Publications] Ichikawa M.et al.: "Constricton of a large coronary artery contributes to serotonininduced myocardial ischemia in the dog with pliable coronary stenosis." J.Am.Coll.Candiol.14. 449-459 (1989)
[Publications] Awano K.el al.: "Role of serotonin,histamine and thromboxane A_2 in plateletーinduced contractions of coronary of arteries and aortae from rabbits." J.Cardiovasc.Pharmcol.13. 781-792 (1989)
[Publications] Kusui A.et al.: "Alpha_2ーadrenoceptors and platelet function in patients with variant angina." Thromb.Res.
[Publications] Isobe M.et al.: "Quantification of myocardial infarct size after coronary reperfusion by serum cardiac myosin light chain II in conscious dogs." Circ.Res.65. 684-694 (1989)
[Publications] Sakai S.et.al.: "Electrophysiological properties of cultured dog myocytes obtained by endomyocardial biopsy." Circ.Res.64. 203-2,12 (1989)
[Publications] Tomoike H.et al.: "Homogeneous distribution and pressure dependent reduction of coronary blood flow in right ventricular free wall during coronary hypoperfusion in anesthetised open chest dogs." Cardiovasc.Res.23. 31-39 (1989)
[Publications] Mohri M.et al.: "Amelioration by βーadrenergic blockade of regional myocardial dysfunction induced by coronary artery occlusion after,but not before collateral development in conscious dogs." Am.Heart J.117. 43-52 (1989)
[Publications] Adachi H.et al.: "Sustained dilation of large coronary artery by αーhuman atrial natriuretic peptide in conscious dogs:a comparison with nitroglycerin." Eur.J.Pharmacol.161. 189-196 (1989)
[Publications] Mohri M.et al.: "Duration of ischemia is vital for collateral development:Repeated brief coronary artery occlusions in conscious dogs." Circ.Res.64. 287-296 (1989)
[Publications] Hisano K.et al.: "Isosordide dinitrate ameliorates myocardial ischemia after development of collateral function in a canine model." J.Pharm.Exp.Ther.248. 1289-1296 (1989)
[Publications] Toyoーoka T.et al.: "Collagenーstimulated humann platelet aggregation is mediated by endogenous calciumーactivatede neutral protease." Circ.Res.64. 407-410 (1989)
[Publications] Matsumori A.et al.: "Myocardial uptake of antimyosin monoclonal antibody in a murine model of viral myocarditie." Circulation. 79. 400-40 (1989)
[Publications] Matsumori A.et al.: "Viral myocarditis:immunopathogenesis and the effect of immunosuppressive treatment in murine model." Jpn.Circ.J.53. 58-60 (1989)
[Publications] Tomoike H.et al.: "Enhanced responsiveness of smooth muscle, impared endotheliumdependent relaxation and the genesis of coronary spasm." Am.J.Cardiol.63. 33E-39E (1989)
[Publications] Nagasawa K.et al.: "Intramural hemorrhage and endothelial changes in atherosclerotic coronary artery after repetitive episodes of spasm in Xーirradiated hypercholesterolemic pigs." Circ.Res.65. 272-282 (1989)
[Publications] Akaike N.et al.: "Lowーvoltage activated calcium current in rat aorta smooth muscle cells in primary culture." J.Physiol.
[Publications] Yokoyama H.et al.: "An explanation of bellーshaped,doseーpositive inotropic effect curves for denopamine in canine right ventricular muscle." J.Cardiovasc.Pharmacol.
[Publications] Yokoyama H.et al.: "Do calcium sensitizers and phosphodiesterase inhibitors affect differently the relation between myocardial contractility and oxygen consumption?" J.Cardiovasc.Pharmacol.
[Publications] Kodama I.et al.: "Electrophysiological effects of TYBー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.
[Publications] Kurachi Y.et al.: "Arachidonic acid metabolites as intracellular modulators of G proteinー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." Eur.J.Physiol.413. 325-327 (1989)

1989 Fiscal Year Annual Research Report

心筋細胞障害の成因と防御に関する基礎的研究

Principal Investigator

多田 道彦 大阪大学, 医学部, 教授 (90093434)

Research Products

[Publications] Fujii J.et al.: "Expression and siteーspecific mutagenesis of phospholamban." J.Biol.Chem.264. 12950-12955 (1989)

[Publications] James P.et al.: "The nature and site of regulation of the calcium pump of sarcoplasmic reticulum by phospholamban." Nature. 324. 90-92 (1989)

[Publications] Kuzuya T.et al.: "Role of free radicals and neutrohils in canine myocardial reperfusion injury:myocardial salvage by a novel free radical scavenger,2ーoctadecylascorbic acid." Cardiovasc.Res.23. 323-330 (1989)

[Publications] Nishida M.et al.: "Polymorphonuclear leukocytes induced vasoconstriction in isolated canine coronary arteries" Circ.Res.66. 253-258 (1990)

[Publications] Kuzuya T.et al.: "Detection of oxygenーderived free radical generation in the canine postischemic heart during late phase of reperfusion." Circ.Res.

[Publications] Honjo H.et al.: "Fluctuations of membrane potential in isolated single ventricular myocytes of guineaーpig upon resumption of oxidative phosphorylation." J.Mol.Cell.Cardiol.21. 241-252 (1989)

[Publications] Suzuki S.et al.: "Evidence against the central nervous system being involved in altered reflex control of sympathtic nerve activity by atrial natriuretic peptide." Brain Res.485. 109-114 (1989)

[Publications] Suzuki S.et al.: "Central nervous system mechanisms involved in ihibition of renal sympathetic nerve activity induced by arginine vasopressin" Circ.Res.65. 1390-1399 (1989)

[Publications] Ichikawa M.et al.: "Constricton of a large coronary artery contributes to serotonininduced myocardial ischemia in the dog with pliable coronary stenosis." J.Am.Coll.Candiol.14. 449-459 (1989)

[Publications] Awano K.el al.: "Role of serotonin,histamine and thromboxane A_2 in plateletーinduced contractions of coronary of arteries and aortae from rabbits." J.Cardiovasc.Pharmcol.13. 781-792 (1989)

[Publications] Kusui A.et al.: "Alpha_2ーadrenoceptors and platelet function in patients with variant angina." Thromb.Res.

[Publications] Isobe M.et al.: "Quantification of myocardial infarct size after coronary reperfusion by serum cardiac myosin light chain II in conscious dogs." Circ.Res.65. 684-694 (1989)

[Publications] Sakai S.et.al.: "Electrophysiological properties of cultured dog myocytes obtained by endomyocardial biopsy." Circ.Res.64. 203-2,12 (1989)

[Publications] Tomoike H.et al.: "Homogeneous distribution and pressure dependent reduction of coronary blood flow in right ventricular free wall during coronary hypoperfusion in anesthetised open chest dogs." Cardiovasc.Res.23. 31-39 (1989)

[Publications] Mohri M.et al.: "Amelioration by βーadrenergic blockade of regional myocardial dysfunction induced by coronary artery occlusion after,but not before collateral development in conscious dogs." Am.Heart J.117. 43-52 (1989)

[Publications] Adachi H.et al.: "Sustained dilation of large coronary artery by αーhuman atrial natriuretic peptide in conscious dogs:a comparison with nitroglycerin." Eur.J.Pharmacol.161. 189-196 (1989)

[Publications] Mohri M.et al.: "Duration of ischemia is vital for collateral development:Repeated brief coronary artery occlusions in conscious dogs." Circ.Res.64. 287-296 (1989)

[Publications] Hisano K.et al.: "Isosordide dinitrate ameliorates myocardial ischemia after development of collateral function in a canine model." J.Pharm.Exp.Ther.248. 1289-1296 (1989)

[Publications] Toyoーoka T.et al.: "Collagenーstimulated humann platelet aggregation is mediated by endogenous calciumーactivatede neutral protease." Circ.Res.64. 407-410 (1989)

[Publications] Matsumori A.et al.: "Myocardial uptake of antimyosin monoclonal antibody in a murine model of viral myocarditie." Circulation. 79. 400-40 (1989)

[Publications] Matsumori A.et al.: "Viral myocarditis:immunopathogenesis and the effect of immunosuppressive treatment in murine model." Jpn.Circ.J.53. 58-60 (1989)

[Publications] Tomoike H.et al.: "Enhanced responsiveness of smooth muscle, impared endotheliumdependent relaxation and the genesis of coronary spasm." Am.J.Cardiol.63. 33E-39E (1989)

[Publications] Nagasawa K.et al.: "Intramural hemorrhage and endothelial changes in atherosclerotic coronary artery after repetitive episodes of spasm in Xーirradiated hypercholesterolemic pigs." Circ.Res.65. 272-282 (1989)

[Publications] Akaike N.et al.: "Lowーvoltage activated calcium current in rat aorta smooth muscle cells in primary culture." J.Physiol.

[Publications] Yokoyama H.et al.: "An explanation of bellーshaped,doseーpositive inotropic effect curves for denopamine in canine right ventricular muscle." J.Cardiovasc.Pharmacol.

[Publications] Yokoyama H.et al.: "Do calcium sensitizers and phosphodiesterase inhibitors affect differently the relation between myocardial contractility and oxygen consumption?" J.Cardiovasc.Pharmacol.

[Publications] Kodama I.et al.: "Electrophysiological effects of TYBー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.

[Publications] Kurachi Y.et al.: "Arachidonic acid metabolites as intracellular modulators of G proteinー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." Eur.J.Physiol.413. 325-327 (1989)

多田道彦大阪大学, 医学部, 教授 (90093434)