1989 Fiscal Year Final Research Report Summary
Mechanism of Oxygen Free Radical-Induced Cellular Damage in Myocardium
| Project/Area Number |
63571102
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Kanagawa Dental College |
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Principal Investigator |
OKABE Eiichiro Kanagawa Dental College, Department of Pharmacology, Associate Professor, 歯学部, 助教授 (50097276)
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| Co-Investigator(Kenkyū-buntansha) |
TOMOKAWA Shigeji Kanagawa Dental College, Department of Pharmacology, Instructor, 歯学部, 助手 (40197918)
TODOKI Kazuo Kanagawa Dental College, Department of Pharmacology, Assistant Professor, 歯学部, 講師 (90139577)
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| Project Period (FY) |
1988 – 1989
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| Keywords | Free Radical / Sarcoplasmic Reticulum / Calcium / Ischemia / Coronary Vessel / Calmodulin |
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| Research Abstract |
We tested the hypothesis that oxygen free radical-induced breakdown in the function of sarcoplasmic reticulum (SR) and sarcolemma may serve as the source of intracellular calcium overload analogous to that seen in the ischemic myocardium, and extrapolated the in vitro results to the ischemic myocardium. The following results were obtained:
1) Oxygen free radicals can produce a dininished level of accumulated calcium of SR, which is reflected by the decreased calcium load and an increase in calcium permeability, and the decreased calcium accumulation in the presence of oxygen free radical generating system may not be mainly due to an inhibited calcium pump. 2) Calmodulin-dependent component of calcium fluxes in SR vesicles is modified directly by oxygen free radicals, and oxygen free radicals can reduce steady-state calcium accumulation due to increased calcium release through a calcium efflux pathway which is inhibited by calmodulin. 3) Oxygen free radicals have no effect on myofibrilla
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r pCa-ATPase curve. 4) Oxygen free radicals reduce sarcolemmal Na^+, K^+ -ATPase activity and stimulate Na^+-Ca^<2+> exchange activity. 5) Oxygen free radicals produce endothelium-dependent and SOD inhibitable contraction of isolated left circumflex coronary arteries. 6) All these effects described above seem to be responsible for ^.O^-_ and/or closely related species of oxygen free radical, possibly ^.OH.
The lack of an effect of oxygen free radicals may suggest that no structural alterations of contractile proteins have occurred. Thus, we would hypothesize that a major target organelles attacked by oxygen free radicals generated during the ischemic process is the portion of the excitation-contraction coupling system that regulates calcium delivery (the SR and sarcolemmal membrane) to the contractile proteins and not the contractile proteins per se. The SR calcium efflux pathways and sarcolemmal Na^+,K^+-ATPase involving Na^+-Ca^<2+> exchange activity may be altered by oxygen free radicals in ischemic myocardium where the occurrence of intracellular calcium overload plays an important role in cardiac dysfunction. Furthermore, it is postulated that oxygen free radicals participate in spasmogenesis in coronary vessels. Less
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