2000 Fiscal Year Final Research Report Summary
Assessment of cardiac excitation-contraction coupling and effect of positive inctropic agent on Ca^<2+> regulating function of sarcoplasmic reticulum in heart failan
| Project/Area Number |
11670684
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Yamaguchi University |
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Principal Investigator |
YANO Masafumi Yamaguchi University School of Medicine Research Associate, 医学部, 助手 (90294628)
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| Co-Investigator(Kenkyū-buntansha) |
KOHNO Michihiro Yamaguchi University Hospital Assistant Professor, 医学部・附属病院, 講師 (70243649)
OHKUSA Tomoko Yamaguchi University School of Medicine Research Associate, 医学部, 助手 (00294629)
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| Project Period (FY) |
1999 – 2000
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| Keywords | heart failure / sarcoplasmic reticulum / ryanodine receptor / FK506 binding protein / Ca^<2+> release |
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| Research Abstract |
In tachycardia-induced heart failure (HF), LV function was assessed in parallel with the function of sarcoplasmic reticulum (SR) taken from LV muscle. First, in HF, positive inotropic effects of milrinone or dobutamine were decreased, whereas positive lusitropic effects were well preserved. The enhancement of the sensitivity of SR Ca^<2+>-ATPase on cyclic AMP was observed in HF, which might be involved in this preservation of positive lusitropy. Second, a prominent abnormal Ca^<2+> leak occurred through the Ca^<2+> release channel of the SR (ryanodine receptor ; RyR) in HF, in which the stoichiometry of FK binding protein per RyR was decreased. This partial loss of RyR-bound FKBP12.6 seems to induce an instability in the channel's properties through a protein conformational change. This leads to a prominent Ca^<2+> leak, which is a possible cause of Ca^<2+> overload and hence diastolic dysfunction, as well as of systolic dysfunction. Third, in HF the altered interaction between FKBP12.6 and RyR induced an instability of RyR-channel properties and a resulting impairment of the Ca^<2+>-release function of RyR.
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