| Project/Area Number |
20591805
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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 |
Anesthesiology/Resuscitation studies
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| Research Institution | Yamaguchi University |
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Principal Investigator |
KOBAYASHI Shigeki Yamaguchi University, 医学部附属病院, 助教 (90397993)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Takeshi 山口大学, 大学院・医学系研究科, 助教 (50363122)
YANO Masafumi 山口大学, 医学部付属病院, 講師 (90294628)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2009: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2008: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 悪性高熱症 / 心室頻拍症 / 心不全 / ダントロレン / リアノジン受容体 / 不整脈 |
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| Research Abstract |
Dantrolene, a specific drug for the treatment of malignant hyperthermia, was found to inhibit Ca^<2+> leak through not only the skeletal ryanodine receptor (RyR1), but also the cardiac ryanodine receptor (RyR2) by correcting the defective inter-domain interaction between N-terminal(1-619 amino acid) amd central (2000-2500 amino acid) domains of RyRs. Here, we examined 1)the effect of dantrolene on the Ca2+ release and cardiomyocyte function in chronic rapid pacing-induced heart failure dog model 2) the anti-arrhythmic effect of dantrolene in human CPVT-associated RyR2^<R2474S /+> knock-in (KI) mouse model. In heart failure model, dantrolene corrects defective inter-domain interactions within RyR2 in failing hearts, inhibits spontaneous Ca^<2+> leak, in turn improves cardiomyocyte function in failing hearts. In human CPVT-associated RyR2^<R2474S /+> knock-in (KI) mouse model, dantrolene prevents CPVT, presumably by correction of catecholamine-induced defective inter-domain interaction within RyR2inhibiting and inhibition of Ca^<2+> leak through RyR2. Thus, dantrolene may have a potential to treat heart failure and lethal arrhythmia, specifically targeting RyR2.
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