| Project/Area Number |
17590717
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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 | Hamamatsu University School of Medicine |
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Principal Investigator |
SATOH Hiroshi Hamamatsu University School of Medicine, Lecturer, 医学部附属病院, 講師 (30293632)
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| Co-Investigator(Kenkyū-buntansha) |
KATOH Hideki Hamamatsu University School of Medicine, Assistant Professor, 医学部, 助教授 (80314029)
URUSHIDA Tsuyoshi Hamamatsu University School of Medicine, Assistant Professor, 医学部, 助教授 (20334980)
WATANABE Yasuhide Hamamatsu University School of Medicine, Professor, 医学部, 教授 (50305380)
HAYASHI Hideharu Hamamatsu University School otMedicine, Professor, 医学部, 教授 (50135258)
寺田 肇 浜松医科大学, 医学部附属病院, 講師 (50252177)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | heart failure / calcium / cardiac myocytes / sarcoplasmic reticulum / Na^+ / Ca^<2+> exchange / protein phosphatases / 心筋 / 興奮収縮連関 |
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| Research Abstract |
Altered cellular Ca^<2+> handling plays a key role in the pathophysiology of heart failure. A typical aspect of failing heart cells is a decrease in the ability to load Ca^<2+> in the sarcoplasmic reticulum (SR), which results in a decreased amplitude and a slowed decay rate of Ca^<2+> transients, and an increased diastolic [Ca^<2+>]_i. This unloaded SR Ca^<2+> could be ascribed to a decrease in Ca^<2+> re-uptake by SR Ca^<2+> ATPase (SERCA), an increase in Ca^<2+> extrusion by the over-expression of Na^+/Ca^<2+> exchange (NCX), and an increase in the SR Ca^<2+> leak by the dissociation of FK506-binding proteins from the SR Ca^<2+> release channel. Many inotropic agents including digitalis and β-receptor agonists have failed to improve long-term prognosis of heart failure in clinical studies. For the SR Ca2+ uptake, drugs that enhance SR Ca^<2+> uptake in a cAMP-independent manner, including protein phosphatase inhibitors and MCC-135, are candidates. In 2005, we initially investigated
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the effect of a direct SERCA activator, MCC-135, on the profiles of Ca^<2+> transients and cell contraction in isolated rat cardiomyocytes. Unfortunately, we could not obtain significant inotropic effects of MCC-135. In 2006, we studied the effect of I-1, a specific protein phosphatase-1 inhibitor on cellular Ca^<2+> handling in permeabilized rat ventricular myocytes. As a result, I-1 increased SR Ca^<2+> content without altering SR Ca^<2+> release manner. For NCX, we clarified the inhibition modality of novel specific inhibitors of NCX, SEA0400 and SN-6 using patch clamp technique in guinea pig ventricular myocytes. SN-6 inhibited Ca^<2+> influx mode of NCX selectively, and SEA0400 equally blocked both Ca^<2+> efflux and influx mode. SEA0400 also protected rat perfused hearts against ischemia/reperfusion injury by preserving high energy metabolism. Despite limitations for clinical use, the combination of these agents may restore cellular Ca^<2+> cycling and improve cardiac function with less toxicity. Less
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