| Project/Area Number |
11670715
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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 | Nippon Medical School |
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Principal Investigator |
YASUTAKE Masahiro Nippon Medical School, First Department of Medicine, Lecturer, 医学部, 講師 (70281433)
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| Co-Investigator(Kenkyū-buntansha) |
KUSAMA Yoshiki Nippon Medical School, First Department of Medicine, Lecturer, 医学部, 講師 (40169983)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | Na^+ / H^+ exchanger / K_<ATP> channel / cardiomyocyte / mitochondria / reperfusion injury / cardioprotection / ミトコンドリア傷害モデル |
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| Research Abstract |
Na^+/H^+ exchanger (NHE) is a ubiquitous integral membrane protein present in the plasma membrane of cells. It plays a key and critical role in regulation of intracellular pH, removing excess intracellular acid from the cell in exchange for extracellular sodium ions. Cloning studies have identified 6 isoforms of NHE from NHE-1 to NHE-6. NHE-1, a ubiquitous isoform present also in cardiac sarcolemma, is known to play a important role in ischemia-reperfusion injury. NHE-6 has been most recently cloned, and it may be present in the mitochondrial mambrane, being different from the other isoforms. Moreover, its pathophysiological role has not been fully examined yet. The primary objective of our study was to investigate any roles of NHE-6 (mitochondrial NHE) in intracellular pH handling, Ca^<2+> homeostasis and mitochondrial redox state. Since NHE-6 knockout or overexpression mice were not available and also there was a technical problem (spending the initial one and a half years to establi
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shed a cell injury model by H_2O_2 or peroxynitrate from 1999 to 2000), we found it difficult to evaluate the function of NHE-6. We therefore changed our subject to study a role of mitochondrial ATP-sensitive potassium channel (mito-K_<ATP>) rather than NHE-6 because both of them were considered to be important in cardioprotection against ischemic insult. We carried out two studies : the first one to show that nicorandil opened mito-K_<ATP> (measured by FAD-linked flavoprotein autofluorescence intensity as an index of mito-K_<ATP> activity using isolated cardiomyocytes) and reduced myocardial infarct size in a 5-HD (a blocker of mito-K_<ATP>) sensitive manner in rat low-flow ischemia model (Jpn J Clin Pharmacol Ther 2002 ; 33 : 27S), the second one to demonstrate for the first time that a novel cardioprotective drug, JTV-519, opened mito-K_<ATP> and that its protective effect (assessed by percent recovery of left ventricular contractile function after 30 mm global ischemia in isolated rat hearts) was synergistic with a potent NHE inhibitor (cariporide), suggesting that mito-K_<ATP> and NHE may play a key role independently in ischemia-reperfusion injury. Less
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