| Project/Area Number |
15209007
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General physiology
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| Research Institution | Kyoto University |
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Principal Investigator |
NOMA Akinori Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (00132738)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUOKA Satoshi Kyoto University, Graduate School of Medicine, Research associate, 医学研究科, 助手 (00263096)
SARAI Nobuaki Kyoto University, Graduate School of Medicine, Lecture, 医学研究科, 科学技術振興講師 (00335259)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥50,440,000 (Direct Cost: ¥38,800,000、Indirect Cost: ¥11,640,000)
Fiscal Year 2005: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
Fiscal Year 2004: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000)
Fiscal Year 2003: ¥30,680,000 (Direct Cost: ¥23,600,000、Indirect Cost: ¥7,080,000)
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| Keywords | cardiac myocyte / Ca^<2+> / mitochondria / NADH / simulation / カルシウムイオン / 興奮-収縮連関 / 心臓 / カルシウム |
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| Research Abstract |
1.To study mechanisms underlying the coupling between energy metabolism and cardiac function, we measured membrane potential and mitochondrial NADH fluorescence, simultaneously with cell shortening in isolated guinea-pig ventricular myocytes. When a step increase in stimulus frequency was applied, the NADH fluorescence first decreased and then increased to a steady level, while the cell shortening was gradually augmented. Upon returning to the control stimulus frequency, the NADH signal showed an overshoot before declining to the control level. Blockers of mitochondrial Ca^<2+> uniporter, Ru360 or ruthenium red, attenuated the increase of NADH fluorescence during the high rate stimulation. Mitochondrial Ca^<2+>, measured with Rhod-2,increased with a similar time course to that of the NADH fluorescence during the high rate stimulation. The biphasic onset time course was well explained by the delayed Ca^<2+> activation of the mitochondrial dehydrogenation superimposed on the feedback control by ADP, while the offset time course with a delayed deactivation of dehydrogenation. Essentially the same results were obtained with rat and mice ventricular cells. Therefore, the suggested mechanism is probably a common mechanism of mammalian ventricular cells.
2.We developed a cardiac cell computer model of excitation-contraction coupling incorporating a mitochondrial oxidative phosphorylation. The computer simulation, on the assumption of Ca^<2+> activation of substrate dehydrogenation, well reconstructed the response of NADH. This model simulation predicted that the activation of substrate dehydrogenation provides 〜23% of driving force of the ATP synthesis, and remaining 〜77% is supplied by the feedback control.
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