| Project/Area Number |
01570484
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Osaka University, School of Medicine |
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Principal Investigator |
HORI Masatsugu Osaka University, School of Medicine, Assistant Professor, 医学部, 助手 (20124779)
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| Co-Investigator(Kenkyū-buntansha) |
SATO Hideyuki Osaka University, School of Medicine, Assistant Professor, 医学部, 助手 (70167435)
KUSUOKA Hideo Osaka University, School of Medicine, Assistant Professor, 医学部, 助手 (00112011)
KITABATAKE Akira Osaka University, School of Medicine, Associate Professor, 医学部, 助教授 (00124769)
佐藤 洋 大阪大学, 医学部附属病院, 医員
鍵谷 俊文 大阪大学, 医学部附属病院, 医員
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| Project Period (FY) |
1989 – 1990
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| Project Status |
Completed (Fiscal Year 1990)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1990: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1989: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | Heart failure / alpha-adrenergic receptor / beta-adrenergic receptor / Cardiomyopathic Syrian hamster / Cardiac hypertrophy / Intracellular pH / Na^+ / H^+ exchange / Ca^<2+> exchange / 交感神経α受容体 / 交感神経β受容体 / H^+交換系 / Ca^<2+>交換系 / プロテインキナ-ゼC |
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| Research Abstract |
We investigated serial changes in myocardial norepinephrine content and myocardial adrenergic receptors during the development of cardiomyopathy and heart failure in Syrian hamsters and their age-matched healthy controls. We found that in the pre-hypertrophic stage, myocardial norepinephrine content and densities of alpha_1-, beta-adrenergic receptors were significantly higher in the cardiomyopathic hamsters than in the controls. However, in the early heart failure stage, beta-receptor density was 28% lower than that of the age-matched controls, though alpha_1-receptor density remained 55% higher. Norepinephrine-stimulated phosphatidylinositide hydrolysis in the cardiomyopathic hamster in the hypertrophic stage was twice that in the controls, indicating that the increase in alpha_1-adrenergic receptors are coupled with the intracellular signal transduction. Furthermore, selective alpha_1-adrenoceptor blockade by bunazosin in the cardiomyopathic hamsters from 70 to 170 days of age reduc
… More
ed myocardial hypertrophy and focal myocardial necrosis. We also studied the effects of alpha_1-adrenoceptor stimulation on intracellular pH and Ca^<2+> concentration ([Ca^<2+>]) in rat cardiomyocytes using fluorescence dyes. Norepinephrine stimulation increased intracellular pH in BCECF-loaded cardiomyocytes. The alkalinization was inhibited by prazosin and phentolamine, but not by yohimbine. The increase in intracellular pH was abolished without extracellular Na^+ or in the presence of hexamethylene-amiloride, a specific Na^+/H^+ exchange inhibitor, indicating that the alkalinization was mediated by Na^+/H^+ exchange. alpha_1-Adrenergic stimulation also increased intracellular [Ca^<2+>] in fura-2 loaded cardiomyocytes. The increase in intracellular [Ca^<2+>] occurrd following intracellular alkalinization and was abolished without extracellular Ca^<2+> or Na^+. The increase in intracellular [Ca^<2+>] was inhibited by hexamethylene-amiloride. These results suggest that alpha_1-receptor stimulation activates Na^+/H^+ exchange, followed by an increase in intracellular [Ca^<2+>] throuh the consequent Na^+/Ca^+ exchange. Thus, we conclude that alpha_1-adrencergic activity plays an important role through Ca^<2+> overload in progression of cardiac hypertrophy and myocardial damage in chronic heart failure. Less
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