Role of Adrenergic Activity, Alpha-Receptor, and Beta-Receptor in Progression of Chronic Heart Failure

肾上腺素能活性、α 受体和 β 受体在慢性心力衰竭进展中的作用

• 批准号: 01570484
• 负责人: HORI Masatsugu
• 金额: $ 1.34万
• 依托单位: Osaka University, School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01570484/
• 关键词: 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

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

我们研究了叙利亚仓鼠及其同龄健康对照在心肌病和心力衰竭发展过程中心肌去甲肾上腺素含量和心肌肾上腺素能受体的一系列变化。我们发现，在肥厚前期，心肌病仓鼠心肌去甲肾上腺素含量和α _1-、β肾上腺素能受体密度显著高于对照组。然而，在早期心力衰竭阶段，β受体密度比年龄匹配的对照组低28%，尽管alpha_1受体密度仍然高出55%。在肥厚期，去甲肾上腺素刺激的心肌病仓鼠的磷脂酰肌苷水解量是对照组的两倍，表明α _1-肾上腺素能受体的增加与细胞内信号转导相结合。此外，布纳唑嗪选择性阻断70 ~ 170日龄心肌病仓鼠α _1-肾上腺素能受体可减少心肌肥厚和局灶性心肌坏死。我们还利用荧光染料研究了α _1-肾上腺素能受体刺激对大鼠心肌细胞内pH和Ca^<2+>浓度（[Ca^<2+>]）的影响。去甲肾上腺素刺激增加了bcecf负载心肌细胞的细胞内pH值。普唑嗪和酚妥拉明对碱化作用有抑制作用，育亨宾对碱化作用无抑制作用。在没有细胞外Na^+或存在特异性Na^+/H^+交换抑制剂六亚甲基酰胺的情况下，细胞内pH升高被消除，表明碱化是由Na^+/H^+交换介导的。α _1-肾上腺素能刺激也增加了fura-2负载心肌细胞的胞内[Ca^<2+>]。细胞内[Ca^<2+>]的增加发生在细胞内碱化之后，并且在没有细胞外Ca^<2+>或Na^+的情况下被消除。六亚甲基酰胺抑制了细胞内[Ca^<2+>]的增加。这些结果表明，alpha_1受体刺激激活Na^+/H^+交换，随后通过随后的Na^+/Ca^+交换增加细胞内[Ca^<2+>]。因此，我们得出结论，α _1-肾上腺素能活性通过Ca^<2+>超载在慢性心力衰竭心肌肥厚和心肌损伤的进展中起重要作用。少

项目成果

M.Hori,Y.Koretsune,T.Kagiya,Y.Watanabe,K.Iwakura,K.Iwai,A.Kitabatake,H.Yoshida,M.Inoue,T.Kamada.: "An increase in myocardial βーadrenoceptors to compensate for postischaemic dysfunction following coronary microーembolisation in dogs." Cardiovasc.Res.XXIII(5

M.Hori、Y.Koretsune、T.Kagiya、Y.Watanabe、K.Iwakura、K.Iwai、A.Kitabatake、H.Yoshida、M.Inoue、T.Kamada.：“心肌 β 肾上腺素受体的增加补偿狗冠状动脉微栓塞后的缺血后功能障碍。”Cardiovasc.Res.XXIII(5

Tamai J., M. Hori, T. Kagiya, K. Iwakura, K. Iwai, A. Kitabatake, Y. Watanabe, H. Yoshida, M. Inoue, T. Kamada: "Role of alpha_1-adrenoceptor activity in progression of cardiac hypertrophy in guinea pig hearts with pressure overload." Cardiovasc. Res.XXII

Tamai J.、M. Hori、T. Kagiya、K. Iwakura、K. Iwai、A. Kitabatake、Y. Watanabe、H. Yoshida、M. Inoue、T. Kamada：“α_1-肾上腺素受体活性在进展中的作用

Iwakura K,Hori M,Watanabe Y,Misaki N,Yoshida H,Kusuoka H,Tada M.: "α_1ーadrergic stimulation increases Ca^<2+> in cardiomyocytes through Na^+/H^+ and Na^+/Ca^+ exchanges." Circulation. 80. II197 (1989)

Iwakura K、Hori M、Watanabe Y、Misaki N、Yoshida H、Kusuoka H、​​Tada M.：“α_1ー肾上腺素刺激通过 Na^+/H^+ 和 Na 增加心肌细胞中的 Ca^<2+> ^+/Ca ^+ 交换。”循环。80. II197 (1989)

edited by M.Hori,H.Suga,J.Baan and E.L.Yellin: "SpringerーVerlag,Tokyo" Cardiac Mechanics and Function in the Normal and Diseased Heart., 360PP (1989)

由 M.Hori、H.Suga、J.Baan 和 E.L.Yellin 编辑：“Springer-Verlag，东京”正常和患病心脏的心脏力学和功能。，360PP (1989)

T.Kagiya,M.Hori,K.Iwakura,K.Iwai,Y.Watanabe,S.Uchida,A.Kitabatake,M.Inoue,T.Kamada: "Role of increased α_1ーadrenergic activity in cardiomyopathic Syrian hamster." Am.J.Physiol.260. H80-H88 (1991)

T. Kagiya、M. Hori、K. Iwakura、K. Iwai、Y. Watanabe、S. Uchida、A. Kitabatake、M. Inoue、T. Kamada：“α_1ー肾上腺素能活性增加在心肌病叙利亚仓鼠中的作用。”美国生理学杂志.260。H80-H88 (1991)