SIGNAL TRANSDUCTION OF ALPHA-ADRENERGIC STIMULATION IN CARDIAC MYOCYTES

心肌细胞中α-肾上腺素刺激的信号转导

• 批准号: 3802239
• 负责人: G GAMBASSI
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3802239
• 关键词: acidity /alkalinity; alkalosis; alpha adrenergic agent; alpha adrenergic receptor; amiloride; biological signal transduction; calcium transporting ATPase; clonidine; cytoplasm; heart cell; heart contraction; heart pharmacology; inhibitor /antagonist; laboratory rat; muscle cells; myocardium; myofibrils; phenylephrine

The positive inotrophic action of alpha-adrenergic stimulation is due to an increase in the cytosolic [Ca 2+], (Cai) transient which triggers the contraction and to an enhanced myofilament responsiveness to Ca 2+. In a variety of cell types alpha-adrenergic stimulation activates Na+/H+ exchange and increases cytosolic pH (pHi) via this mechanism. In the heart alkalosis is known to have a positive inotropic action due to an increased myofilament sensitivity to Ca 2+. We tested the hypothesis that, at least in part, the positive inotropic action of alpha -adrenergic stimulation may be due to an increased pH i. The effect of alpha-adrenergic stimulation with phenylephrine and nadolol was assessed in ventricular myocytes from the adult rat loaded with the pH probe SNARF-1 and bathed in a bicarbonate buffer with 1.5 mM [Ca 2+]. Alpha-adrenergic stimulation enhanced twitch amplitude and pH i. There was a significant correlation between the increase in twitch amplitude and pHi. Both effects were antagonized by ethylisopropylamiloride, a Na+/H+ exchange inhibitor. Other experiments aimed at characterizing the role of two known alpha 1 receptor subtypes, alpha 1A and alpha 1B, on myocardial contraction and pHi. The two alpha 1 receptor subtypes are distinguished by their sensitivity to chloroethylclonidine (alpha 1B) and WB-4101 (alpha 1A). The positive inotropic effect of alpha-adrenergic stimulation was abolished by WB-4101. In contrast, the addition of chloroethylclonidine in the presence of alpha- adrenergic stimulation caused a further enhancement in contractility. Thus, alpha 1A and alpha 1B receptors have opposing effect on myocardial contraction and additional experiments will aim at establishing the role of each alpha 1 receptor subtype on pHi homeostasis.

α-肾上腺素能刺激的阳性肌营养作用是由于 增加胞质[Ca 2+]，（CAI）瞬态，触发触发 收缩和增强对Ca 2+的肌丝反应能力。 在 各种细胞类型α-肾上腺素能刺激激活Na+/H+ 通过这种机制交换和增加胞质pH（PHI）。 在心中 众所周知，碱性病由于增加而具有正性作用 肌丝对Ca 2+的敏感性。 我们检验了至少的假设 在某种程度上，α-肾上腺素能刺激的阳性肌力作用可能 由于pH I的增加。 α-肾上腺素能刺激的作用 在心室肌细胞中评估了苯肾上腺素和nadolol 成年大鼠装有pH探针SNARF-1并在碳酸氢盐中沐浴 缓冲液为1.5 mm [Ca 2+]。 α-肾上腺素能刺激增强了抽搐 振幅和pH i。 在 增加抽搐幅度和PHI。 两种效应都通过 Na+/H+交换抑制剂乙基异丙基胺。 其他实验 旨在表征两个已知的alpha 1受体亚型的作用， Alpha 1a和Alpha 1b，在心肌收缩和PHI上。 两个alpha 1 受体亚型以其对 氯乙基氯替氨酸（Alpha 1b）和WB-4101（Alpha 1a）。 积极 WB-4101废除了α-肾上腺素能刺激的肌力作用。 相反，在存在α- 肾上腺素能刺激导致收缩性进一步增强。 因此，α1a和alpha 1b受体对心肌具有相反的作用 收缩和其他实验将旨在确定 PHI稳态上的每个alpha 1受体亚型。