ALPHA-ADRENERGIC STIMULATION IN MYOCARDIAL CELLS

心肌细胞中的α-肾上腺素刺激

• 批准号: 3767789
• 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/3767789
• 关键词: acidity /alkalinity; alpha adrenergic agent; alpha adrenergic receptor; amiloride; antihypertensive agents; arrhythmia; beta antiadrenergic agent; chloride channels; clonidine; enzyme inhibitors; heart cell; heart contraction; heart pharmacology; laboratory rat; muscle cells; myocardium; myofibrils; phenylephrine; phorbols; protein kinase C; reperfusion; respiratory acidosis; single cell analysis; sodium channel

We have previously shown that the positive inotropic action of alpha1- adrenoceptor (alpha1-AR) stimulation, at least in part is due to an enhanced myofilament responsiveness to Ca2+ mediated by protein kinase C (PKC)-dependent activation of Na+/H+ exchange and an increase in cytosolic pH (pHi). We have also examined the effect of alpha1-AR subtypes, alpha1A and alpha1B on contraction, Cai and myofilament response to Ca2+ of isolated myocardial cells. alpha1A-AR stimulation (phenylephrine, nadolol and alpha1B-AR inactivation with chloroethylclonidine) increased contraction, Cai transient amplitude and myofilament response to Ca2+. In contrast alpha1B-AR stimulation (phenylephrine, nadolol and alpha1A-blockade with WB-4101) decreased contraction, Cai transient amplitude and downregulated the alpha1A-AR effect to increase myofilament response to Ca2+. In additional experiments we have examined the effect of alpha1A- and alpha1B-AR stimulation on pHi and the PKC-dependence of the alpha1B-AR effect on pHi and contraction of isolated myocardial cells. In HCO3-/CO2- buffered saline, alpha1A increased cytosolic pH. In contrast alpha1B decreased cytosolic pH and this effect persisted in HCO3-/CO2-free solution. alpha1B-mediated cytosolic acidification was abolished by staurosporine, a protein kinase C inhibitor, and by protein kinase C down-regulation with prolonged exposure to 4beta-phorbol 12-myristate 13-acetate. Changes in twitch amplitude paralleled those in cytosolic pH due either to alpha1A- or alpha1B- adrenoceptor stimulation. Our results show that alpha1A-AR and alpha-1B-AR have opposite effects on pHi homeostasis of isolated myocardial cells.

我们以前已经表明，α1-的阳性肌力作用 adrenoceptor（alpha1-ar）刺激，至少部分是由于 增强了对蛋白激酶介导的Ca2+的肌膜反应性 C（PKC）依赖性Na+/H+交换的激活和增加 胞质pH（PHI）。 我们还检查了alpha1-ar的效果 亚型，α1a和alpha1b收缩，CAI和肌膜 对分离的心肌细胞的Ca2+反应。 alpha1a-ar刺激 （苯肾上腺素，nadolol和alpha1b-ar灭活， 氯乙基丙氨酸）增加了收缩，CAI瞬态幅度 和肌丝对Ca2+的反应。 相反，α1b-ar刺激 （苯肾上腺素，Nadolol和Alpha1a-Blockade wb-4101）降低 收缩，CAI瞬态幅度并下调α1A-AR 增加对Ca2+的肌丝反应的效果。 附加 实验我们已经检查了α1A-和alpha1b-ar的效果 刺激PHI和α1B-AR效应的PKC依赖性 PHI和分离的心肌细胞的收缩。 在hco3-/co2-中 缓冲盐水，α1a增加了胞质pH值。 相反，α1b 胞质pH值降低，这种效应持续在无HCO3/CO2中 解决方案。 α1b介导的胞质酸化被废除了 蛋白激酶C抑制剂和蛋白激酶C 长时间暴露于4beta-phorbol 12-渴望的下调 13-乙酸盐。 抽搐振幅的变化与胞质中的变化平行 pH值是由于α1A-或α1b-肾上腺素受体刺激。 我们的 结果表明，alpha1a-ar和alpha-1b-ar对 孤立心肌细胞的PHI体内平衡。