COMPARISON BETA2 VS BETA1 ADRENOCEPTOR STIMULATION IN RAT CARDIOCYTE STIMULATION

大鼠心肌细胞刺激中BETA2 与BETA1 肾上腺素受体刺激的比较

• 批准号: 3789799
• 负责人: R P XIAO
• 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/3789799
• 关键词: action potentials; beta adrenergic receptor; beta antiadrenergic agent; calcium flux; calcium indicator; cytoplasm; drug interactions; evoked potentials; heart cell; heart contraction; heart pharmacology; heart ventricle; isoproterenol; laboratory rat; membrane potentials; myocardium; myofibrils; norepinephrine; sarcolemma; sarcoplasmic reticulum; single cell analysis; stimulant /agonist; voltage /patch clamp

Bolus beta1 and beta2 adrenoceptors exist in the heart. While the cellular effects of the former are widely studied, the specific effects of the later have not been elucidated. We studied the effects of beta2- and beta1-adrenoceptor (beta2AR and beta1AR) agonists on the cytosolic Ca2+ (Cai) transient, indexed by the transient increase in Indo-1 fluorescence ratio following excitation, twitch amplitude, measured via photodiode array, and membrane potential and L-type sarcolemmal Ca2+ current, and ICa, measured by whole cell patch electrode in single rat ventricular myocytes. The selective beta2AR agonist Zinterol (Zint) increased the amplitudes of both the Cai transient and twitch in a concentration- dependent manner. Similar results were obtained when beta2AR's were stimulated with isoproterenol (ISO) in the presence of the selective beta1AR antagonist, CGP 20712A (CGP). Beta1AR stimulation induced by norepinephrine (NE) increased twitch amplitude to about the same extent as beta2AR. However, several striking differences between response to beta1AR and beta2AR stimulation were observed. Beta1AR stimulation had a potent effect to abbreviate the time course of the twitch contraction and Cai transient; beta2AR stimulation did not reduce the time course of the Cai transient and had only a minor effect on the twitch duration. For a given increase in twitch amplitude, beta1AR stimulation caused a greater increase in Cai transient, suggesting a diminished Cai-myofilament interaction. beta1AR, but not beta2AR stimulation, evoked spontaneous Cai oscillations, increased the diastolic indo-fluorescence level and caused a decline in resting cell length. Beta1AR and beta2AR also differed in their effects on ICa. While both beta1AR and beta2AR stimulation increased the peak ICa amplitude, beta2 markedly prolonged the ICa inactivation time. Accordingly, beta2AR stimulation prolonged the action potential duration to a greater extent than beta1AR stimulation did. CPT cAMP mimicked the effects of beta1AR stimulation by NE but not those due to beta2AR stimulation. These results clearly indicate that both beta2AR and beta1AR adrenoceptors functionally coexist in rat ventricular myocytes, but that stimulation of these receptor subtypes elicits qualitatively different cell responses at the levels of ionic channels, the myofilaments, and sarcoplasmic reticulum (SR).

心脏中存在β 1和β 2肾上腺素能受体。 而 前者的细胞效应被广泛研究， 后者尚未阐明。 我们研究了β 2-和 β 1-肾上腺素能受体（β 2 AR和β 1 AR）激动剂对胞质Ca 2+的影响 (Cai)瞬时，以Indo-1荧光的瞬时增加为指标 通过光电二极管测量的激发后比率、颤搐幅度 阵列、膜电位和L型肌膜Ca 2+电流，以及 全细胞贴片电极测定单个大鼠心室肌细胞内钙伊卡 肌细胞 选择性β 2AR激动剂Zintrol（Zint）增加了 Cai瞬变和抽搐的幅度在一个浓度- 依赖的方式。 当β 2 AR被抑制时， 用异丙肾上腺素（ISO）刺激， β 1 AR拮抗剂，CGP 20712 A（CGP）。 β 1 AR刺激诱导 去甲肾上腺素（NE）增加抽搐幅度的程度与 β 2AR。 然而，在反应之间的几个显着差异 观察β 1 AR和β 2 AR刺激。 β 1 AR刺激具有 有效缩短抽搐收缩的时间进程， Cai短暂; β 2 AR刺激并没有减少 蔡短暂，只有轻微的影响抽搐持续时间。 用于 在抽搐幅度增加的情况下，β 1 AR刺激引起更大的 Cai瞬变增加，表明Cai-肌丝减少 互动 刺激β 1 AR，而不是β 2 AR，诱发自发性Cai 振荡，增加了舒张期的吲哚荧光水平， 休眠细胞长度的下降。 β 1 AR和β 2 AR在以下方面也不同： 对伊卡的影响 当β 1 AR和β 2 AR刺激 增加伊卡峰值幅度，β 2显著延长伊卡 灭活时间。 因此，β 2 AR刺激延长了 在更大程度上比β 1 AR刺激的潜在持续时间。 CPT cAMP模拟NE刺激β 1 AR的效应，但不模拟NE刺激β 1 AR的效应。 β 2AR刺激。 这些结果清楚地表明，β 2 AR 大鼠心室肌中β 1和β 1 AR肾上腺素受体功能共存 但这些受体亚型的刺激 在离子通道水平上的不同细胞反应， 肌丝和肌浆网（SR）。