ELECTROPHYSIOLOGY OF RIGHT ATRIAL PACEMAKERS

右心房起搏器的电生理学

• 批准号: 2609213
• 负责人: STEPHEN Lloyd LIPSIUS
• 金额: $ 16.39万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-07-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2609213
• 关键词: G protein; acetylcholine; adenylate cyclase; arrhythmia; biological signal transduction; calcium channel; cats; cell type; cholinergic receptors; cyclic AMP; cyclic GMP; digitalis; electron microscopy; electrophysiology; heart function; heart pharmacology; isoproterenol; nitric oxide; phosphodiesterases; potassium channel; protein kinase A; second messengers; vagus nerve

My long-range goals are to understand the physiological mechanisms that determine and regulate atrial pacemaker function, particularly with respect to latent atrial pacemakers and their contribution to atrial dysfunction. Thus, primary and/or latent atrial pacemaker activities have been implicated in various types of atrial dysrhythmias such as sick sinus syndrome. Although cholinergic stimulation exerts antiarrhythmic effects on atrial function, it also generates atrial dysrhythmias, the mechanisms of which are not known. Moreover, there are several aspects of cholinergic regulation of atrial pacemaker activity that are not completely understood. As examples, 1) cholinergic inhibition of the heartbeat is followed by a rebound tachycardia, i.e. postvagal tachycardia, 2) digitalis elicits a bradycardia by somehow sensitizing the atria to cholinergic inhibition, 3) nitric oxide may play an obligatory role in the inhibitory effects of ACh, and 4) the mechanisms of accentuated antagonism may not be entirely understood. In the present research, we plan to use a perforated patch/whole cell recording method to analyze cholinergic regulation of K+ and Ca2+ conductances in single pacemaker cells isolated from cat right atrium. We will use voltage clamp protocols, and selective agonist and antagonist to determine the second messenger signaling pathways that underlie cholinergic regulation of both primary (SA node) and latent atrial pacemaker activities. The present proposal will address the following specific questions: 1) What are the second messenger signaling pathways underlying ACh- induced inhibition and the rebound stimulation of I/Ca,L and I/f elicited by withdrawal of ACh? What role does nitric oxide play? 2) What are the second messenger signaling pathways underlying ACh- induced activation of ATP-sensitive K currents (I/K,ATP)? 3) How do agents or interventions that raise intracellular Ca2+ such as isoproterenol, enhance ACh-induced activation of I/K,ATP? How do these mechanisms contribute to accentuated antagonism and digitalis-induced bradycardia? 4) What are the relative contributions of the different second messenger signaling pathways to cholinergic regulation of primary and latent atrial pacemaker function? How do these mechanisms contribute to postvagal tachycardia and dysrhythmias initiated by vagal withdrawal? The proposed experiments will provide a new understanding of how ACh regulates Ca2+ and K+ conductances, and how adrenergic/cholinergic interactions operate to autonomically regulate atrial pacemaker activity. This work will contribute to our understanding of atrial brady-tachy dysrhythmias and dysrhythmias initiated by withdrawal of vagal nerve activity.

我的长期目标是了解 确定和调节心房起搏器功能，特别是在 关于潜在的心房起搏器及其对心房的贡献 功能障碍。因此，初级和/或潜在的心房起搏器活动 与各种类型的房性心律失常有关，如病态窦性心动过速 综合症。虽然胆碱能刺激具有抗心律失常的作用 在心房功能上，它还会产生房性心律失常，其机制 其中有哪些是未知的。此外，还有几个方面 胆碱能对非心房起搏器活动的调节 完全理解。例如，1)胆碱能抑制 心跳后会出现反跳性心动过速，即迷走后心动过速 心动过速，2)洋地黄通过某种方式敏化 心房对胆碱能抑制，3)一氧化氮可能起强制性作用 在ACh抑制作用中的作用，以及4)ACh的作用机制 加剧的对抗可能并不完全被理解。在现在 研究中，我们计划使用穿孔贴片/全细胞记录法 单细胞胆碱能钾、钙离子电导调节分析 从猫右心房分离起搏细胞。我们将使用电压钳位 方案，以及选择性激动剂和拮抗剂以确定第二 两者胆碱能调节的信使信号通路 初级(窦房结)和潜伏性心房起搏活动。现在 提案将涉及以下具体问题： 1)ACh的第二信使信号通路是什么？ I/Ca、L和I/f的诱导抑制和反弹刺激 通过撤销ACH？一氧化氮扮演着什么角色？ 2)ACh的第二信使信号通路是什么？ 诱导激活ATP敏感性钾电流(I/K，ATP)？ 3)提高细胞内钙离子的试剂或干预措施，如 异丙肾上腺素，增强ACh诱导的K/K、ATP？这些是如何做到的 增强拮抗和洋地黄诱导的机制 心动过缓？ 4)不同的第二信使的相对贡献是什么 初级和潜伏期心房胆碱能调节的信号通路 起搏器功能？这些机制是如何促进迷走神经后效应的 迷走神经戒断引起的心动过速和心律失常？ 拟议的实验将提供对ACH如何 调节钙离子和钾离子电导，以及肾上腺素能/胆碱能 相互作用自动调节心房起搏器的活动。 这项工作有助于我们对房性心动过速的认识 由迷走神经撤退引起的节律失常和节律失常 活动。