ELECTROPHYSIOLOGY OF RIGHT ATRIAL PACEMAKERS

我的长期目标是了解 确定和调节心房起搏器功能，特别是 关于潜伏性心房起搏器及其对心房起搏的作用 功能障碍 因此，原发性和/或潜伏性心房起搏活动 与各种类型的房性心律失常有关， 综合征 虽然胆碱能刺激具有抗癫痫作用， 对心房功能的影响，它也会产生心房节律障碍， 其中有哪些是未知的。 此外，还有几个方面， 心房起搏器活动的胆碱能调节， 完全理解 作为实例，1）胆碱能抑制 心跳之后是反跳性心动过速，即迷走神经后 心动过速，2）洋地黄通过某种方式使 心房胆碱能抑制，3）一氧化氮可能发挥强制性 在ACh抑制效应中的作用，以及4） 可能不能完全理解增强的拮抗作用。 本 研究中，我们计划使用穿孔贴片/全细胞记录方法， 分析胆碱能调节的K+和Ca 2+电导在单一的 从猫右心房分离起搏细胞。 我们将使用电压钳 方案，以及选择性激动剂和拮抗剂，以确定第二个 信使信号通路是胆碱能调节的基础， 原发性（SA结）和潜伏性心房起搏器活动。 本 建议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的诱导抑制和反跳刺激 通过ACh的撤销？ 一氧化氮有什么作用？ 2)ACh的第二信使信号通路是什么？ 诱导ATP敏感性K电流（I/K，ATP）激活？ 3)提高细胞内Ca 2+的药物或干预措施，如 异丙肾上腺素增强ACh诱导I/K、ATP？ 这些怎么 机制有助于增强拮抗作用和洋地黄诱导 心动过缓？ 4)不同的第二信使的相对贡献是什么 胆碱能调节原发性和潜伏性心房肌的信号通路 起搏器功能？ 这些机制是如何促进迷走神经后的 迷走神经收缩引起的心动过速和心律失常 拟议的实验将提供一个新的理解乙酰胆碱如何 调节Ca 2+和K+电导，以及肾上腺素能/胆碱能 相互作用起作用以化学方式调节心房起搏器活动。 这一工作将有助于我们对房性心动过缓的认识 节律失调和迷走神经收缩引起的节律失调 活动

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.