POTASSIUM CHANNEL MODULATION BY ISCHEMIA OR ANTIARRHYTHMIC DRUGS

这个项目的目的是了解异常是如何在 细胞状况，例如在局部缺血期间发生的那些， 心肌梗死可影响心脏K通道功能， III类抗肿瘤药物的作用。 在心脏，干扰 在K通道功能将导致心脏电紊乱 活动，并有助于胚胎发育。 选择性抑制 心脏K通道可延长动作电位时程， 预防或终止折返性心律失常（III类抗心律失常药） 行动）。 然而，病理条件如缺血和 梗死可能影响III类药物的治疗作用，或 促进他们的专业活动。 支持的研究 方案项目和其他人进行的项目表明， 细胞内和细胞外环境的深刻和持续变化 由缺血诱导，可能影响其性质和药理学 心脏K通道 特别是， 本申请的项目C表明， 细胞内钙处理与β-肾上腺素能-PKA信号转导 犬心外膜分离心室肌细胞的信号通路 边界区（EBZ），它损害了 梗死性心脏，是本计划提出的研究重点 项目 在这个项目中，我们将重点关注如何提高[Ca]i和 单独或联合激活PKA可影响K 对调节心脏电活动最重要的通道 活动（瞬时外向，快速和缓慢延迟整流， 和向内整流器通道）。 我们还将研究选择性 两种有效的III类药物（多非利特和NE 10064）对这些K 渠道 对于那些可以被这些药物阻断的， 治疗相关浓度、状态和时间依赖性 和药物作用的片面性将被检查。 此外，药物 控制条件下的行动将与控制后的行动进行比较。 通道已经通过[Ca]i的升高或通过激活 PKA提供缺血和梗死如何影响 这些III类药物的作用。 本文提出的研究将 生成关于K通道改变所起作用的信息 在缺血和梗死期间的血管生成中的作用， III类药物的抗癫痫或预防癫痫作用的机制 在这种情况下。

The objective of this project is to understand how abnormalities in cellular conditions such as those occurring during ischemia and infarction can influence the function of cardiac K channels and the actions of class III antiarrhythmic drugs. In the heart, disturbances in K channel function will lead to derangements of cardiac electrical activity and contribute to arrhythmogenesis. A selective inhibition of cardiac K channels can prolong the action potential duration and may prevent or terminate reentrant arrhythmias (class III antiarrhythmic action). However, pathological conditions such as ischemia and infarction may influence the therapeutic action of class III drugs or promote their proarrhythmic activities. Research supported by this Program Project and those carried out by others have shown that there are profound and persistant changes in intra- and extra-cellular milieu induced by ischemia that can impact on the properties and pharmacology of cardiac K channels. In particular, preliminary results presented in Project C of this application indicate that-there are abnormalities in intracellular Ca handling and the Beta-adrenergic-PKA signal transduction pathway in canine ventricular myocytes isolated from the epicardial border zone (EBZ), which compromises the reentrant circuit of the infarcted heart and is the focus of research proposed in this Program Project. In this project, we will focus on how elevating [Ca]i and activating PKA, singly and in combination, can affect the function of K channels that are most important for regulating cardiac electrical activity (the transient outward, the rapid and slow delayed rectifier, and the inward rectifier channels). We will also study the selectivity of two potent class III agents (dofetilide and NE10064) on these K channels. For those that can be blocked by these drugs at therapeutically relevant concentrations, the state- and time-dependences and sidedness of drug actions will be examined. Furthermore, drug actions under control conditions will be compared with those after the channels have been modified by an elevation of [Ca]i or by activation of PKA to provide insights into how ischemia and infarction can influence the actions of these class III drugs. The studies proposed here will generate information about the roles played by alterations in K channel function in arrhythmogenesis during ischemia and infarction, and the mechanisms of antiarrhythmic or proarrhythmic actions of class III drugs under these conditions.