POTASSIUM CHANNEL MODULATION BY ISCHEMIA OR ANTIARRHYTHMIC DRUGS

这个项目的目标是了解异常现象是如何发生的 细胞状况，如发生在缺血和 心肌梗死可影响心脏K通道功能 三类抗心律失常药物的作用。在内心，纷扰 In K通道功能将导致心脏电活动紊乱 活动和导致心律失常的因素。选择性地抑制 心肌K通道可延长动作电位时程，并可能 预防或终止折返性心律失常(III类抗心律失常药 行动)。然而，病理情况，如缺血和 脑梗塞可能影响III类药物的治疗作用或 促进他们的心律失常活动。这项研究得到了支持 计划项目和其他人进行的计划项目表明，有 细胞内外环境的深刻而持久的变化 缺血引起的对其性质和药理作用的影响 心脏K通道。特别是，在报告中提出了初步结果 本申请的项目C表明-存在异常 细胞内钙调节与β-肾上腺素能-PKA信号转导 犬心外膜分离的心室肌细胞的通路 边界区(EBZ)，它危及 心肌梗死，是本计划建议的研究重点 项目。在这个项目中，我们将重点关注如何提升[Ca]i和 单独和联合激活PKA均可影响K_4的功能 对心脏电调节最重要的通道 有源(瞬变向外、快速和缓慢延迟整流、 以及向内整流通道)。我们还将研究选择性 两种有效的III类药物(多非利特和NE10064)对这些K 频道。对于那些可以被这些药物在 与治疗相关的浓度、状态和时间依赖性 并将审查毒品行动的侧面性。此外，毒品 控制条件下的操作将与 通过升高[Ca]i或通过激活 PKA提供对缺血和脑梗塞如何影响的见解 这些三类药物的作用。这里提出的研究将 生成有关K通道变化所起作用的信息 在缺血和梗塞时的心律失常发生中的作用，以及 III类药物的抗心律失常或致心律失常作用机制 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.