K+ CURRENTS AND REPOLARIZATION IN CARDIAC ARRHYTHMIAS

了解心律失常的发生需要 了解正常细胞电生理学，以及 伴随心脏病的电紊乱。 此外该 合理的抗肿瘤药物治疗方法需要 评价这些药物的电生理作用， 参与心脏发生的各种离子通道 动作电位 近期心律失常抑制的结果 试验导致了对使用和未来发展的新的兴趣 除了减缓传导外， 包括改变复极化和延长作用的药剂 潜在持续时间 一般来说，这些影响是封锁造成的， 或钾离子通道的改变。 拟议的研究重点是 描述了心室肌细胞中两个钾电流的特征 复极化，即延迟整流电流（iK）和内向 整流器电流（iK 1）使用心室肌细胞分离自 作为实验模型。 标准 全细胞膜片钳技术、隔离膜片钳技术和 将采用“穿孔贴片”技术来研究这些电流 宏观（全细胞）和微观（单通道记录） 水平，以及与动作电位配置相关的发现。 的 iK的电压、时间依赖性和整流特性将 其特征在于它的两个动力学分量。 的影响 还将研究选定的III类抗肿瘤药物，沿着 一种新的假设，即一些药物可能延长动作电位， 通过减少iK，而是通过改变或重新分配 iK的每个分量。 其他研究将评估iK的调节 通过改变细胞外K+浓度和β- 肾上腺素能刺激，将离子电流的改变与 动作电位构型的改变。 的特点 内向整流器也将被检查，并与其在以下方面的作用有关： 动作电位的终末复极化。 调制本 通过降低pH值和改变细胞外K+等干预措施， 将进行研究，以了解目前类似的混乱 在心脏病中。 这些研究的结果将推动我们的 了解心室肌纤维化的潜在机制 复极化，以及复极化如何可能被生理改变， 条件和药物，最终目标是了解（和 控制）引起心律失常的复极异常。

Understanding the genesis of cardiac arrhythmias necessitates an understanding of normal cellular electrophysiology, as well as the electrical derangements that accompany cardiac disease. In addition, the rational approach towards antiarrhythmic drug therapy requires an appreciation of the electrophysiologic effects of these agents on the various ion channels which participate in the genesis of the cardiac action potential. Results from the recent Cardiac Arrhythmia Suppression Trial have lead to a renewed interest in the use and future development of antiarrhythmic drugs which act by means other than slowing conduction, including agents which alter repolarization and prolong the action potential duration. In general, these effects result from the blockade or alteration of potassium channels. The proposed studies focus on characterizing two potassium currents involved in ventricular repolarization, namely the delayed rectifier current (iK) and the inward rectifier current (iK1) using ventricular myocytes isolated from the midwall of the canine left ventricle as an experimental model. Standard whole cell patch clamp techniques, isolated patch techniques, and "perforated patch" techniques will be employed to study these currents on macroscopic (whole cell) and microscopic (single channel recording) levels, and findings related to the action potential configuration. The voltage-, time-dependence, and rectification properties of iK will be characterized in terms of its two kinetic components. The effects of select Class III antiarrhythmic agents will also be studied, along with a novel hypothesis that some agents may prolong the action potential not by reducing iK, but by altering or redistributing the contributions of each component of iK. Additional studies will assess modulation of iK and its components by altered extracellular K+ concentration and beta- adrenergic stimulation, relating alterations of ionic currents to alterations of action potential configuration. The characteristics of the inward rectifier will also be examined and related to its role in terminal repolarization of the action potential. Modulation of this current by such interventions as reduced pH and altered extracellular K+ will be studied in an effort to understand similar derangements present in cardiac disease. Results from these studies will advance our understanding of the underlying mechanisms responsible for ventricular repolarization, and how repolarization may be altered by physiologic conditions and drugs, with the ultimate goal of understanding (and controlling) repolarization abnormalities responsible for arrhythmias.