K+ CURRENTS AND REPOLARIZATION IN CARDIAC ARRHYTHMIAS

了解心律失常的发生需要一种 了解正常的细胞电生理学，以及 伴随心脏病而来的电错乱。此外， 合理的抗心律失常药物治疗需要 这些药物对心脏电生理影响的研究进展 参与心脏发生的各种离子通道 动作电势。近期心律失常抑制的结果 试验重新引起了人们对该产品的使用和未来发展的兴趣 通过减缓传导以外的方式起作用的抗心律失常药物， 包括改变复极和延长作用的药物 潜在持续时间。总的来说，这些影响是由封锁造成的。 或钾通道的改变。建议的研究集中在 两种与心室肌有关的钾电流特征 复极化，即延迟整流电流(Ik)和内向 从心肌细胞分离的整流电流(IK1) 以犬左室中壁为实验模型。标准 全细胞膜片钳技术、隔离膜片技术和 “穿孔补丁”技术将被用来研究这些洋流。 论宏观(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。这个 IK的电压、时间依赖和整流特性将是 以其两个动力学成分为特征的。的影响 还将研究部分III类抗心律失常药物，以及 一些药物可能延长动作电位的新假说不是 通过减少IK，但通过更改或重新分配 IK的每个组件。其他研究将评估对IK的调制 及其组分通过改变胞外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。其特点是 内向整流器也将被检查，并与其在 动作电位的末端复极。对此进行调制 由诸如降低pH和改变细胞外K+等干预所引起的电流 将被研究以努力理解目前存在的类似的混乱 在心脏病方面。这些研究的结果将推动我们的 对室性心动过速的潜在机制的理解 复极，以及生理因素如何改变复极 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.