K+ CURRENTS AND REPOLARIZATION IN CARDIAC ARRHYTHMIAS

了解心律失常的发生需要一个

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.