Major class III anti-arrhythmic agents (C3As) acts by prolonging action potential duration. K+ channels act as receptors for these agents and the actions of these agents differently modulate these channel subtypes. Dysfunction of some of these channel subtypes may also be the underlying cause in many types of cardiac arrhythmic during the ischemic and post-ischemic periods in patients. Anti-arrhythmic drug research attempts to invent drugs that rate unlike many of the available C3As. One the other hand may of the potassium channel openers (PCOs) used mainly as anti-hypertensive agents have anti-arrhythmic properties. Thus, there is a need to invent drugs that are like C3As, but would be effective (at faster heart rate) in dealing with early depolarization induced extrasystoles (""""""""Torsades de pointes""""""""). These last events are mostly calcium mediated. The long term aim of this proposal would be to determine the effects of several new classes of K+ channel modulators ( e.g., 2,3 Butanedione monoxime containing compounds which are also possible Ca2+ channel blockers, others are PCOs) besides C3As in whole cells (atrial tumor cells and native rat myocytes) and test the effectiveness of theses agents on drug induced or physiologically induced arryhthmias in canine cardiac tissue. A major strategy will be to use two functionally diverse K+ channel subtypes in two different cell types: atrial tumor cells (AT-1 cells, prominently studied for delayed rectifier type K+ channel) and rat myocyte (prominently generates transient outward K+ current). One rationale for extending the study to the tissue level is that many C3As reduce force of contradiction while some of the monoxime containing compounds increased contracted force in ventricular muscle tissue in our laboratory.
The specific aims of this proposal will be: 1) Investigate the effects of C3As, monoxime containing compounds and PCOs on K+ currents in rat myocytes and AT-1 cells; 2) Investigate the effects of physiologically (metabolic blockage/hypoxia) induced changes in K+ currents and contrast these with those in aim 1; 3) Investigate the effects of several of these anti-arrhythmic drugs on myocardial force and drug (or physiologically) induced arryhthmias (or membrane potential perturbations). Parallel comparison and contrast of whole cell current and potential in the presence of these novel channel modulators with their effects in whole tissue will facilitate the understanding and development of more specific and effective anti-arrhythmic agents.
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