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.
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