The goal of this proposal is to investigate the mechanism underlying the development of abnormal cardiac rhythms in single cells isolated from the hearts of guinea pigs with cardiac hypertrophy induced by pressure overload. This model produces animals that develop cardiac hypertrophy both with and without heart failure. Based on our previous experimental work our working hypothesis is that alterations or altered interactions between the following electrical components may be involved in generating arrhythmias in hypertrophied hearts. (1) The voltage and time-dependence of spontaneous and induced oscillations of current, (2) Changes in the net conductance of the membrane during repolarization and during diastole, (3) The contribution of changes in the magnitude of kinetics of calcium currents. An important related goal is to investigate the effects of cardioactive agents (digitalis, catecholamines, low K+, quinidine, and verapamil on these factors) since the sensitivity of pathologic tissue to potentially toxic electrical effects of these agents has not been studied systematically. The goals of the proposal will be achieved by using the voltage clamp technique with two microelectrodes to study the oscillatory currents, calcium currents, and both isochronal and steady-state current-voltage relationships in single myocytes isolated from hearts of guinea pigs with cardiac hypertrophy with and without heart failure. Our studies should allow us to describe the critical interactions between these potentially arrhythmogenic currents and changes in membrane conductances that generate or fail to generate abnormal rhythmic activity in a realistic pathologic model of cardiac hypertrophy and failure. The results of the proposal also should provide a better understanding of the role of cardioactive agents in the either promoting or inhibiting abnormal rhythmic activity in the diseased heart. We believe the results of our proposed studies may lead to improved ways to treat or prevent the lethal arrhythmias associated with cardiac hypertrophy and failure.
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