The studies in this proposal are designed to increase our understanding of the factors responsible for the rate-dependent slowing of ventricular conduction induced by myocardial ischemia, the effects of commonly used antiarrhythmia drugs on these factors, and the effect of ischemia on the electropharmacology of the antiarrhythmic drugs. We will utilize guinea pig papillary muscle and microelectrode techniques to determine the changes in Vmax of the action potential upstroke, internal longitudinal resistance, intracellular pH and sodium, and conduction velocity under conditions of simulated ischemia. Sodium and calcium channel blocking agents and agents which influence calcium release from the sarcoplasmic reticulum will be used to test specific hypotheses relative to the causes of the conduction slowing, as well as to provide clinically relevant information concering the effects of these agents in the setting of acute ischemia. We hypothesize that the ischemia-induced increase in coupling resistance is due in part to calcium release from the SR, that it increases as a function of stimulus frequency, and that it contributes to the rate-dependent conduction slowing. We postulate that this change in coupling resistance will be associated with ischemia-induced changes in intracellular Na and pH which are also exaggerated by an increase in stimulation frequency. We also hypothesize that the sodium channel blocking agents will exaggerate the rate-dependent conduction slowing by further depressing Vmax of the action potential upstroke; whereas the calcium blocking agents will lessen the rate-dependent conduction slowing by lessening the increase in coupling resistance, and that this will be mediated by a diminished fall in intracellular pH. Finally, we postulate that the use-dependent effects of the antiarrhythmic drugs which block the sodium channel will be altered by simulated ischemia. We believe that these studies will provide information relevant to an understanding of the genesis of ischemia-induced ventricular fibrillation--the ultimate cause of sudden cardiac death--and its prevention or precipitation by commonly used antiarrhythmic drugs.
