The mechanisms which determine the rate-dependent decrease in conduction during ischemia have not been studied extensively. Presumably, conduction slowing associated with ischemia is due to changes in active and passive membrane properties, such as Vmax; and internal longitudinal resistance (ri), an index of cellular electrical coupling. Type 1 antiarrhythmic drugs exert their effect on conduction primarily through rate-dependent changes in Vmax. Ischemic conditions accentuate the drug induced rate- dependent changes in conduction, in part, via prolongation of the recovery kinetics and rate-dependent changes in Vmax. However, the mechanism by which ischemic conditions prolong the recovery of Vmax in the presence of a Type 1 drug has not been studied extensively. In addition, the contribution of cellular uncoupling to the observed conduction slowing, the associated intracellular ionic events and their modification by antiarrhythmic drugs have not been studied.
The specific aims of the proposal are to: 1) understand the relative contributions of rate-dependent changes in Vmax and cellular coupling to rate-dependent conduction slowing associated with simulated ischemia. 2) understand the relationship of rate-dependent changes in intracellular H+, Na+ and Ca++ to rate-dependent conduction slowing associated with simulated ischemia. 3) understand the modification of rate-dependent conduction slowing, Vmax and cellular coupling by drugs which alter the inward sodium current in a rate-dependent fashion. 4) understand the effect of simulated ischemia on rate-dependent conduction slowing induced by the Type 1 antiarrhythmic drugs (lidocaine, procainamide, flecainide) and Tetrodotoxin.
These aims will be attained by utilizing standard microelectrode techniques to determine Vmax, conduction velocity and ri, as well as ion-sensitive intracellular microelectrodes to determine aiNa, aiH+ and possibly aiCa++ at different stimulation rates both in the presence and absence of sodium channel blockers and simulated ischemia. The effect of simulated ischemia on antiarrhythmic drug effect will be determine by measuring changes in Vmax, conduction velocity, and the kinetics of onset and recovery of rate-dependent changes in Vmax. The ability to determine the magnitude and cause of rate- dependent slowing of conduction associated with acute ischemia and the effect of antiarrhythmic drugs on these changes should provide new insights into factors important in the genesis of ventricular fibrillation and the mechanism of the antiarrhythmic and proarrhythmic effects of drugs which affect the rapid inward current.
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