Previous studies have reported that enhanced antiarrhythmic effects occur when agents that prolong repolarization are combined with agents that block the sodium channels. The mechanism(s) of this interaction have not been elucidated. In this study, the interactions between the prolongation of action potential duration (APD) by a potassium channel blocker and the reduction in the maximal upstroke velocity of phase 0 of action potential (V(max)) by sodium channel blockers were investigated in guinea pig papillary muscle using conventional microelectrode techniques. Agents that produce selective electrophysiologic effects were chosen, including low concentrations of barium chloride (BaCl2), which selectively blocks the inwardly rectifying potassium current without effects on other repolarizing or depolarizing currents, O-demethyl-encainide (ODME), which blocks the activated sodium channel with slow onset/offset kinetics, and mexiletine, which preferentially blocks the inactivated sodium channel with rapid onset/offset kinetics. Mexiletine (4 x 10-6 M) decreased V(max) from 195 ± 29 V/sec at baseline to 180 ± 26 V/sec (P < .05). Whereas BaCl2 (10-5 M) prolonged action potential duration, it had no effect on V(max). However, the addition of BaCl2 to mexiletine synergistically decreased V(max) from 180 ± 26 V/sec with mexiletine to 166 ± 18 V/sec (P < .05). ODME (3 x 10-7 M) decreased V(max) from 179 ± 17 V/sec at baseline to 133 ± 15 V/sec (P < .01). However, the addition of BaCl2 to ODME did not produce a further decrease in V(max) as compared with ODME alone. In summary, a synergistic effect on V(max) was observed when BaCl2 and mexiletine were combined. However, no synergistic effect on V(max) occurred when BaCl2 was added to ODME. These results suggest that action potential prolongation can modulate the action of this inactivated sodium channel blocker.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1993|
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