Clinical studies suggest that metabolites contribute to the antiarrhythmic effects of encainide (EN). This study compares the electrophysiological effects of EN and two recently identified metabolites (MJ14030, MJ9444) on canine Purkinje (PF) and ventricular fibers. The fibers were stimulated in vitro at 2 Hz and superfused with Tyrode's solution. Standard microelectrode techniques were used to measure the resting potential, action potential amplitude and duration at 90% of repolarization (APD90), maximum upstroke velocity (V(max)) and propagation velocity. Rheobasic current was determined by intracellular injection of constant current pulses of 100 msec in duration. Current injection through a single sucrose gap was used to determine the voltage threshold and the voltage dependency of cellular automaticity in shortened PF. In PF, the relative potency of these compounds was 9:1:1 for MJ9444, MJ14030 and EN, respectively. The threshold dose for EN and MJ14030 ranged between 10-8 and 10-7 M, that for MJ9444 ranged between 10-9 and 10-8 M. At a concentration of 10-6 M, these compounds significantly (P < .05) decreased APD90, V(max) and propagation velocity. Resting potential was not altered. Only MJ9444 significantly decreased action potential amplitude. The effects on V(max) and APD90 were markedly rate-dependent. Rheobasic current was increased from 280 ± 20 nA to 360 ± 35, 375 ± 32 and to 645 ± 40 nA (mean ± S.E.M.., n = 5) by EN, MJ14030 and MJ9444, respectively. None of the compounds altered voltage threshold for all-or-none depolarization and all failed to suppress slow channel-dependent action potentials induced in PF by superfusion with KCl (22 mM) and isoproterenol (10-5 M). Similar findings were obtained in ventricular fibers except that none of these compounds reduced APD90. In sucrose gap experiments, cellular automaticity arising from the high level of transmembrane potential was markedly slowed by MJ9444 (10-6 M) but not by EN or MJ14030 (10-6 M). Automaticity arising from the low level of transmembrane potential was not altered by any compound. We conclude that the metabolites have electrophysiological profiles similar to EN and that MJ9444 is most potent. These metabolites may contribute to the antiarrhythmic action of encainide.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1 1982|
ASJC Scopus subject areas
- Molecular Medicine