Effects of the enantiomers of disopyramide and its major metabolite on the electrophysiological characteristics of the guinea-pig papillary muscle

Abstract

Disopyramide, a Class Ia antiarrhythmic drug, is clinically used as a racemic mixture; R(-)disopyramide and S(+)disopyramide. The major metabolite in man is desisopropyldisopyramide: R(-)desisopropyldisopyramide and S(+)desisopropyldisopyramide. The effects of the four compounds were compared on the electrophysiological characteristics of the guinea-pig papillary muscle using the standard microelectrode technique. At an external K+ concentration of 5.4 mmol/l and a stimulation frequency of 1 Hz, S(+)disopyramide (20 μmol/l) increased action potential duration(APD) by more than 18%, while it was diminished by 6% in the presence of R(-)disopyramide. Resting membrane potential amounted to -87.1 ± 0.5 mV (n = 14) and -85.6 ± 1.2 mV (n = 10), respectively. Also a small but significant difference in effect on the maximal rate of depolarization was observed, R(-)disopyramide being more potent, related with a slower recovery of the maximal rate of depolarization. The enantiomers of the metabolite appeared to be three times less potent than those of the parent drug in their effect on the maximal rate of depolarization. The characteristics of the enantiomers of the metabolite correlated with those of the parent drug: also the R(-)enantiomer was more potent in decreasing the maximal rate of depolarization and caused more shortening of the action potential than the S(+)enantiomer. Time constants for onset and recovery of/from rate dependent block of the maximal rate of depolarization were dependent upon the external K+ concentration, both for the enantiomers of the parent drug and those of the metabolite. Onset slowed down while recovery accelerated when external K+ was increased. Time constants were lower for the metabolite. When stimulation interval was shortened, the effect on the maximal rate of depolarisation increased. Only for the metabolite statistical significant stereoselective differences were observed at all stimulation intervals. The effects on the action potential duration were dependent upon stimulation interval; for all enantiomers the action potential duration tended to be relatively (% of control) higher at short stimulation intervals than at large stimulation intervals. The effect on the maximal rate of depolarization was also voltage dependent, but no significant differences were observed between the enantiomers, for the parent drug as well as for the metabolite.