Different electrophysiological effects of the levo- and dextro-rotatory isomers of mexiletine in isolated rabbit cardiac muscle

Abstract

Racemic mexiletine is a widely used antiarrhythmic agent which blocks sodium channels. The effects of R-(-) and S-(+) mexiletine stereoisomers on maximum rate of depolarization (Vmax), conduction time and repolarization have not yet been investigated in isolated cardiac preparations. We studied the effect of the R-(-) and S-(+) mexiletine on rabbit cardiac action potential parameters by using the conventional microelectrode technique. Both enantiomers at 20 µM of therapeutically and experimentally relevant concentration, significantly depressed the Vmax at fast heart rates (BCLs 300 -700 ms). R-(-) mexiletine has more potent inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine significantly inhibited the Vmax of early extrasystoles measured at 70 ms diastolic interval induced by S1-S2 stimuli. R-(-) mexiletine has more pronounced inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine increased significantly the ERP/APD 90 ratio. The time constant (τ) of recovery of Vmax was found to be τ = 376.0 ± 77.8 ms for R-(-) mexiletine and τ = 227.1 ± 23.4 ms for S-(+) mexiletine which indicates a slower offset kinetics for R-(-) mexiletine from sodium channels than that of the S-(+) enantiomer. These data suggest that R-(-) mexiletine might be more potent antiarrhythmic agent than S-(+) mexiletine.

Cellular mechanisms underlying the effects of cilostazol, milrinone, isoproterenol and ajmaline on electrographic and arrhythmic manifestations of early repolarization syndrome, and comparative analysis of the cardiac electrophysiological effects of the optical isomers of mexiletine

“…Although the differential effects of its stereoisomers on sodium current and excitability of skeletal muscle has been established more than twenty years ago [De Luca 1995], studies directed to exhaustive comparison of the electrophysiological effects of the R-(-) and S-(+) mexiletine isomers on cardiac ventricular muscle preparations were scarce until the recent past: In a lately published work of our research team we have investigated the electrophysiological effects of the levo-and dextrorotatory isomers of mexiletine in isolated rabbit cardiac muscle [Gurabi 2017]. We have observed a slower dissociation (offset) kinetics for R-(-) mexiletine from sodium channels than that for the S-(+) enantiomer.…”

“…Previously [Gurabi 2017] our research group analysed the effects of R-(-) and S-(+) enantiomers of mexiletine on AP parameters in rabbit right ventricular papillary muscle preparations. We have found that R-(-) optical isomer displays a tendency to a more potent inhibitory effect on Vmax when compared to the S-(+) stereoisomer.…”