(+)-sotalol causes significant occupation of beta-adrenoceptors at concentrations that prolong cardiac repolarization

The racemate (+/-) and the two enantiomers of sotalol were studied with regard to the effects on cardiac repolarization. In addition, the affinity to cardiac beta-adrenoceptors was investigated for the enantiomers. The effect on left ventricular monophasic action potential duration was assessed in the isolated perfused guinea-pig heart and the beta-adrenoceptor affinity of the compounds was studied, using a radioligand binding technique, in cellular membranes prepared from the left ventricular free wall of the cat. Moreover, the beta-adrenoceptor blocking potency of (+)-sotalol was studied in isolated strips of guinea-pig papillary muscles. Both the racemate and the two enantiomers of sotalol caused a concentration-dependent prolongation of the ventricular monophasic action potential duration. The maximal effect and the concentration causing half maximal effect (EC50 = 13 mumol/l) were similar for the racemate and the enantiomers, indicating lack of stereoselectivity for this effect. The beta-adrenoceptor affinity (equilibrium dissociation constant) of (+)-sotalol was 11 mumol/l and 4 mumol/l as estimated by the binding technique and in the isolated muscle strips, respectively. The affinity for (-)-sotalol, estimated by binding, was 0.6 mumol/l. Thus, at concentrations of (+)-sotalol required for a significant prolongation of cardiac repolarization, this isomer may cause significant beta-blockade. In this study the enantiomeric purity was better than 98%, so that the degree of beta-blockade may be even more pronounced if the enantiomeric purity of the (+)-enantiomer is less than 98%.