title: (+)-sotalol causes significant occupation of beta-adrenoceptors at concentrations that prolong cardiac repolarization.
abstract: 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%.
authors.affiliation: Department of Pharmacology, Hässle Cardiovascular Research Laboratories, Mölndal, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Reid
authors.forename: G
authors.initials: G
authors.lastname: Duker
authors.forename: O
authors.initials: O
authors.lastname: Almgren
authors.forename: V
authors.initials: V
authors.lastname: Nerme
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D010869:Pindolol; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013015:Sotalol / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D007457:Iodine Radioisotopes; D011943:Receptors, Adrenergic, beta; D013015:Sotalol; D010869:Pindolol