Studies on the stereoisomers of beta-adrenoceptor antagonists in conscious A-V blocked dogs

Abstract

Atrial and ventricular chronotropic effects of the individual stereoisomers of propranolol, pindolol, metoprolol and penbutolol were studied in conscious dogs with chronic atrio-ventricular (A-V) block. Ventricular beta-adrenoceptor blocking activity was assessed for all drugs against isoprenaline under the same experimental conditions. At low doses, the stereoisomers of propranolol and penbutolol decreased atrial rate, whereas those of pindolol and metoprolol produced an increase. At higher doses, all drugs increased atrial rate. All drugs decreased ventricular rate dose-dependently except (+)-pindolol. Relative ventricular beta-blocking potencies of the (-)-isomers of propranolol, pindolol, metoprolol and penbutolol were respectively 38, 21, greater than 43 and 31 times higher than those of their corresponding (+)-isomers. In addition, beta-blocking potencies of (-)- and (+)-pindolol were respectively 60 and 120 times higher, those of (-)- and (+)-penbutolol 7 and 8 times higher and those of (-)- and (+)-metoprolol 4 and greater than 4 times weaker than those of (-)- and (+)-propranolol. At comparable levels of ventricular beta-adrenoceptor blockade, (-)-pindolol and (-)-metoprolol were more potent in producing ventricular bradycardia than their respective (+)-isomers, whereas (-)- and (+)-propranolol and (-)- and (+)-penbutolol were equiactive. In addition, regardless of which isomer was being studied, the order of ventricular bradycardiac potencies, at comparable levels of beta-adrenoceptor blockade, was metoprolol greater than propranolol greater than penbutolol greater than pindolol. In addition, regardless of which isomer was being studied, the order of ventricular bradycardiac potencies, at comparable levels of beta-adrenoceptor blockade, was metoprolol > propranolol > penbutolol >pindolol. 5 These results show that antagonism of beta-adrenoceptors in the ventricle is at least partly responsible for the ventricular bradycardiac effect produced by these drugs, but also that some other factor, apparently distinct from the membrane stabilizing activity, is involved, suggesting the existence of some other as yet unknown pharmacological property of the beta-adrenoceptor blocking drugs, especially evident in metoprolol. Finally, these results demonstrate that the intrinsic sympathomimetic activity exhibited by some of these drugs attenuate their bradycardiac effect.