Abstract

Recently a new beta receptor antagonist (tolamolol) has been introduced which is structurally different from most available compounds in that it has as its N-substituent a p-carbamoyl phenoxy-ethyl group. The present study was undertaken to quantitate the beta receptor blocking and antiarrhythmic properties of tolamolol and to determine whether the activity of this compound is governed by known structural restraints or if new structure activity relationships could be identified. In in vivo studies, tolamolol was found to be a potent antagonist of isoproterenol-induced increases in heart rate and myocardial contractile force but was less active in blocking peripheral conductance (blood flow to hind limbs/aortic pressure) responses to isoproterenol. In dogs pretreated with 6-hydroxydopamine, tolamolol, in beta blocking doses up to 5 mg/kg, produced no significant cardiac depression. Tolamolol (5-20 mg/kg) reversed ouabain-induced vantricular tachycardia in four of nine experiments in dogs. These doses were associated with significant reductions in blood pressure. In isolated Purkinje fibers, tolamolol produced changes characteristic of antiarrhythmic beta blocking drugs only at high concentrations (30 mg/l). In terms of known structure activity relationships, the contribution of the p-carbamoyl phenoxy-ethyl substituent is probably significant in two respects. 1) The carbamoyl group in the para position contributes to the cardioselectivity of the beta receptor blockade and 2) the electron withdrawing nature of the carbamoyl moiety would probably decrease the membrane effects of the drug.