Demonstration of beta adrenoceptor blockade by propafenone hydrochloride: clinical pharmacologic, radioligand binding and adenylate cyclase activation studies.

The postulated beta adrenoceptor blocking properties of the new antiarrhythmic drug propafenone were studied by in vivo comparison against placebo and propranolol in the antagonism of both exercise- and isoproterenol-induced tachycardia and by in vitro radioligand binding studies of animal and human left ventricular muscle membrane preparations. Interaction with frog erythrocyte membrane adenylate cyclase was also investigated. In the clinical studies, a double blind crossover comparison of oral propafenone (300 mg), propranolol (40 mg) and placebo indicated significant antagonism of chronotropic response to isoproterenol 2 hr postdose with dose ratios of 4.1 +/- 1.3 (mean +/- S.E.M.) for propafenone and 16.8 +/- 5.1 for propranolol. Chronotropic response to exercise was modestly reduced by propafenone. Analysis of the binding of [125I]iodocyanopindolol to human left ventricular membranes revealed specific beta adrenoceptor competition by propafenone with an EC50 of 111 +/- 13 nM. Propranolol EC50 was 2.4 +/- 0.2 nM in this system. Competitive inhibition of isoproterenol-stimulated frog erythrocyte membrane adenylate cyclase activity was also obtained with propafenone. The ratio of affinities (calculated from the apparent dissociation constant; KD) for propranolol-propafenone was 1:40 for the in vivo study and 1:50 for the in vitro system. Propafenone is a specific antagonist of the human beta adrenoceptor and this action can be demonstrated during in vivo study in human subjects. At clinical dosages it appears likely that it will achieve a modest degree of beta blockade which may contribute to its antiarrhythmic effect.