Cardiovascular pharmacology of ACC-9089--a novel, ultra-short-acting, beta-adrenergic receptor antagonist.

Abstract

The beta-adrenergic receptor blocking properties of ACC-9089 were studied in isolated cardiac and tracheal tissues from guinea pigs and in anesthetized dogs. The compound was a potent, nonselective beta-blocker in isolated tissues (atrial pA2 8.01; tracheal pA2 8.16). ACC-9089 was without intrinsic sympathomimetic action and caused direct cardiac depression only at concentrations that were four orders of magnitude higher than its pA2. In anesthetized dogs, ACC-9089 produced steady-state beta-blockade within 20 min of initiation of 3-h intravenous infusions. Recovery from beta-blockade occurred rapidly following termination of infusion (80% recovery in 17 +/- 2 min after 1.2 microgram/kg/min). Intravenous infusion of ACC-9089 caused dose-dependent inhibition of heart rate responses to sympathetic nerve stimulation and inhibition of isoproterenol-induced decreases in perfusion pressure in a perfused hindlimb preparation. The compound (a) did not produce alpha-blockade; (b) had no direct effect on hindlimb vascular resistance; and (c) did not alter hemodynamic variables in catecholamine-depleted dogs. The results indicate that ACC-9089 is a novel, ultra-short-acting beta-blocker that does not possess direct cardiovascular effects beyond those expected as a result of beta-blockade.