Cardiovascular pharmacology of ACC-9089--a novel, ultra-short-acting, beta-adrenergic receptor antagonist.
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.
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002395:Catecholamines / Q000502:physiology; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D005464:Fluorobenzenes; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006614:Hindlimb / Q000098:blood supply; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D005464:Fluorobenzenes; D011412:Propanolamines; D011433:Propranolol; D007545:Isoproterenol; C047847:flestolol; D009638:Norepinephrine