Effects of nebivolol, atenolol and propranolol on in vivo cardiovascular and metabolic responses to isoproterenol in dogs

CR Bowden and CS Marchione

Department of Biological Reserch, Janssen Research Foundation, Spring House, Pennsylvania.

Pentobarbital-anesthetized dogs were administered either dl- propranolol, atenolol or dl-nebivolol at cumulative doses of 0 (vehicle), 0.0025, 0.01, 0.04, 0.16 and 0.64 mg/kg i.v. After each dose, heart rate and diastolic blood pressure responses to isoproterenol (0.125 micrograms/kg/min i.v. for 5 min), as well as plasma glucose, insulin, lactate and free fatty acid responses, were measured. Heart rate and free fatty acid changes were taken as beta-1 adrenergic indices, with the other parameters taken as beta-2 adrenergic indices. The antagonist dose estimated to cause 50% inhibition of each isoproterenol response (ID50) was calculated. Nebivolol and atenolol had nearly identical cardiovascular profiles, which were much more beta-1 selective than that of propranolol [heart rate and blood pressure ID50 values, mg/kg: 0.034, 0.036 (propranolol); 0.058, 0.713 (nebivolol); 0.047, 0.506 (atenolol)]. Propranolol also potently inhibited isoproterenol-stimulated glucose, insulin and lactate increases (ID50S: 0.020, 0.078 and 0.007 mg/kg, respectively). Nebivolol and atenolol were much weaker inhibitors of these metabolic responses than propranolol (5-fold-35-fold and 8-fold-greater than 90- fold, respectively). Insulin responses were equivalently inhibited by both nebivolol and atenolol (ID50S greater than 0.4 mg/kg), whereas glucose and lactate ID50S for nebivolol were 0.183 and 0.243 mg/kg, respectively, with atenolol ID50S greater than 0.64 mg/kg. Free fatty acid responses were attenuated by all three antagonists with ID50 values of 0.103, 0.100 and 0.028 mg/kg for propranolol, nebivolol and atenolol, respectively. These in vivo studies demonstrate that dl- nebivolol significantly inhibited the beta-1 cardiac response at doses which did not produce either beta-2 cardiovascular or metabolic effects.

Volume 251, Issue 2, pp. 599-605, 11/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics