Effects of nebivolol, atenolol and propranolol on in vivo cardiovascular and metabolic responses to isoproterenol in dogs.
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.
Bowden
C R
CR
Department of Biological Reserch, Janssen Research Foundation, Spring House, Pennsylvania.
Marchione
C S
CS
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001262:Atenolol / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects*; D004285:Dogs; D004983:Ethanolamines / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D007328:Insulin / Q000097:blood; D007545:Isoproterenol / Q000494:pharmacology*; D000068577:Nebivolol; D011433:Propranolol / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D001578:Benzopyrans; D001786:Blood Glucose; D004983:Ethanolamines; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D000068577:Nebivolol; D001262:Atenolol; D011433:Propranolol; D007545:Isoproterenol