title: In vitro pharmacologic profile of the novel beta-adrenoceptor antagonist and vasodilator, carvedilol.
abstract: The pharmacologic profile of the novel beta-adrenoceptor antagonist/vasodilator, carvedilol, has been investigated in vitro. Carvedilol produced competitive antagonism of the beta 1-adrenoceptor mediated positive chronotropic response to isoproterenol in guinea pig atria, and the beta 2-adrenoceptor mediated relaxation to isoproterenol in carbachol (1 mumol/l) precontracted guinea pig trachea, with a dissociation constant (KB) for beta 1-adrenoceptors of 0.8 nmol/l and beta 2-adrenoceptors of 1.3 nmol/l. At slightly higher concentrations, carvedilol produced competitive inhibition of the alpha 1-adrenoceptor mediated contractile response to norepinephrine in rabbit aorta with a KB of 11 nmol/l. Carvedilol had no significant effect on the contractile response to angiotensin II in rabbit aorta at concentrations up to 10 mumol/l, thus demonstrating the lack of nonspecific vasodilator actions in arteries. In canine saphenous vein, carvedilol produced noncompetitive blockade of alpha 2-adrenoceptor mediated vasoconstriction, indicative of some additional activity. In estrogen-primed rat uterus precontracted by depolarization with KCl (70 mmol/l), carvedilol produced concentration-dependent relaxation (IC50 of 7.6 mumol/l), consistent with the notion that carvedilol may be a calcium channel antagonist. Support for this hypothesis was obtained in KCl (70 mmol/l) depolarized rabbit aorta where carvediol (10 mumol/l) produced a 10-fold parallel rightward shift in the concentration-response curve to calcium chloride. These studies demonstrate that carvedilol is a potent beta 1-, beta 2- and alpha 1-adrenoceptor antagonist, and a moderately potent calcium channel antagonist. These multiple activities of carvedilol may contribute to the antihypertensive activity of the compound.
authors.affiliation: Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, Pa.
authors.forename: A J
authors.initials: AJ
authors.lastname: Nichols
authors.forename: A C
authors.initials: AC
authors.lastname: Sulpizio
authors.forename: D J
authors.initials: DJ
authors.lastname: Ashton
authors.forename: J P
authors.initials: JP
authors.lastname: Hieble
authors.forename: R R
authors.initials: RR
authors.lastname: Ruffolo
mesh_terms: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D013045:Species Specificity; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D014665:Vasodilator Agents; D000077261:Carvedilol