No abstract

No abstract

The pharmacologic profile of the novel β-adrenoceptor antagonist/vasodilator, carvedilol, has been investigated in vitro. Carvedilol produced competitive antagonism of the β₁-adrenoceptor mediated positive chronotropic response to isoproterenol in guinea pig atria, and the β₂-adrenoceptor mediated relaxation to isoproterenol in carbachol (1 μmol/l) precontracted guinea pig trachea, with a dissociation constant (KB) for β₁-adrenoceptors of 0.8 nmol/l and β₂-adrenoceptors of 1.3 nmol/l. At slightly higher concentrations, carvedilol produced competitive inhibition of the α₁-adrenoceptor mediated contractile response to norepinephrine in rabbit aorta with a K_b of 11 nmol/l. Carvedilol had no significant effect on the contractile response to angiotensin II in rabbit aorta at concentrations up to 10 μmol/l, thus demonstrating the lack of nonspecific vasodilator actions in arteries. In canine saphenous vein, carvedilol produced noncompetitive blockade of α₂-adrenoceptor mediated vasoconstriction, indicative of some additional activity. In estrogen-primed rat uterus precontracted by depolarization with KC1 (70 mmol/l), carvedilol produced concentration-dependent relaxation (IC50 of 7.6 μmol/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 carvedilol (10 μmol/l) produced a 10-fold parallel rightward shift in the concentration-response curve to calcium chloride. These studies demonstrate that carvedilol is a potent β₁, β₂- and α₁-adrenoceptor antagonist, and a moderately potent calcium channel antagonist. These multiple activities of carvedilol may contribute to the antihypertensive activity of the compound.

No abstract

No abstract