In vitro Pharmacologic Profile of the Novel Beta-Adrenoceptor Antagonist and Vasodilator, Carvedilol

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.

Inhibitory Effects of Carvedilol on Calcium Channels in Vascular Smooth Muscle Cells.

“…The major findings of the present study are: (1) 3,7,8) and antagonized Bay Kinduced contractions and hypertensive effects. and the inhibitory effect was observed at concentrations higher than 0.2 µM.…”

“…Furthermore, carvedilol reduces the contraction induced by membrane depolarization in a high K + medium in isolated rabbit coronary artery and rat aortic preparations. 3,7,8) It also antagonizes the Bay K-induced contraction in vascular smooth muscle. 8) These observations suggest that carvedilol may inhibit voltage-dependent L-type Ca 2+ channels (I Ca.L ) in vascular smooth muscle cells (VSMCs).…”

The Effect of Carvedilol on Blood Glucose Levels In Normal Albino Rats

“…It is β1, β2 antagonist(onset in 1 hour), α1 antagonist( onset in 30 minutes) and on oral administration it is rapidly absorbed and reaches peak plasma concentration within one to 2 hours. At higher doses, it has calcium channel blocking property of moderate potency (blocks L-type voltage gated channels) [11,12] but the effect of this blockade on blood glucose levels is a scantily explored domain [13,14]. Some studies reported beta blocking induced hyperglycaemia contradicting the ideas of its vasodilating property inducing hypoglycaemia by improving insulin sensitivity [15,16,17].…”

Cardiovascular and Renal Effects of Carvedilol in Dogs with Heart Failure.

“…However, the α-blocking activity of carvedilol in dogs is 3.8 times less potent than the β-blocking activity [19]. In the isolated rabbit aorta, carvedilol is approximately ten-fold less potent as an α 1 -antagonist than as a β-antagonist [29]. In this study, the response of the heart rate to isoproterenol was diminished by 40% with 0.4 mg/kg carvedilol.…”

“…Carvedilol's β 2 -adrenergic antagonism also inhibits the β 2 -receptor-mediated relaxation induced by isoproterenol in guinea pig trachea in a concentration-dependent manner [29]. An in vivo study in rats has shown that intravenous carvedilol significantly inhibits the β 2 -adrenoceptor-mediated vasodilator response to salbutamol and suggests that carvedilol inhibits β 1 -and β 2 -adrenoceptors to a similar degree in vivo [30].…”