The interaction of the enantiomers of carvedilol with α₁‐ and β₁‐adrenoceptors

The stereoselectivity of carvedilol, a novel β‐adrenoceptor antagonist and vasodilator with one asymmetric carbon atom, was examined at α 1 ‐ and β 1 ‐adrenoceptors in vitro and in vivo. (−)‐(S)‐Carvedilol is a potent, competitive antagonist of the β 1 ‐adrenoceptor‐mediated positive chronotropic response to isoproterenol in guinea pig atrium, with a dissociation constant ( K B ) of 0.4 n M . (+)‐(R)‐Carvedilol was more than 100‐fold less potent than the (−)‐S‐enantiomer as an antagonist of β; 1 ‐andrenoceptors, having a K B of approximately 45 n M . Consistent with these findings (−)‐(S)‐carvedilol (0.1 mg/kg, i.v.) produced a 25‐fold rightward shift in the β 1 ‐adrenoceptor‐mediated positive chronotropic response to isoproterenol in pithed rats, whereas the (+)‐R‐enantiomer had no β 1 ‐adrenoceptor blocking activity in vivo at this dose. In contrast to the marked degree of stereoselectivity observed at βl 1 ‐adrenoceptors, both (−)‐(S)‐ and (+)‐(R)‐carvedilol produced equal antagonism of the α 1 ‐‐‐‐adrenoceptor‐mediated vasoconstrictor response to norepinephrine in rabbit aorta, with K B values of 14 and 16 n M , respectively. Furthermore, in the pithed rat, the α 1 ‐adrenoceptor‐mediated pressor dose–response curve to cirazoline was shifted approximately 6‐fold to the right by both the (+)‐R‐ and (−)‐S‐enantiomers of carvedilol at a dose of 1 mg/kg, i.v. In anesthetized spontaneously hypertensive rats, (−)‐(S)‐carvedilol was 6‐fold more potent as an antihypertensive than (+)‐(R)‐carvedilol. The vasodilator and acute antihypertensive activity of carvedilol results from α 1 ‐andrenoceptor blockade produced by both enantiomers, and the concomitant β 1 ‐adrenoceptor blockade produced by the (−)‐S‐enantiomer, which prevents reflex tachycardia that can offset the antihypertensive response, leading to greater overall antihypertensive potency of (−)‐(S)‐carvedilol relative to the (+)‐R‐enantiomer. These data also suggest that distinct regions of the carvedilol molecule are responsible for blocking α 1 ‐ and β 1 ‐adrenoceptors, with β 1 ‐adrenoceptor blockade resulting from an area of the molecule containing the asymmetric carbon atom, specifically the carbazolyloxy propanolamine moiety, and α 1 ‐adrenoceptor blockade resulting from a part of the molecule that does not contain the asymmetric carbon atom, most likely the phenoxyethylamine moiety.