The stereoselectivity of carvedilol, a novel P-adrenoceptor antagonist and vasodilator with one asymmetric carbon atom, was examined a t al-and p,-adrenoceptors in vitro and in vivo. (-)-(S)-Carvedilol is a potent, competitive antagonist of the PI -adrenoceptor-mediated positive chronotropic response to isoproterenol in guinea pig atrium, with a dissociation constant ( K , ) of 0.4 nM. ( +)-(R)-Carvedilol was more than 100-fold less potent than the (-)-S-enantiomer as an antagonist of &-andrenoceptors, having a K, of approximately 45 nM. Consistent with these findings (-)-(S)-carvedilol (0.1 mg/kg, i.v.) produced a 25-fold rightward shift in the /I,-adrenoceptor-mediated positive chronotropic response to isoproterenol in pithed rats, whereas the (+)-R-enantiomer had no P,-adrenoceptor blocking activity in vivo at this dose. In contrast to the marked degree of stereoselectivity observed at 8,-adrenoceptors, both ( -)-(S)and ( + )-(R)-carvedilol produced equal antagonism of the a,-adrenoceptor-mediated vasoconstrictor response to norepinephrine in rabbit aorta, with K , values of 14 and 16 nM, respectively. Furthermore, in the pithed rat, the a,-adrenoceptor-mediated pressor dose-response curve to cirazoline was shifted approximately 6-fold to the right by both the (+)-Rand (-)-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 a,-andrenoceptor blockade produced by both enantiomers, and the concomitant &-adrenoceptor blockade produced by the ( -)-Senantiomer, 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 a,-and P,-adrenoceptors, with Pi-adrenoceptor blockade resulting from an area of the molecule containing the asymmetric carbon atom, specifically the carbazolyloxy propanolamine moiety, and a, -adrenoceptor blockade resulting from a part of the molecule that does not contain the asymmetric carbon atom, most likely the phenoxyethylamine moiety.