The interaction of the enantiomers of carvedilol with ?1- and ?1-adrenoceptors

Autor: Nichols Aj, Hieble Jp, A C Sulpizio, Robert R. Ruffolo, Ashton Dj
Rok vydání: 1989
Předmět:
Zdroj: Chirality. 1:265-270
ISSN: 1520-636X
0899-0042
Popis: The stereoselectivity of carvedilol, a novel beta-adrenoceptor antagonist and vasodilator with one asymmetric carbon atom, was examined at alpha 1- and beta 1-adrenoceptors in vitro and in vivo. (-)-(S)-Carvedilol is a potent, competitive antagonist of the beta 1-adrenoceptor-mediated positive chronotropic response to isoproterenol in guinea pig atrium, with a dissociation constant (KB) of 0.4 nM. (+)-(R)-Carvedilol was more than 100-fold less potent than the (-)-S-enantiomer as an antagonist of beta 1-andrenoceptors, having a KB of approximately 45 nM. Consistent with these findings (-)-(S)-carvedilol (0.1 mg/kg, i.v.) produced a 25-fold rightward shift in the beta 1-adrenoceptor-mediated positive chronotropic response to isoproterenol in pithed rats, whereas the (+)-R-enantiomer had no beta 1-adrenoceptor blocking activity in vivo at this dose. In contrast to the marked degree of stereoselectivity observed at beta 1-adrenoceptors, both (-)-(S)- and (+)-(R)-carvedilol produced equal antagonism of the alpha 1-adrenoceptor-mediated vasoconstrictor response to norepinephrine in rabbit aorta, with KB values of 14 and 16 nM, respectively. Furthermore, in the pithed rat, the alpha 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Databáze: OpenAIRE
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