Effects of beta adrenoceptor down-regulation on the cardiovascular responses to the stereoisomers of dobutamine

JS Hayes, N Bowling and GD Pollock

Effects of prolonged in vivo infusion of either saline (control) or isoproterenol (beta adrenoceptor desensitization) on acute cardiovascular responses to (+) (beta agonist)-, (-) (alpha agonist)- and (+/-)-dobutamine were studied in pithed rats. Each form of dobutamine resulted in comparable dose-dependent increases in maximum left ventricular dP/dt (LVdP/dtmax) in control animals. Effects of (+)- dobutamine were blocked by propranolol whereas those of l-dobutamine were sensitive to prazosin; both alpha and beta antagonists were required to block the inotropic effects of the racemic mixture. Contractile responses to (+)- and (+/-)-dobutamine were accompanied by tachycardia (characteristic of beta adrenoceptor stimulation) whereas (- )-dobutamine enhanced LVdP/dtmax without altering heart rate (characteristic of alpha adrenoceptor stimulation). Isoproterenol infusion resulted in a pronounced desensitization to the inotropic effects (LVdP/dtmax) of (+/-)- and (+)-dobutamine. Ed30 values for (+/- )- and (+)-dobutamine were increased by approximately 15- and 50-fold, respectively, and maximal responses to both drugs were severely attenuated. Prazosin further blunted remaining inotropic responses to (+/-)-dobutamine and propranolol resulted in a complete block. Responses to (+)-dobutamine were only sensitive to propranolol. Attenuation of heart rate responses paralleled those observed for LVdP/dtmax. By contrast, the inotropic effects of (-)-dobutamine in either control or desensitized rats were both qualitatively and quantitatively comparable; responses were blocked by the alpha-1 antagonist, prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 235, Issue 1, pp. 58-65, 10/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics