Effects of beta adrenoceptor down-regulation on the cardiovascular responses to the stereoisomers of dobutamine.
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)
D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D003655:Decerebrate State; D004280:Dobutamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013237:Stereoisomerism; D013997:Time Factors
D011943:Receptors, Adrenergic, beta; D004280:Dobutamine; D011433:Propranolol; D007545:Isoproterenol