Vascular effects of the stereoisomers of dobutamine

Abstract

The stereoisomers of dobutamine have been evaluated for their effects on the vasculature of the pithed rat. The (-)-isomer of dobutamine possessed potent pressor activity which was of a direct nature and mediated predominantly via postsynaptic vascular alpha-1 adrenergic receptors. The pressor activity of (-)-dobutamine was significantly potentiated by pretreatment with propranolol, indicating that this isomer also possesses beta agonist activity which partially opposes the alpha receptor-mediated pressor response. Conversely, (+)-dobutamine was an extremely weak pressor agent in pithed rats. This activity was also mediated via postsynaptic vascular alpha-1 adrenergic receptors and was potentiated by pretreatment with propranolol, indicating a concurrent beta receptor-mediated relaxation of vascular smooth muscle. Both stereoisomers of dobutamine elicited beta-2 adrenergic receptor-mediated depressor responses in pithed rats with vascular tone maintained by constant angiotensin II infusion. The beta-2 receptor-mediated depressor effect was greatest for the (+)-isomer. A similar selectivity for (+)-dobutamine was also observed for beta-1 receptor-mediated tachycardia in pithed rats. These results are consistent with our previous in vitro studies indicating that the (-)-isomer of dobutamine is a relatively potent alpha adrenergic agonist and a relatively weaker beta-1 and beta-2 agonist, whereas its enantiomer, (+)-dobutamine, is a strong beta-1 and beta-2 agonist and possesses only minimal alpha agonist activity. It is likely that the complex cardiovascular effects of racemic dobutamine used clinically result from the sum of the unique alpha and beta adrenergic effects of the individual stereoisomers. The reason that only minimal changes in blood pressure occur clinically with dobutamine at doses which significantly increase the inotropic state of the heart is due, in part, to the ability of the individual steroisomers that comprise the racemic mixture to offset the vascular effects of each other by both a pharmacological and physiological antagonism.