Characterization of the peripheral and central effects of SK&F 82526, a novel dopamine receptor agonist

Abstract

SK&F 82526 (6-chloro-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-(1H)-3-benzazepine) was evaluated for its peripheral cardiovascular activity, effect on renal and central dopamine receptors and mechanism of action. Comparisons were made with dopamine. In anesthetized dogs, SK&F 82526 i.v., produced dose-related dilation of the renal vasculature, apparently through stimulation of postsynaptic dopamine receptors. Unlike dopamine, the increased renal perfusion was not accompanied by increases in arterial blood pressure or heart rate, but rather a decrease in arterial blood pressure at higher doses. The relative lack of efficacy of SK&F 82526 on alpha and beta adrenergic receptors was confirmed in pithed rats and isolated electrically paced papillary muscles of guinea pigs. In conscious dogs, oral administration of SK&F 82526 produced dose-dependent and sustained decreases in renal vascular resistance. The renal hemodynamic activity of SK&F 82526 in anesthetized dogs was not attenuated by phenoxybenzamine, propranolol, atropine, mepyramine plus metiamide, meclofenamic acid or reserpine but was inhibited by metoclopramide and bulbocapnine in a manner suggesting competitive antagonism. In the central nervous system studies, SK&F 82526 stimulated dopamine-sensitive adenylate cyclase of rat caudate (which was inhibited in a concentration-dependent manner by haloperidol and bulbocapnine), induced contralateral rotation in caudate-lesioned rats after intracaudal injection, but did not alter serum prolactin levels after systemic administration. Peripheral administration, however, did not result in significant activation of central dopamine receptors, indicating that SK&F 82526 does not readily cross the blood-brain barrier. These findings demonstrate that SK&F 82526 is a potent, selective, orally active renal vasodilator which acts, at least in part, through stimulation of renal vascular dopamine receptors and is without significant effect on central dopamine receptors after systemic administration.