Pharmacological characterisation of renal dopamine receptors

Abstract

The population of specific vascular dopamine receptors thought to mediate renal vasodilatation has been studied in the prazosin pretreated guinea pig. The increase of cortical renal blood flow produced by dopamine was compared with the ability of the catecholamine to stimulate cAMP production in renal particulate preparations. In addition, radioligand binding studies have been used to investigate the interaction of [3H] sulpiride, a novel dopamine receptor antagonist of the substituted benzamide group, with renal cortical membranes. 

Renal vascular responses to dopamine, ADTN and SKF 38393 were propranolol resistant but were specifically inhibited by (±)-sulpiride. Similarly the elevation of cAMP content produced by these agonists was unaffected by (±)-propranolol and atenolol but was powerfully inhibited by the classical neuroleptic fluphenazine. In contrast (±)-sulpiride, the highly specific antagonist of renal vasodilator responses to agonists was completely ineffective at inhibiting dopamine-sensitive adenylate cyclase activity. Analogous results obtained in the study of dopamine receptors in the central nervous system have been interpreted as evidence for the existence of two subtypes of dopamine receptors (Kebabian and Caine, 1979); one linked to a stimulatory adenylate cyclase and unaffected by sulpiride and the other noncyclase linked and selectively inhibited by sulpiride. In order to clarify these anomolous results the possibility that (±)-sulpiride might function as an antagonist by exerting its effects on a subclass of adenylate cycl ase- independent dopamine receptors was investigated using radioligand labelling techniques. [3H] sulpiride bound selectively and with high affinity to membranes prepared from dopaminergic regions of the kidney in a stereospecific, saturable manner. The pharmacological profile of this binding component provided corroborative evidence of a highly specific interaction between sulpiride and dopaminergic sites but failed to vindicate sulpiride as a selective antagonist of the noncyclase linked receptor. Possible nodes of action of sulpiride at the basic receptor level are discussed as are the advantages of combining the measurement of physiological responses with direct biochemical models in the study of neurotransmitter receptors.

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