N-(3-acetylaminophenyl)piperazine hydrochloride (BEA 1654), a putative 5-HT1 agonist, causes constriction of arteriovenous anastomoses and dilatation of arterioles

Abstract

Using 3H-ligands and radioactive microspheres we studied the binding characteristics and the effects on the distribution of carotid arterial blood flow of n-(3-acetylaminophenyl)piperazine hydrochloride (BEA 1654). The compound had a Ki value of 32 nM (5-HT: 8 nM) on 5-HT1 but no or very weak affinity for 5-HT2, alpha 1- and alpha 2-adrenoceptor sites in rat cerebral cortex homogenates. Intracarotid infusions of BEA 1654 (0.1-1.0 mg X kg-1 X min-1) were nearly equieffective in untreated and treated (phentolamine plus ketanserin) pigs in redistributing carotid arterial blood towards the nutrient compartment (particularly the skin and ears) at the expense of shunting via arteriovenous anastomoses (AVAs). In view of the high and selective affinity of BEA 1654 to 5-HT1 binding sites, the similarity of pharmacological responses between 5-HT and BEA 1654, and the ineffectiveness of antagonists of 5-HT2 and alpha-adrenergic receptors to block the AVA constriction and arteriolar dilatation caused by both 5-HT and BEA 1654, we conclude that these effects are mediated by 5-HT1 receptors. The vast difference between the ratios of Ki values for 5-HT1 binding sites and of the pharmacologically effective doses of BEA 1654 and 5-HT suggests that either BEA 1654 may be a partial agonist of 5-HT1 receptors or, while the drug binds with both subsets of 5-HT1 receptors, it is only one type which mediates the pharmacological response.