α-Adrenoceptor blocking properties of vesamicol

Abstract

The side-effects of vesamicol, an inhibitor of acetylcholine storage, on α 1- and α 2-adrenoceptors have been studied in the isolated rat vas deferens. Antagonism of α 1-adrenoceptors was determined from the ability of vesamicol to reduce contractions elicited by exogenous noradrenaline. Antagonism of α 2-adrenoceptors was determined from the ability of vesamicol to block the inhibitory effects of the α 2-adrenoceptor agonist clonidine on electrically evoked twitches. In the absence of noradrenaline uptake block, (−) vesamicol, the isomer active at cholinergic synapses, produced a leftward shift of the noradrenaline concentration-effect curve. This effect was abolished by desipramine suggesting that it is due to an ability of (−)-vesamicol to block uptake 1. In the presence of noradrenaline uptake blockers, (−)-vesamicol produced a competitive, non-selective block of both α 2- and α 2adrenoceptors with a K d of around 40 μM (pA 2 4.4). ( + )-Vesamicol, the isomer that has no activity at cholinergic synapses, was equipotent with the (−)-isomer for blocking α 2 adrenoceptors. In addition to its α-adrenoceptor antagonist activity, (−)-vesamicol augmented the maximum response of the tissue to exogenous and endogenous noradrenaline. This study was unable to determine the exact nature of this effect. We suggest that the α-adrenoceptor blocking activity of vesamicol is a function of the phenylpiperidino moiety of the molecule.