Alpha-adrenoceptor blocking properties of vesamicol.

The side-effects of vesamicol, an inhibitor of acetylcholine storage, on alpha 1- and alpha 2-adrenoceptors have been studied in the isolated rat vas deferens. Antagonism of alpha 1-adrenoceptors was determined from the ability of vesamicol to reduce contractions elicited by exogenous noradrenaline. Antagonism of alpha 2-adrenoceptors was determined from the ability of vesamicol to block the inhibitory effects of the alpha 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 uptake1. In the presence of noradrenaline uptake blockers, (-)-vesamicol produced a competitive, non-selective block of both alpha 1- and alpha 2-adrenoceptors with a Kd of around 40 microM (pA2 4.4). (+)-Vesamicol, the isomer that has no activity at cholinergic synapses, was equipotent with the (-)-isomer for blocking alpha 2-adrenoceptors. In addition to its alpha-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 alpha-adrenoceptor blocking activity of vesamicol is a function of the phenylpiperidino moiety of the molecule.