A Study of the Action of Prazosin on Isolated Vascular Muscle from the Rat

Abstract

Contractions of the rat isolated aorta to NA were resolved into a fast component, dependent upon intracellular calcium release, and a secondary slow component dependent upon extracellular calcium. Prazosin caused an unsurmountable depression of the fast component but a competitive inhibition of the slow component whereas phentolamine caused a competitive inhibition of both components. This action of prazosin upon the fast component was attributed to adrenoceptor blockade since it was reversed by phentolamine, and prazosin had no effect upon contractions to 5-HT, angiotensin or caffeine. A non-competitive depression of the NA fast response was also observed with the prazosin analogues doxazosin, tiodazosin and UK-18596 and with the structurally dissimilar agent WB-4101, but not with trimazosin or corynanthine. Prazosin caused an unsurmountable inhibition of the fast response to the full agonists phenylephrine and guanfacine, and delayed the onset of contractions to the partial agonists St-587 and UK-14304 which were monophasic and dependent upon extracellular calcium. It was concluded that non-competitive inhibition of a-adrenoceptor responses by prazosin is i) unrelated to the selectivity of antagonists or agonists for α1,-adrenoceptors ii) for prazosin-like agents, is related to PA2, of the antagonist. Contractions of the rat isolated longitudinal portal vein to NA were monophasic, dependent upon extracellular calcium and inhibited in a competitive manner by prazosin. However, pressor responses of the rat isolated perfused mesenteric bed to NA were largely independent of extracellular calcium and were depressed in a non-competitive manner by prazosin. There were no significant differences in the pA2, values determined for each antagonist in the aorta and the portal vein, but marked differences in the relative potency of agonists were observed. It is suggested that, whereas the binding site for the receptors are similar in these preparations, the structural requirements for receptor activation differ. The possible link between receptor activation and calcium mobilization is discussed in relation to a suggested mode of action of prazosin.