Agonists interaction with radiolabeled alpha-adrenoceptor antagonists binding sites in rat mesenteric artery.

The nature of the postsynaptic alpha-adrenoceptors in vasculature has been a matter of debate with the differences in the observations from in vivo and in vitro experiments. These studies were done on the basis of the selectivity of the alpha-adrenoceptor agonists. In the present study, we investigated the nature of these agonists interaction with the [3H]prazosin and [3H]yohimbine binding sites in the plasma membrane vesicles of rat mesenteric artery. Phenylephrine and methoxamine were used as the putative alpha 1-adrenoceptor agonists. Clonidine, naphazoline, B-HT 920, and UK-14,304 were used as the putative alpha 2-adrenoceptor agonists. All these agonists except B-HT 920 competed with similar affinity for the specific binding sites of [3H]prazosin and [3H]yohimbine. The order of the potency for the agonists in competing for [3H]prazosin binding sites was clonidine greater than naphazoline greater than UK-14,304 greater than phenylephrine much greater than B-HT 920 greater than or equal to methoxamine, and for the [3H]yohimbine binding sites, the order was clonidine greater than naphazoline greater than B-HT 920 greater than UK-14,304 greater than phenylephrine much greater than methoxamine. Similar pA2 values for prazosin and yohimbine were calculated regardless of whether alpha 1-selective agonist, methoxamine, or alpha 2-selective agonist, B-HT 920 were used. Putative alpha 2-adrenoceptor-selective agonists behave as partial agonists in functional studies inhibiting just maximal responses to alpha 1-adrenoceptor agonists and norepinephrine in a dose-dependent fashion. It is therefore concluded that in rat mesenteric artery, there are two distinct sites of interaction for the antagonists, prazosin and yohimbine, but the alpha-adrenoceptor agonists interact nonselectively with a single site in such a way that they are capable of affecting binding of either antagonist. A model for the postsynaptic alpha-adrenoceptor as a macromolecule has been proposed.