Differential Interactions of Clonidine and Methoxamine with the Postsynaptic α-Adrenoceptor of Rabbit Main Pulmonary Artery

Abstract

We investigated the dependence upon extracellular Ca^2· of contractile responses of the isolated rabbit main pulmonary artery to the α-adrenoceptor subtype-selective agonists clonidine (α₂) and methoxamine (α₁). The calcium-entry blocker verapamil caused a weak, surmountable antagonism of contractile responses to methoxamine, whereas the concentration-response curve of clonidine was antagonized in a noncompetitive manner with a marked depression of maximal responses. Withdrawal of Ca^2· from the physiological saline solution virtually abolished contractile responses to clonidine, without significantly affecting methoxamine-induced responses. We, therefore, determined if clonidine and methoxamine were interacting with the same population of vascular postsynaptic α-adrenoceptors. We found that the α₁-antagonist prazosin and the α₂-antagonist yohimbine caused competitive blockade of contractile responses to both agonists. However, the potency of both antagonists was significantly greater against clonidine than methoxamine. This may reflect a heterogeneity in the population of postsynaptic α-adrenoceptors of the rabbit main pulmonary artery. On the other hand, the difference in extracellular Ca^2· sensitivity of clonidine-and methoxamine-induced contractions may be explained as a differential mode of stimulation of the postsynaptic α₁-adrenoceptor, possibly through separate, interacting recognition sites for both agonists.