Differential interactions of clonidine and methoxamine with the postsynaptic alpha-adrenoceptor of rabbit main...

We investigated the dependence upon extracellular Ca2+ of contractile responses of the isolated rabbit main pulmonary artery to the alpha-adrenoceptor subtype-selective agonists clonidine (alpha 2) and methoxamine (alpha 1). 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 Ca2+ 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 alpha-adrenoceptors. We found that the alpha 1-antagonist prazosin and the alpha 2-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 alpha-adrenoceptors of the rabbit main pulmonary artery. On the other hand, the difference in extracellular Ca2+ sensitivity of clonidine- and methoxamine-induced contractions may be explained as a differential mode of stimulation of the postsynaptic alpha 1-adrenoceptor, possibly through separate, interacting recognition sites for both agonists.