Evidence for a complex interaction between the subtypes of the α₁-adrenoceptor

Ligand binding studies with WB 4101 revealed that the rat aorta contains both the α_1a- and α_1b-adrenoceptor subtypes. Results obtained following treatment with the irreversible antagonists phenoxybenzamine, chlorethylclonidine or SZL-49 (4-amino-6,7-dimethoxy-2-quinazolinyl-4-(2-bicyclo[2,2,2]octa-2,5-dienylcarbonyl-2-piperazine) suggest that there is a complex interaction between the α₁-adrenoceptor subtypes in the aorta. Chlorethylclonidine affects only the α_1b-adrenoceptor, whereas the predominant action of SZL-49 is on the α_1a-subtype. Chlorethylclonidine significantly inhibited the response to either methoxamine or phenylephrine, agents which are selective α_1a-adrenoceptor agonists. Following inactivation with either chlorethylclonidine or SZL-49, the response of the rat aorta to phenylephrine was only partially antagonized by either prazosin or WB 4101. SZL-49 also inhibited the response of the rat tail artery to electrical stimulation. The response of the tail artery obtained following inactivation with SZL-49 was effectively antagonized by prazosin. Phenylephrine, prazosin or WB 4101 afforded complete protection from chlorethylclonidine adrenoceptor inactivation, while these same ligands were only partially effective against SZL-49. Either SZL-49 or chlorethylclonidine significantly impaired the irreversible adrenoceptor blocking actions of phenoxybenzamine. These results suggest: (1) only the α_1a-adrenoceptor subtype appears to be associated with nerve terminals in the tail artery, (2) there may be a complex interaction between the α₁-adrenoceptor subtypes such that both receptors must be iniact and functional to observe normal agonist and antagonist interactions, (3) there may be three sites of action for agonists associated with the rat aorta.