Dominant antagonistic action of alpha 2-adrenoceptor agonists on alpha 1-agonist-induced vasoconstriction

The action of clonidine and xylazine to suppress constrictor responses to norepinephrine (NE) and phenylephrine was analysed in isolated, perfused dog and monkey lingual arteries. In both kinds of arteries, alpha 1-adrenoceptor agonists, NE and phenylephrine induced strong vasoconstrictor responses, whereas alpha 2-adrenoceptor agonists, clonidine and xylazine, produced only a slight but long-lasting increase in perfusion pressure. Pretreatment with bolus injections of 300 micrograms clonidine or 1000 micrograms xylazine caused a significant inhibition of vasoconstrictor responses to NE and phenylephrine and shifted the dose-responses curves to the right. Clonidine induced a more potent inhibition than did xylazine. However, neither clonidine nor xylazine pretreatment inhibited 5-HT- and KCl-induced vasoconstriction. In preparations preconstricted with phenylephrine, clonidine and xylazine induced vasodilatation dose relatedly, but in preparations preconstricted with prostaglandin F2 alpha (PGF2 alpha), clonidine and xylazine never induced vasodilatation but only vasoconstriction. The vasoconstrictor effect of clonidine was readily blocked by bunazosin (an alpha 1-adrenoceptor antagonist), but was not affected by midaglizole (an alpha 2-antagonist). It was now demonstrated that alpha 2-agonists act as partial agonists on alpha 1-adrenoceptors when added alone but antagonized alpha 1 activation by alpha 1-agonists, suggesting that alpha 2-agonists have a high affinity for alpha 1-adrenoceptors in isolated lingual arteries.