Alpha1-adrenoceptor subtypes mediating vasoconstriction in the carotid circulation of anaesthetized pigs: possible avenues for antimigraine drug development

Abstract

It has recently been shown that the alpha-adrenoceptors mediating vasoconstriction of porcine carotid arteriovenous anastomoses resemble both alpha1- and alpha2-adrenoceptors, but no attempt was made to identify the specific subtypes (alpha1A, alpha1B and alpha1D) involved. Therefore, the present study was designed to elucidate the specific subtype(s) of alpha1-adrenoceptors involved in the above response, using the alpha1-adrenoceptor agonist phenylephrine and alpha1-adrenoceptor antagonists 5-methylurapidil (alpha1A), L-765 314 (alpha1B) and BMY 7378 (alpha1D). Ten-minute intracarotid infusions of phenylephrine (1, 3 and 10 microgkg-1.min-1) induced a dose-dependent decrease in total carotid and arteriovenous anastomotic conductance, accompanied by a small tachycardia. These carotid vascular effects were abolished by L-765 314 (1000 microgkg-1; i.v.), while these responses were only attenuated by 5-methylurapidil (1000 microgkg-1; i.v.), and BMY 7378 (1000 microgkg-1; i.v.). Furthermore, intravenous bolus injections of phenylephrine (3 and 10 microgkg-1) produced a dose-dependent vasopressor response, which was only affected by 1000 microgkg-1 of 5-methylurapidil, while the other antagonists were ineffective. These results, coupled to the binding affinities of the above antagonists at the different alpha1-adrenoceptors, suggest that both alpha1A- and alpha1B-adrenoceptors mediate constriction of carotid arteriovenous anastomoses in anaesthetized pigs. In view of the less ubiquitous nature of alpha1B- compared to alpha1A-adrenoceptors, the development of potent and selective alpha1B-adrenoceptor agonists may prove to be important for the treatment of migraine.