Porcine carotid vascular effects of eletriptan (UK-116,044): a new 5-HT1B/1D receptor agonist with anti-migraine activity.

Abstract

It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine. Indeed, a number of acutely acting anti-migraine drugs, including the ergot alkaloids and sumatriptan, constrict porcine carotid arteriovenous anastomoses. In this study, using pentobarbital anaesthetised pigs, we investigated the effects of eletriptan, a close structural analogue of sumatriptan, on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient (capillary) fractions. Eletriptan (10, 30, 100, 300 and 1000 microg kg(-1), i.v.) decreased the total carotid blood flow, exclusively by decreasing cephalic arteriovenous anastomotic blood flow; nutrient blood flow, particularly to the ear, skin and fat, was significantly increased. The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50% (ED50) were, respectively, 117+/-21 microg kg(-1) (251+/-45 nmol kg(-1)) and 184+/-42 microg kg(-1) (396+/-91 nmol kg(-1)); the highest dose caused reductions of 84+/-3% and 77+/-4%, respectively. The eletriptan-induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective 5-HT1B/1D receptor antagonist GR127935 (0.5 mg kg(-1)). On the basis of these results, we conclude that (1) the eletriptan-induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by 5-HT1B/1D receptors, and (2) eletriptan should be effective in aborting migraine headache. Clinical studies have already demonstrated its therapeutic action in migraine patients.