title: 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Willems
authors.forename: P
authors.initials: P
authors.lastname: De Vries
authors.forename: J P
authors.initials: JP
authors.lastname: Heiligers
authors.forename: P R
authors.initials: PR
authors.lastname: Saxena
mesh_terms: D000818:Animals; D001163:Arteriovenous Anastomosis / Q000187:drug effects; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007601:Jugular Veins / Q000187:drug effects / Q000502:physiology; D008881:Migraine Disorders / Q000188:drug therapy; D010101:Oxygen Consumption / Q000187:drug effects; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D013552:Swine; D014363:Tryptamines
chemical_list: D007211:Indoles; D011759:Pyrrolidines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C115647:eletriptan