The antimigraine agent alniditan selectively constricts porcine carotid arteriovenous anastomoses via 5-HT1B/1D receptors.
In previous studies, we have shown that several 5-HT1B/1D receptor agonists, including sumatriptan, potently constrict porcine carotid arteriovenous anastomoses. This effect seems to be of high predictive value for antimigraine activity. In the present experiments, we studied the effects of a new non-indole 5-HT1B/1D receptor agonist, alniditan, on systemic and carotid haemodynamics in anaesthetised pigs. In control animals, no significant changes in either systemic or carotid haemodynamics were observed after four consecutive i.v. injections of physiological saline (0.5 ml each, every 20 min; n = 4). On the other hand, i.v. doses of alniditan (3, 10, 30 and 100 microg kg(-1) in 0.5 ml saline, every 20 min; n = 6) dose-dependently decreased total carotid conductance (maximum change: -31 +/- 6%) by a selective vasoconstrictor action on arteriovenous anastomoses (maximum change: -72 +/- 5%); the nutrient vascular bed dilated in response to alniditan (maximum change: +103 +/- 39%). The dose of alniditan that decreased arteriovenous anastomotic conductance by 50% was 24 +/- 8 microg kg(-1) (64 +/- 20 nmol kg(-1)). Alniditan produced a slight bradycardia (maximum change: -4 +/- 1%) and a more pronounced hypotensive effect (maximum change: -23 +/- 5%). In six animals pre-treated with the potent and selective 5-HT1B/1D receptor antagonist, GR127935, the alniditan-induced changes in carotid haemodynamics were clearly antagonised, whereas the bradycardia and hypotension remained unaffected. These results suggest that alniditan selectively constricts porcine carotid arteriovenous anastomoses mainly via 5-HT1B/1D receptors and should be able to abort migraine headaches. The latter has indeed been confirmed in initial clinical studies in man.
Department of Pharmacology, Cardiovascular Research Institute COEUR, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, Netherlands. p.devries@farma.fgg.eur.nl
P
P
De Vries
E W
EW
Willems
J P
JP
Heiligers
C M
CM
Villalón
P R
PR
Saxena
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001163:Arteriovenous Anastomosis / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007601:Jugular Veins / Q000187:drug effects / Q000502:physiology; D008297:Male; D008881:Migraine Disorders; D010069:Oxadiazoles / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000700:Analgesics; D001578:Benzopyrans; C470302:HTR1B protein, human; D010069:Oxadiazoles; D010879:Piperazines; D011437:Propylamines; D011743:Pyrimidines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; C090701:GR 127935; C100822:alniditan; D010100:Oxygen