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 ago nists, including sumatriptan, potently constrict porcine carotid arter iovenous 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 haemodyn amics were observed after four consecutive i.v. injections of physiolo gical saline (0.5 ml each, every 20 min; n = 4). On the other hand, i. v. doses of alniditan (3, 10, 30 and 100 mu g kg(-1) in 0.5 ml saline, every 20 min; n = 6) dose-dependently decreased total carotid conduct ance (maximum change: -31 +/- 6%) by a selective vasoconstrictor actio n on arteriovenous anastomoses (maximum change: -72 +/- 5%); the nutri ent vascular bed dilated in response to alniditan (maximum change: + 1 03 +/- 39%). The dose of alniditan that decreased arteriovenous anasto motic conductance by 50% was 24 +/- 8 mu g 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 carot id haemodynamics were clearly antagonised, whereas the bradycardia and hypotension remained unaffected. These results suggest that alniditan selectively constricts porcine carotid arteriovenous anastomoses main ly via 5-HT1B/1D receptors and should be able to abort migraine headac hes. The latter has indeed been confirmed in initial clinical studies in man. (C) 1998 Elsevier Science B.V. All rights reserved.