Bovine isolated middle cerebral artery contractions to antimigraine drugs

Ergot alkaloids, sumatriptan and the newer 5-HT1B/1D receptor agonists all contract cranial blood vessels and this effect seems to be primarily respon sible for their efficacy in migraine. We have compared the contractile effe cts of a number of ergot and triptan derivatives on the bovine isolated mid dle cerebral artery and characterised the 5-hydroxytryptamine (5-HT) recept ors involved by using 5-HT2A (ketanserin: 10, 30, 100 nM) and 5-HT1B/1D (GR 127935: 30, 100, 300 nM) receptor antagonists. The rank order of agonist p otency (pD(2)) was ergotamine (8.0+/-0.1) approximate to dihydroergotamine (8.0+/-0.1) > avitriptan (7.4+/-0.3) > 5-HT (7.0+/-0.1) > naratriptan (6.8/-0.1) > methylergometrine (major metabolite of methysergide; 6.5+/-0.2) > rizatriptan (6.3+/-0.3) approximate to zolmitriptan (6.2+/-0.1) approximate to sumatriptan (6.0+/-0.2) approximate to methysergide (5.9+/-0.3). The ra nk order of efficacy (E-max expressed as % of contraction to 100 mM K+) was 5-HT (127+/-11) > sumatriptan (56+/-5) > ergotamine (48+/-5) approximate t o dihydroergotamine (44+/-8) approximate to methyl-ergometrine (44+/-7) > a vitriptan (37+/-7) approximate to rizatriptan (33+/-5) approximate to methy sergide (29+/-10) approximate to zolmitriptan (28+/-3) approximate to narat riptan (23+/-2). The concentration-response curve to 5-HT appeared to be bi phasic in the presence of 100 nM ketanserin, which hardly affected sumatrip tan-induced contractions, but clearly antagonised the second more efficacio us phase of the curve to 5-HT. On the other hand, GR127935 caused a rightwa rd shift of the concentration-response curves to 5-HT tin the presence of 1 0 mu M ketanserin) and sumatriptan with pA(2) values of 7.0 and 8.1, respec tively. In conclusion, all acutely acting antimigraine drugs contract the b ovine isolated middle cerebral artery. Whereas sumatriptan contracts the ar tery via the 5-HT1B/1D receptor, the 5-HT-induced contraction is mediated p artly by the 5-HT2A receptor and partly by another, possibly novel receptor differing from the 5-HT1B/1D receptor. This receptor may be a target for t he development of future antimigraine drugs.