Ergot alkaloids, sumatriptan and the newer 5-HT(1B/1D) receptor agonists all contract cranial blood vessels and this effect seems to be primarily responsible for their efficacy in migraine. We have compared the contractile effects of a number of ergot and triptan derivatives on the bovine isolated middle cerebral artery and characterised the 5-hydroxytryptamine (5-HT) receptors involved by using 5-HT(2A) (ketanserin: 10, 30, 100 nM) and 5- HT(1B/1D) (GR127935: 30, 100, 300 nM) receptor antagonists. The rank order of agonist potency (pD2) was ergotamine (8.0±0.1) ≃ 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) ≃ zolmitriptan (6.2±0.1) ≃ sumatriptan (6.0±0.2) ≃ methysergide (5.9±0.3). The rank order of efficacy (E(max) expressed as % of contraction to 100 mM K+) was 5-HT (127±11) > sumatriptan (56±5) > ergotamine (48±5) ≃ dihydroergotamine (44±8) ~ methylergometrine (44±7) > avitriptan (37±7) ≃ rizatriptan (33±5) ≃ methysergide (29±10) ≃ zolmitriptan (28±3) ≃ naratriptan (23±2). The concentration-response curve to 5-HT appeared to be biphasic in the presence of 100 nM ketanserin, which hardly affected sumatriptan-induced contractions, but clearly antagonised the second more efficacious phase of the curve to 5-HT. On the other hand, GR127935 caused a rightward shift of the concentration-response curves to 5- HT (in the presence of 10 μM ketanserin) and sumatriptan with pA2 values of 7.0 and 8.1, respectively. In conclusion, all acutely acting antimigraine drugs contract the bovine isolated middle cerebral artery. Whereas sumatriptan contracts the artery via the 5-HT(1B/1D) receptor, the 5-HT- induced contraction is mediated partly by the 5-HT(2A) receptor and partly by another, possibly novel receptor differing from the 5-HT(1B/1D) receptor. This receptor may be a target for the development of future antimigraine drugs.

5-HT receptors, Ergotamine, Methysergide, Middle cerebral artery, Migraine, Serotonin, Sumatriptan, Triptans,
Naunyn-Schmiedeberg's Archives of Pharmacology
Department of Pharmacology

Roon, K.I, Maassen van den Brink, A, Ferrari, M.D, & Saxena, P.R. (1999). Bovine isolated middle cerebral artery contractions to antimigraine drugs. Naunyn-Schmiedeberg's Archives of Pharmacology, 360(5), 591–596. doi:10.1007/s002109900095