Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation

Aims Sumatriptan is a 5-HT1B/1D-receptor agonist which also has affinity fo r 5-HT1F-recoptors. The vasoconstrictor effects of sumatriptan are thought to be 5-HT1B-receptor mediated and these receptors have been shown to be ex pressed in human cranial blood vessels. However, in the same tissue mRNA co ding for 5-HT1F-receptors has also been identified and this study addresses the possibility of whether 5-HT1F-receptor activation contributes to vasoc onstriction. Methods The ability of two selective 5-HT1B/1D-receptor antagonists (GR125, 743 and GR127,935) with no affinity for 5-HT1F-receptors, to inhibit sumatr iptan evoked contractions in human isolated middle meningeal artery was inv estigated. Using a series of5-HT1B/1D-rcceptor agonists (sumatriptan, zolmi triptan, CP122,288, L-741,519 and L-741,604), some with high affinity for 5 -HT1F-receptors and the non-selective 5-HT-receptor agonists 5-HT and 5-CT, we compared the vasoconstrictor potency of these drugs in human isolated m iddle meningeal artery with their affinities at cloned human 5-HT1B-, 5-HT1 D- and 5-HT1F-receptors expressed in CHO cell lines. Results GR125,743 antagonized sumatriptan evoked contractions in a competit ive manner (apparent pA(2) 9.1) and GR127,935 antagonized sumatriptan-induc ed responses in a non-competitive manner (reducing the maximum contraction to 27%). There was a significant correlation between vasoconstrictor potenc y and 5-HT1B-receptor affinity (r = 0.93, P = 0.002) but not with 5-HT1D- o r 5-HT1F-receptor affinity (r = 0.74, P = 0.06; r = 0.31, P = 0.49, respect ively). Conclusions These experiments show that in human middle meningeal artery va soconstriction to sumatriptan-like agents is 5-HT1B-receptor mediated with little if any contribution from 5-HT1F-receptor activation.