Vasoconstriction in human isolated middle meningeal arteries: Determining the contribution of 5-HT(1B)- and 5-HT(1F)-receptor activation

Abstract

Aims. Sumatriptan is a 5-HT(1B/1D)-receptor agonist which also has affinity for 5-HT(1F)-receptors. The vasoconstrictor effects of sumatriptan are thought to be 5-HT(1B)-receptor mediated and these receptors have been shown to be expressed in human cranial blood vessels. However, in the same tissue mRNA coding for 5-HT(1F)-receptors has also been identified and this study addresses the possibility of whether 5-HT(1F)-reccptor activation contributes to vasoconstriction. Methods. The ability of two selective 5-HT(1B/1D)-receptor antagonists (GR125,743 and GR127,935) with no affinity for 5-HT(1F)-receptors, to inhibit sumatriptan evoked contractions in human isolated middle meningeal artery was investigated. Using a series of 5-HT(1B/1D)-receptor agonists (sumatriptan, zolmitriptan, CP122,288, L-741,519 and L-741,604), some with high affinity for 5-HT(1F)-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 middle meningeal artery with their affinities at cloned human 5-HT(1B)-, 5-HT(1D)- and 5-HT(1F)-receptors expressed in CHO cell lines. Reults. GR125,743 antagonized sumatriptan evoked contractions in a competitive manner (apparent pA2 9.1) and GR127,935 antagonized sumatriptan-induced responses in a non-competitive manner (reducing the maximum contraction to 27%). There was a significant correlation between vasoconstrictor potency and 5-HT(1B)-receptor affinity (r = 0.93, P = 0.002) but not with 5-HT(1D)- or 5-HT(1F)-receptor affinity (r = 0.74, P = 0.06; r = 0.31, P = 0.49, respectively). Conclusions. These experiments show that in human middle meningeal artery vasoconstriction to sumatriptan-like agents is 5-HT(1B)-receptor mediated with little if any contribution from 5-HT(1F)-receptor activation.