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Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5‐HT 1B ‐ and 5‐HT 1F ‐receptor activation
Author(s) -
Z. Razzaque,
Monique Heald,
John D. Pickard,
L. Maskell,
Margaret S. Beer,
R.G. Hill,
J. Longmore
Publication year - 1999
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1999.00851.x
Subject(s) - sumatriptan , receptor , 5 ht1 receptor , 5 ht receptor , agonist , pharmacology , vasoconstriction , serotonin , medicine , endocrinology , chemistry , zolmitriptan , biology
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 ‐receptor 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.Results GR125,743 antagonized sumatriptan evoked contractions in a competitive manner (apparent pA 2 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.