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

Abstract

Aims: Sumatriptan is a 5-HT1B/1D-receptor agonist which also has affinity for 5-HT1F-receptors. The vasoconstrictor effects of sumatriptan are thought to be 5-HT1B-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-HT1F-receptors has also been identified and this study addresses the possibility of whether 5-HT1F-receptor activation contributes to vasoconstriction.

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 sumatriptan evoked contractions in human isolated middle meningeal artery was investigated. Using a series of 5-HT1B/1D-receptor agonists (sumatriptan, zolmitriptan, CP122,288, L-741,519 and L-741,604), some with high affinity for 5-HTIF-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-HT1B-, 5-HT1D-and 5-HT1F-receptors expressed in CHO cell lines.

Results: 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-HT1B-receptor affinity (r=0.93, P=0.002) but not with 5-HT1D- or 5-HT1F-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-HT1B-receptor mediated with little if any contribution from 5-HT1F-receptor activation.

Figure 1

Effect of sumatriptan in human isolated middle meningeal arteries. a) concentration-effect curves to sumatriptan in the absence (open circles) and presence of GR127,935 (10 nm, filled circles). b) concentration-effect curves to sumatriptan in the absence (open circles) and presence of GR125,743 (10 nm, filled circles). c) concentration-effect curves to sumatriptan performed consecutively in the absence of antagonist (first concentration-effect curve—open circles, second concentration-effect curve—closed circles). Each point (mean value, n = 4–5) is expressed as a percentage of the maximum contraction obtained in the control curve and vertical bars signify±s.e.mean. Curves were fitted to a model using weighted least squares non-linear regression analysis.

Figure 2

Correlations between binding affinity (IC₅₀) at human cloned 5-HT_1B, 5-HT_1D and 5-HT_1F-receptors expressed in CHO cell lines and vasoconstrictor potency (EC₅₀) in human isolated middle meningeal arteries. a) 5-HT_1B-receptor affinity vs vasoconstrictor potency, r = 0.93 (P = 0.002). b) 5-HT_1D-receptor affinity vs vasoconstrictor potency, r = 0.74 (P = 0.06). c) 5-HT_1F-receptor affinity vs vasoconstrictor potency, r = 0.31 (P = 0.49).