Comparison of the vasoconstrictor effects of the selective 5-HT1D-receptor agonist L-775,606 with the mixed 5-HT1B/1D-receptor agonist sumatriptan and 5-HT in human isolated coronary artery

Abstract

Aims: Vasoconstriction in human coronary artery can be mediated via activation of both 5-HT2 and 5-HT1B-receptors. Coronary vasoconstriction is a rare, but potential adverse effect of the antimigraine drug sumatriptan. In order to investigate the receptor population involved we compared the vasoconstrictor effects of sumatriptan (a mixed 5-HT1B/1D-receptor agonist) with those of L-775, 606 (a selective 5-HT1D-receptor agonist) and 5-HT (the endogenous ligand) in human isolated coronary arteries.

Methods: Coronary arteries were obtained from human hearts removed prior to transplant surgery. Several endothelium denuded ring segments (4 mm in length) were obtained from each artery and mounted for isometric tension recording. Each segment was first exposed to 45 mm KCl and then to 5-HT (1 nm-100 microm ). Concentration-effect curves to L-775,606 (1-(3-(5-(1,2, 4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)p ipe razine) and sumatriptan were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments.

Results: Twenty-five segments from seven different coronary arteries were studied. Concentration-effect curves were fitted to the data using nonlinear regression analysis. The maximum contraction for L-775,606 was significantly less than that for sumatriptan with Emax values (% relative to 45 mm KCl=100%) of 30.1+/-4.22 and 41.5+/-2.7, respectively. L-775,606 was significantly (30-fold) less potent than sumatriptan in causing contraction compared with sumatriptan (EC50 values were 6.0 microm and 0.2 microm, respectively). For comparison the Emax value for 5-HT was 77.2% and the EC50 value was 0.2 microm.

Conclusions: The selective 5-HT1D-receptor agonist L-775,606 has less propensity towards vasoconstriction in human isolated coronary artery (endothelium-denuded) than was mixed 5-HT1B/1D-receptor agonist sumatriptan. The contractions produced were at concentrations where L-775,606 would be expected to occupy 5-HT1B-receptors.

Figure 1

Concentration-effect curves to 5-HT (closed squares), sumatriptan (closed circles) and L-775,606 (open diamonds) obtained in isolated segments of endothelium-denuded human coronary artery. Points represent mean data expressed relative to the contraction evoked by 45 mm KCl. Vertical bars signify ±s.e. mean. Curves were fitted to the data using nonlinear regression analysis.