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

Aims Vasoconstriction in human coronary artery can be mediated via activati on of both 5-HT2 and 5-HT1B-receptors. Coronary vasoconstriction is a rare, but potential adverse effect of the antimigraine drug sumatriptan. In orde r to investigate the receptor population involved we compared the vasoconst rictor effects of sumatriptan (a mixed 5-HT1B/1D-receptor agonist) with tho se of L-775,606 (a selective 5-HT1D-receptor agonist) and 5-HT (the endogen ous 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 leng th) were obtained from each artery and mounted for isometric tension record ing. Each segment was first exposed to 45 mM KCl and then to 5-HT (1 nM-100 mu M) Concentration-effect curves to L-775,606 (1-(3-(5-(1,2,4-triazol-4-y l)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)piperazine) and sumatri ptan were then performed in a consecutive and random manner. The response t o repeated application of 5-HT was obtained in separate segments. Results Twenty-five segments from seven different coronary arteries were st udied. Concentration-effect curves were fitted to the data using nonlinear regression analysis. The maximum contraction for L-775,606 was significantl y less than that for sumatriptan with E-max values (% relative to 45 mM KCl =100%) Of 30.1 +/- 4.22 and 41.5+/-2.7, respectively. L-775,606 was signifi cantly (30-fold) less potent than sumatriptan in causing contraction compar ed with sumatriptan (EC50 values were 6.0 mu M and 0.2 mu M, respectively). For comparison the E-max value for 5-HT was 77.2% and the EC50 value was 0 .2 mu M Conclusions The selective 5-HT1D-receptor agonist L-775,606 has less propen sity towards vasoconstriction in human isolated coronary artery (endotheliu m-denuded) than was mixed 5-HT1B/1D-receptor agonist sumatriptan. The contr actions produced were at concentrations where L-775,606 would be expected t o occupy 5-HT1B-receptors.