Pharmacological analysis of contractile effects of eletriptan and sumatriptan on human isolated blood vessels

Eletriptan, a second-generation triptan with high affinity for 5-HT1B/1D re ceptors, is highly effective in migraine, with or without aura. We compared the effects of eletriptan and sumatriptan on the human isolated middle men ingeal and coronary arteries and saphenous vein, used as models for therape utic efficacy and potential side effects, and have investigated the role of 5-HT1B/1D receptors in contractions induced by these triptans. Concentrati on-response curves to eletriptan and sumatriptan were constructed in the ab sence or presence of a selective 5-HT1B/1D receptor antagonist, N-[4-methox y-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide (GR1257 43). All three blood vessels constricted in response to eletriptan and suma triptan, but the middle meningeal artery relaxed following the highest conc entration (100 muM) of eletriptan. In the middle meningeal artery, GR125743 antagonised the contractions induced by both eletriptan (pEC(50): 7.34 +/- 0.13) and sumatriptan (pEC(50): 6.91 +/- 0.17) to a similar degree (pA(2): 8.81 +/- 0.17 and 8.64 +/- 0.21, respectively). In the human coronary arte ry and saphenous vein, sumatriptan-induced contractions (pEC(50): 6.24 +/- 0.14 and 6.19 +/- 0.12, respectively) were also potently antagonised by GR1 25743 (pA(2): 8.18 +/- 0.27 and 8.34 +/- 0.12, respectively). The eletripta n-induced contractions of the human saphenous vein (pEC(50): 6.09 +/- 0.13) were antagonised less effectively by GR125743 (pK(B): 7.73 +/- 0.18), and those of the human coronary artery (pEC(50): 5.54 +/- 0.22) remained unaffe cted by GR125743 up to a concentration of 100 nM. These results suggest tha t (i) based on the differences in pEC(50) values, the cranioselectivity of eletriptan (63-fold) is higher than that of sumatriptan (5-fold) in coronar y artery, (ii) the contractile effects of sumatriptan and eletriptan (lower concentrations) in the three blood vessels are mediated via the 5-HT1B rec eptor, and (iii) additional mechanisms seem to be involved in coronary arte ry and saphenous vein contractions and middle meningeal artery relaxation f ollowing high concentrations of eletriptan. (C) 2000 Elsevier Science B.V. All rights reserved.