ABSTRACT: Eletriptan, a second-generation triptan with high affinity for 5-HT1B/1D receptors, is highly effective in migraine, with or without aura. We compared the effects of eletriptan and sumatriptan on the human isolated middle meningeal and coronary arteries and saphenous vein, used as models for therapeutic efficacy and potential side effects, and have investigated the role of 5-HT1B/1D receptors in contractions induced by these triptans. Concentration–response curves to eletriptan and sumatriptan were constructed in the absence or presence of a selective 5-HT1B/1D receptor antagonist, N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide (GR125743). All three blood vessels constricted in response to eletriptan and sumatriptan, but the middle meningeal artery relaxed following the highest concentration (100 μM) of eletriptan. In the middle meningeal artery, GR125743 antagonised the contractions induced by both eletriptan (pEC50: 7.34±0.13) and sumatriptan (pEC50: 6.91±0.17) to a similar degree (pA2: 8.81±0.17 and 8.64±0.21, respectively). In the human coronary artery and saphenous vein, sumatriptan-induced contractions (pEC50: 6.24±0.14 and 6.19±0.12, respectively) were also potently antagonised by GR125743 (pA2: 8.18±0.27 and 8.34±0.12, respectively). The eletriptan-induced contractions of the human saphenous vein (pEC50: 6.09±0.13) were antagonised less effectively by GR125743 (pKB: 7.73±0.18), and those of the human coronary artery (pEC50: 5.54±0.22) remained unaffected by GR125743 up to a concentration of 100 nM. These results suggest that (i) based on the differences in pEC50 values, the cranioselectivity of eletriptan (63-fold) is higher than that of sumatriptan (5-fold) in coronary artery, (ii) the contractile effects of sumatriptan and eletriptan (lower concentrations) in the three blood vessels are mediated via the 5-HT1B receptor, and (iii) additional mechanisms seem to be involved in coronary artery and saphenous vein contractions and middle meningeal artery relaxation following high concentrations of eletriptan.
European Journal of Pharmacology.