van den Broek R W, MaassenVanDenBrink A, de Vries R, Bogers A J, Stegmann A P, Avezaat C J, Saxena P R
Department of Pharmacology, Erasmus University Medical Centre Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, Netherlands.
Eur J Pharmacol. 2000 Oct 27;407(1-2):165-73. doi: 10.1016/s0014-2999(00)00712-3.
Eletriptan, a second-generation triptan with high affinity for 5-HT(1B/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-HT(1B/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-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-py rid yl) benzamide (GR125743). All three blood vessels constricted in response to eletriptan and sumatriptan, but the middle meningeal artery relaxed following the highest concentration (100 microM) 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 artery and saphenous vein, sumatriptan-induced contractions (pEC(50): 6.24+/-0.14 and 6.19+/-0.12, respectively) were also potently antagonised by GR125743 (pA(2): 8.18+/-0.27 and 8.34+/-0.12, respectively). The eletriptan-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 unaffected by GR125743 up to a concentration of 100 nM. These results suggest that (i) based on the differences in pEC(50) 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-HT(1B) 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.
依立曲坦是一种对5-HT(1B/1D)受体具有高亲和力的第二代曲坦类药物，对有或无先兆的偏头痛均有高效。我们比较了依立曲坦和舒马曲坦对人体离体脑膜中动脉、冠状动脉和大隐静脉的作用，这些血管用作治疗效果和潜在副作用的模型，并研究了5-HT(1B/1D)受体在这些曲坦类药物诱导的收缩中的作用。在不存在或存在选择性5-HT(1B/1D)受体拮抗剂N-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]-3-甲基-4-(4-吡啶基)苯甲酰胺(GR125743)的情况下，构建了依立曲坦和舒马曲坦的浓度-反应曲线。所有三根血管对依立曲坦和舒马曲坦均有收缩反应，但脑膜中动脉在依立曲坦最高浓度(100μM)后出现舒张。在脑膜中动脉中，GR-125743对依立曲坦(半数有效浓度对数：7.34±0.13)和舒马曲坦(半数有效浓度对数：6.91±0.17)诱导的收缩具有相似程度的拮抗作用(拮抗常数：分别为8.81±0.17和8.64±0.21)。在人体冠状动脉和大隐静脉中，舒马曲坦诱导的收缩(半数有效浓度对数：分别为6.24±0.14和6.19±0.12)也被GR125743有效拮抗(拮抗常数：分别为8.18±0.27和8.34±0.12)。GR125743对依立曲坦诱导的人体大隐静脉收缩(半数有效浓度对数：6.09±0.13)的拮抗作用较弱(平衡解离常数：7.73±0.18)，而对人体冠状动脉收缩(半数有效浓度对数：5.54±0.22)的作用在浓度高达100 nM时仍不受GR125743影响。这些结果表明：(i)基于半数有效浓度对数的值的差异，依立曲坦在冠状动脉中的颅选择性(63倍)高于舒马曲坦(5倍)；(ii)舒马曲坦和依立曲坦(较低浓度)在三根血管中的收缩作用是通过5-HT(1B)受体介导的；(iii)在高浓度依立曲坦后，冠状动脉和大隐静脉收缩以及脑膜中动脉舒张似乎涉及其他机制。
