Roon K I, Maassen Van Den Brink A, Ferrari M D, Saxena P R
Department of Pharmacology, Erasmus University Medical Centre Rotterdam, The Netherlands.
Naunyn Schmiedebergs Arch Pharmacol. 1999 Nov;360(5):591-6. doi: 10.1007/s002109900095.
Ergot alkaloids, sumatriptan and the newer 5-HT1B/1D receptor agonists all contract cranial blood vessels and this effect seems to be primarily responsible for their efficacy in migraine. We have compared the contractile effects of a number of ergot and triptan derivatives on the bovine isolated middle cerebral artery and characterised the 5-hydroxytryptamine (5-HT) receptors involved by using 5-HT2A (ketanserin: 10, 30, 100 nM) and 5-HT1B/1D (GR127935: 30, 100, 300 nM) receptor antagonists. The rank order of agonist potency (pD2) was ergotamine (8.0+/-0.1) approximately dihydroergotamine (8.0+/-0.1) > avitriptan (7.4+/-0.3) >5-HT (7.0+/-0.1) > naratriptan (6.8+/-0.1) > methylergometrine (major metabolite of methysergide; 6.5+/-0.2) > rizatriptan (6.3+/-0.3) approximately zolmitriptan (6.2+/-0.1) approximately sumatriptan (6.0+/-0.2) approximately methysergide (5.9+/-0.3). The rank order of efficacy (Emax expressed as % of contraction to 100 mM K+) was 5-HT (127+/-11) > sumatriptan (56+/-5) > ergotamine (48+/-5) approximately dihydroergotamine (44+/-8) approximately methyl-ergometrine (44+/-7) > avitriptan (37+/-7) approximately rizatriptan (33+/-5) approximately methysergide (29+/-10) approximately zolmitriptan (28+/-3) approximately naratriptan (23+/-2). The concentration-response curve to 5-HT appeared to be biphasic in the presence of 100 nM ketanserin, which hardly affected sumatriptan-induced contractions, but clearly antagonised the second more efficacious phase of the curve to 5-HT. On the other hand, GR127935 caused a rightward shift of the concentration-response curves to 5-HT (in the presence of 10 microM ketanserin) and sumatriptan with pA2 values of 7.0 and 8.1, respectively. In conclusion, all acutely acting antimigraine drugs contract the bovine isolated middle cerebral artery. Whereas sumatriptan contracts the artery via the 5-HT1B/1D receptor, the 5-HT-induced contraction is mediated partly by the 5-HT2A receptor and partly by another, possibly novel receptor differing from the 5-HT1B/1D receptor. This receptor may be a target for the development of future antimigraine drugs.
麦角生物碱、舒马曲坦及新型5 - HT1B/1D受体激动剂均可使颅脑血管收缩，这种效应似乎是它们对偏头痛有效的主要原因。我们比较了多种麦角和曲坦衍生物对牛离体大脑中动脉的收缩作用，并通过使用5 - HT2A（酮色林：10、30、100 nM）和5 - HT1B/1D（GR127935：30、100、300 nM）受体拮抗剂来鉴定所涉及的5 - 羟色胺（5 - HT）受体。激动剂效价（pD2）的排序为：麦角胺（8.0±0.1）≈二氢麦角胺（8.0±0.1）＞阿维曲坦（7.4±0.3）＞5 - HT（7.0±0.1）＞那拉曲坦（6.8±0.1）＞甲基麦角新碱（麦角酰二乙胺的主要代谢产物；6.5±0.2）＞利扎曲坦（6.3±0.3）≈佐米曲坦（6.2±0.1）≈舒马曲坦（6.0±0.2）≈麦角酰二乙胺（5.9±0.3）。效能（Emax表示为对100 mM K⁺收缩的百分比）的排序为：5 - HT（127±11）＞舒马曲坦（56±5）＞麦角胺（48±5）≈二氢麦角胺（44±8）≈甲基麦角新碱（44±7）＞阿维曲坦（37±7）≈利扎曲坦（33±5）≈麦角酰二乙胺（29±10）≈佐米曲坦（28±3）≈那拉曲坦（23±2）。在存在100 nM酮色林的情况下，对5 - HT的浓度 - 反应曲线似乎呈双相，这几乎不影响舒马曲坦诱导的收缩，但明显拮抗了曲线对5 - HT更有效的第二个阶段。另一方面，GR127935使对5 - HT（在存在10 μM酮色林的情况下）和舒马曲坦的浓度 - 反应曲线右移，pA2值分别为7.0和8.1。总之，所有急性作用的抗偏头痛药物均可使牛离体大脑中动脉收缩。舒马曲坦通过5 - HT1B/1D受体使动脉收缩，而5 - HT诱导的收缩部分由5 - HT2A受体介导，部分由另一种可能不同于5 - HT1B/1D受体的新型受体介导。该受体可能是未来抗偏头痛药物开发的靶点。
