Brändli Peter, Löffler Bernd-Michael, Breu Volker, Osterwalder Rolf, Maire Jean-Paul, Clozel Martine
F. Hoffmann-La Roche, CH-4002 Basel, Switzerland.
Pain. 1996 Feb;64(2):315-322. doi: 10.1016/0304-3959(95)00106-9.
In addition to their potent vasoconstrictor properties, the endothelins (endothelin-1 and -3) may possess neurotransmitter/neuromediator and neuroendocrine actions. The aim of the present study was to evaluate the role of endothelins (ET) in mediating neurogenic inflammation of cephalic tissues in the rat. For this purpose, bosentan, a specific non-peptide mixed antagonist of ET receptors, was tested in rat models of neurogenic and non-neurogenic plasma extravasation in the dura mater and extracranial tissues (eyelid, conjunctiva, lip, tongue). Bosentan was effective for preventing neurogenic inflammation in the dura mater induced by unilateral electrical stimulation of the trigeminal ganglion or intravenous injection of capsaicin, whereas it was ineffective in extracranial tissues or after injection of substance P (non-neurogenic inflammation). The effect of nerve fiber stimulation on ET plasma concentrations in superior sagittal sinus was measured using selective radioimmunoassays for ET-1 and -3. Endothelin-3 concentration significantly increased after intravenous injection of capsaicin, whereas ET-1 levels remained unchanged. Competition binding assays on microsomal membranes from the trigeminal ganglion revealed a single class of binding sites with equal affinity for ET-1 and ET-3, suggesting a homogenous population of ETB receptors. The role of ETB receptors in mediating inflammation was evidenced by the lack of efficacy of a selective ETA receptor antagonist, in contrast to the full efficacy of a selective ETB receptor antagonist, for preventing neurogenic inflammation induced by unilateral stimulation of the trigeminal ganglion. The role of ETB receptors was finally confirmed by the observation that exogenous administration of the ETB receptor agonist sarafotoxin S6c also induced plasma protein extravasation in the dura mater. This extravasation was not a direct effect of ETB receptor stimulation, because it was inhibited by spantide, a selective tachykinin receptor antagonist. These data strongly suggest that ET, acting through ETB receptors, may play an important role in mediating neurogenic inflammation in the meninges of rats. Since the profile of activity of bosentan is similar to that of the 5-HT1D/B agonists, sumatriptan and ergot alkaloids, one may speculate that ET receptor antagonists might be potentially effective in the treatment of acute migraine attacks.
除了具有强大的血管收缩特性外，内皮素（内皮素 -1 和 -3）可能还具有神经递质/神经介质及神经内分泌作用。本研究的目的是评估内皮素（ET）在介导大鼠头部组织神经源性炎症中的作用。为此，在硬脑膜和颅外组织（眼睑、结膜、嘴唇、舌头）的神经源性和非神经源性血浆外渗大鼠模型中测试了波生坦，一种ET受体的特异性非肽类混合拮抗剂。波生坦可有效预防由三叉神经节单侧电刺激或静脉注射辣椒素诱导的硬脑膜神经源性炎症，而在颅外组织或注射P物质后（非神经源性炎症）则无效。使用针对ET -1和 -3的选择性放射免疫测定法测量了神经纤维刺激对上矢状窦中ET血浆浓度的影响。静脉注射辣椒素后，内皮素 -3浓度显著升高，而ET -1水平保持不变。对三叉神经节微粒体膜的竞争结合试验显示存在一类对ET -1和 -3具有同等亲和力的结合位点，表明存在同质的ETB受体群体。与选择性ETB受体拮抗剂的完全有效性相反，选择性ETA受体拮抗剂预防三叉神经节单侧刺激诱导的神经源性炎症无效，这证明了ETB受体在介导炎症中的作用。最后，通过观察到外源性给予ETB受体激动剂沙拉沙星S6c也会诱导硬脑膜血浆蛋白外渗，证实了ETB受体的作用。这种外渗不是ETB受体刺激的直接作用，因为它被选择性速激肽受体拮抗剂spantide抑制。这些数据强烈表明，ET通过ETB受体发挥作用，可能在介导大鼠脑膜神经源性炎症中起重要作用。由于波生坦的活性谱与5 - HT1D/B激动剂舒马曲坦和麦角生物碱相似，因此可以推测ET受体拮抗剂可能对治疗急性偏头痛发作具有潜在疗效。
