Pierre L N, Davenport A P
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Stroke. 1999 Mar;30(3):638-43. doi: 10.1161/01.str.30.3.638.
Substantial evidence now implicates endothelin (ET) in the pathophysiology of cerebrovascular disorders such as the delayed vasospasm associated with subarachnoid hemorrhage and ischemic stroke. We investigated the ET receptor subtypes mediating vasoconstriction in human pial arteries.
ET receptors on human pial and intracerebral arteries were visualized with the use of autoradiography, and the subtypes mediating vasoconstriction were identified by means of wire myography.
ET-1 was more potent than ET-3 as a vasoconstrictor, indicating an ETA-mediated effect. Similarly, the selective ETB agonist sarafotoxin S6c had no effect on contractile action at concentrations up to 30 nmol/L. The nonpeptide ETA receptor antagonist PD156707 (3 to 30 nmol/L) caused a parallel rightward shift of the ET-1-induced response, yielding a pA2 of 9.2. Consistent with these results, PD156707 (30 nmol/L) fully reversed an established constriction in pial arteries induced by 1 nmol/L ET-1, while the selective ETB receptor antagonist BQ788 (1 micromol/L) had little effect. The calcium channel blocker nimodipine (0.3 to 3 micromol/L) significantly attenuated the maximum response to ET-1 in a concentration-dependent manner without changing potency. In agreement with the functional data, specific binding of [125I]PD151242 to ETA receptors was localized to the smooth muscle layer of pial and intracerebral blood vessels. In contrast, little or no [125I]BQ3020 binding to ETB receptors was detected.
These data indicate an important role for ETA receptors in ET-1-induced constriction of human pial arteries and suggest that ETA receptor antagonists may provide additional dilatory benefit in cerebrovascular disorders associated with raised ET levels.
目前大量证据表明内皮素（ET）参与了脑血管疾病的病理生理过程，如蛛网膜下腔出血和缺血性卒中相关的迟发性血管痉挛。我们研究了介导人软脑膜动脉血管收缩的ET受体亚型。
利用放射自显影技术观察人软脑膜和脑动脉上的ET受体，通过线肌张力测定法确定介导血管收缩的亚型。
ET-1作为血管收缩剂比ET-3更有效，表明是ETA介导的效应。同样，选择性ETB激动剂沙拉新毒素S6c在浓度高达30 nmol/L时对收缩作用无影响。非肽类ETA受体拮抗剂PD156707（3至30 nmol/L）使ET-1诱导的反应呈平行右移，pA2为9.2。与这些结果一致，PD156707（30 nmol/L）完全逆转了1 nmol/L ET-1诱导的软脑膜动脉既定收缩，而选择性ETB受体拮抗剂BQ788（1 μmol/L）几乎没有影响。钙通道阻滞剂尼莫地平（0.3至3 μmol/L）以浓度依赖方式显著减弱对ET-1的最大反应，而不改变效价。与功能数据一致，[125I]PD151242与ETA受体的特异性结合定位于软脑膜和脑内血管的平滑肌层。相反，几乎未检测到[125I]BQ3020与ETB受体的结合。
这些数据表明ETA受体在ET-1诱导的人软脑膜动脉收缩中起重要作用，并提示ETA受体拮抗剂可能在与ET水平升高相关的脑血管疾病中提供额外的扩张益处。
