Zimmermann M, Seifert V
Neurosurgical Clinic, University of Leipzig, Germany.
Neurosurgery. 1998 Oct;43(4):863-75; discussion 875-6. doi: 10.1097/00006123-199810000-00083.
Delayed cerebral vasospasm occurring after subarachnoid hemorrhage (SAH) is still responsible for a considerable percentage of the morbidity and mortality in patients with aneurysms. It has been suggested that the pathogenesis of delayed cerebral vasospasm is related to a number of pathological processes, including endothelial damage and smooth muscle cell contraction resulting from spasmogenic substances generated during lysis of subarachnoid blood clots, changes in vascular responsiveness, and inflammatory or immunological reactions of the vascular wall. It has been recognized that the endothelium plays an important role in the regulation of the cerebral vascular tone. In 1988, endothelin (ET)-1, a potent vasoconstrictor, was isolated from cultured porcine aortic endothelial cells.
ET-1, which is one of three distinct isoforms of ETs (ET-1, ET-2, and ET-3), has a more marked effect on cerebral arteries than do the other two isoforms. Elevated levels of ETs have been demonstrated in the cerebrospinal fluid and plasma of patients after SAH and cerebral infarction. ETs act by at least three different receptor subtypes, the ET(A) receptor, which is localized in vascular smooth muscle cells and mediates vasoconstriction, and two different ET(B) receptor subtypes. The ET(B1) receptor subtype is present in vascular endothelial cells and mediates the endothelium-dependent vasodilation. The ET(B2) receptor subtype is present in smooth muscle cells causing vasoconstriction. ET-1 acts from the adventitial but not from the luminal side of cerebral arteries. In vivo and in vitro ET-1 causes a dose-dependent and long-lasting vasoconstriction, similar to cerebral vasospasm after SAH. The vasoconstriction caused by ET-1 can be reversed by selective ET(A) receptor antagonists or combined ET(A) and ET(B) receptor antagonists.
The results of current clinical and experimental investigations support the hypothesis that ET-1 is a major cause of cerebral vasospasm after SAH. Other studies indicate that SAH causes complex changes in the ET system and increased ET-1 levels after SAH, which are not solely responsible for the development of vasospasm but may occur after cerebral ischemia. Further investigations are therefore needed to clarify these different hypotheses.
蛛网膜下腔出血（SAH）后发生的迟发性脑血管痉挛仍然是动脉瘤患者相当一部分发病和死亡的原因。有人提出，迟发性脑血管痉挛的发病机制与许多病理过程有关，包括蛛网膜下腔血凝块溶解过程中产生的致痉挛物质导致的内皮损伤和平滑肌细胞收缩、血管反应性变化以及血管壁的炎症或免疫反应。人们已经认识到内皮在调节脑血管张力方面起着重要作用。1988年，一种强效血管收缩剂内皮素（ET）-1从培养的猪主动脉内皮细胞中分离出来。
ET-1是内皮素三种不同异构体（ET-1、ET-2和ET-3）之一，对脑动脉的作用比其他两种异构体更为显著。SAH和脑梗死患者的脑脊液和血浆中已证实内皮素水平升高。内皮素通过至少三种不同的受体亚型起作用，即ET（A）受体，其位于血管平滑肌细胞中并介导血管收缩，以及两种不同的ET（B）受体亚型。ET（B1）受体亚型存在于血管内皮细胞中并介导内皮依赖性血管舒张。ET（B2）受体亚型存在于平滑肌细胞中导致血管收缩。ET-1从脑动脉的外膜侧而非管腔侧起作用。体内和体外实验中，ET-1都会引起剂量依赖性和持久的血管收缩，类似于SAH后的脑血管痉挛。ET-1引起的血管收缩可被选择性ET（A）受体拮抗剂或ET（A）和ET（B）受体联合拮抗剂逆转。
当前临床和实验研究结果支持ET-1是SAH后脑血管痉挛主要原因的假说。其他研究表明，SAH会导致内皮素系统发生复杂变化，SAH后内皮素-1水平升高，这并非是血管痉挛发生的唯一原因，但可能在脑缺血后出现。因此需要进一步研究来阐明这些不同的假说。
