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Endothelium-derived vasoactive peptide and cerebral vasospasm

内皮源性血管活性肽与脑血管痉挛

基本信息

批准号：
03670091
负责人：
SAITO Akira
金额：
$ 1.28万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

Cerebral vasospasm develops following subarachnoid hemorrhage (SAH). The mechanism of the severe vasoconstriction is still not known. Recently, endothelin was isolated from the culture medium of vascular endothelial cells and found to be a potent vasoconstrictor peptide. We examined a possible contribution of endothelin in the pathogenesis of cerebral vasospasm. In isolated cerebral arteries of dogs, both endothelin-1 and endothelin-2 elicited sustained contractions. The contraction induced by endothelin was not reversed by repeated washings, indicating the irreversible nature of the endothelin action. Endothelin-3 and big endothelin were weak vasoconstrictors. Thus, ET-Atype endothelin receptors are dominant in cerebral arteries. Next, we determined the endothelin contents in plasma and cerebrospinal fluid (CSF) by a sandwich enzymatic immunoassay. Endothelin content in CSF of patients with SAH increased at 7th and 14th day of hemorrhage. The time course of the change of endothelin content was further examined in dogs with experimental SAH. In the CSF of normal dogs, endothelin was undetectable. However, 2 and 4 days following SAH, the endothelin levels increased significantly. Immunohistochemical studies revealed the presence of few endothelin-positive endothelial cells in the basilar artery of control dogs. Two and 4 days after the hemorrhage, many endothelin-positive cells appeared. These indicate that the production of endothelin increased in cerebral arteries following SAH. Treatment of the dogs with actinomycin D, which inhibits the production of mRNA for endothelin, prevented the generation of cerebral vasospasm after SAH. These results suggest that endothelin plays a critical role in the pathogenesis of cerebral vasospasm.

蛛网膜下腔出血（SAH）后发生脑血管痉挛。严重的血管收缩的机制仍不清楚。最近，内皮素从血管内皮细胞的培养液中被分离出来，并被发现是一种有效的血管收缩肽。我们研究了内皮素在脑血管痉挛发病机制中的可能作用。在离体犬脑动脉中，内皮素-1和内皮素-2均引起持续收缩。内皮素诱导的收缩不能通过反复冲洗逆转，表明内皮素作用的不可逆性。内皮素-3和大内皮素为弱缩血管剂。因此，ET-A型内皮素受体在脑动脉中占主导地位。然后，我们用夹心酶免疫法测定血浆和脑脊液（CSF）中内皮素的含量。蛛网膜下腔出血患者脑脊液中内皮素含量在出血第7天和第14天升高。进一步观察了实验性SAH犬血浆内皮素含量变化的时程。正常犬脑脊液中未检测到内皮素。而SAH后2、4天内皮素水平明显升高。免疫组织化学研究显示，在对照犬的基底动脉中存在少量内皮素阳性内皮细胞。出血后第2天和第4天出现大量内皮素阳性细胞。提示SAH后脑动脉内皮素生成增加。用放线菌素D治疗狗，抑制内皮素mRNA的产生，防止SAH后脑血管痉挛的产生。提示内皮素在脑血管痉挛的发病机制中起重要作用。