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）后出现脑血管痉挛。严重的血管收缩的机制尚不清楚。最近，内皮素是从血管内皮细胞的培养基中分离出来的，发现是有效的血管收缩肽。我们检查了内皮素在脑血管痉挛的发病机理中的可能贡献。在狗的孤立脑动脉中，内皮素-1和内皮素-2都引起了持续的收缩。内皮素引起的收缩并没有反复洗涤，表明内皮素作用的不可逆性。内皮素3和大内皮素是薄弱的血管收缩。因此，ET-型内皮蛋白受体在脑动脉中占主导地位。接下来，我们通过三明治酶免疫测定法确定了血浆和脑脊液（CSF）中的内皮素含量。在出血的第七天和14日，CSF中CSF中的内皮素含量增加。在具有实验性SAH的狗中，进一步检查了内皮素含量变化的时间过程。在普通狗的CSF中，内皮素是无法检测的。但是，在SAH之后2和4天，内皮素水平显着增加。免疫组织化学研究揭示了对照犬基底动脉中的几个内皮蛋白阳性内皮细胞的存在。出血后两天和4天，出现了许多内皮素阳性细胞。这些表明SAH后内皮素的产生在脑动脉中增加。用放线霉素D治疗狗，抑制了内皮素的mRNA产生，可防止SAH后脑血管痉挛的产生。这些结果表明，内皮素在脑血管痉挛的发病机理中起关键作用。