Endothelium-derived vasoactive peptide and cerebral vasospasm

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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.