Division of Neurosurgery, St Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, Ontario, Canada, M5B 1W8.
Stroke. 2011 May;42(5):1454-60. doi: 10.1161/STROKEAHA.110.604728. Epub 2011 Mar 31.
Endothelin receptor antagonists such as clazosentan decrease large-artery vasospasm after experimental and clinical subarachnoid hemorrhage. We used clazosentan to gain insight into the pathophysiology of subarachnoid hemorrhage by determining if decreasing vasospasm is associated with alleviation of other secondary complications of subarachnoid hemorrhage such as oxidative stress, endothelial nitric oxide synthase dysfunction, microthromboembolism, and neuronal injury.
Mice were subjected to subarachnoid hemorrhage by injection of blood into the chiasmatic cistern. They were treated with clazosentan or vehicle by continuous intraperitoneal infusion for 48 hours. Middle cerebral artery vasospasm, superoxide anion radical, peroxynitrite, microthromboemboli, endothelial nitric oxide synthase uncoupling, cerebral blood flow, neuronal injury, and mortality were assessed.
Clazosentan preserved cerebral blood flow, alleviated vasospasm, and decreased mortality but did not affect superoxide anion radical, peroxynitrite, or microthromboemboli in the brain. Endothelial nitric oxide synthase uncoupling and neuronal injury also were not reduced by clazosentan.
This study shows large-artery vasospasm is pathophysiologically independent of some other effects of subarachnoid hemorrhage. The findings have implications for development of treatments for this disease.
内皮素受体拮抗剂如氯沙坦可降低实验性和临床性蛛网膜下腔出血后的大动脉血管痉挛。我们使用氯沙坦通过确定减少血管痉挛是否与缓解蛛网膜下腔出血的其他继发性并发症（如氧化应激、内皮型一氧化氮合酶功能障碍、微血栓栓塞和神经元损伤）相关，来深入了解蛛网膜下腔出血的病理生理学。
通过向视交叉池内注射血液使小鼠发生蛛网膜下腔出血。通过连续腹腔内输注氯沙坦或载体 48 小时对其进行治疗。评估大脑中动脉血管痉挛、超氧阴离子自由基、过氧亚硝酸盐、微血栓栓塞、内皮型一氧化氮合酶解偶联、脑血流量、神经元损伤和死亡率。
氯沙坦可维持脑血流量、缓解血管痉挛并降低死亡率，但不会影响大脑中的超氧阴离子自由基、过氧亚硝酸盐或微血栓栓塞。氯沙坦也不会减少内皮型一氧化氮合酶解偶联和神经元损伤。
本研究表明，大动脉血管痉挛在病理生理学上与蛛网膜下腔出血的其他一些影响无关。这些发现对这种疾病的治疗方法的发展具有重要意义。
