Kwan A L, Bavbek M, Jeng A Y, Maniara W, Toyoda T, Lappe R W, Kassell N F, Lee K S
Department of Neurological Surgery, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
J Neurosurg. 1997 Aug;87(2):281-6. doi: 10.3171/jns.1997.87.2.0281.
Delayed cerebral ischemia due to cerebral vasospasm is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Increasing evidence implicates the potent vasoconstrictor peptide endothelin (ET) in the pathophysiology of cerebral vasospasm. In the present study the authors examined the therapeutic value of blocking the production of ET-1 by inhibiting the conversion of its relatively inactive precursor, Big ET-1, to a physiologically active form. An inhibitor of ET-converting enzyme (ECE), CGS 26303, was injected intravenously after inducing SAH in New Zealand white rabbits. Injections of CGS 26303 were initiated either 1 hour after SAH (prevention protocol) or 24 hours after SAH (reversal protocol). One of three concentrations (3, 10, or 30 mg/kg) of CGS 26303 was injected twice daily, and all animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed and sectioned, and their cross-sectional areas were measured in a blind manner by using computer-assisted videomicroscopy. Treatment with CGS 26303 attenuated arterial narrowing after SAH in both the prevention and reversal protocols. The protective effect of CGS 26303 achieved statistical significance at all dosages in the prevention protocol and at 30 mg/kg in the reversal protocol. These findings demonstrate that inhibiting the conversion of Big ET-1 to ET-1 via intravenous administration of an ECE inhibitor can be an effective strategy for limiting angiographic vasospasm after SAH. Moreover, the results demonstrate that treatment with the ECE inhibitor is capable of reducing vasospasm even when initiated after the process of arterial narrowing has begun. Finally, the results provide further support for the role of ET in the establishment of cerebral vasospasm. The ECE inhibitor CGS 26303 thus represents a promising therapeutic agent for the treatment of cerebral vasospasm following aneurysmal SAH.
因脑血管痉挛导致的迟发性脑缺血是动脉瘤性蛛网膜下腔出血（SAH）患者发病和死亡的主要原因。越来越多的证据表明，强效血管收缩肽内皮素（ET）参与了脑血管痉挛的病理生理过程。在本研究中，作者通过抑制ET-1相对无活性的前体大ET-1转化为生理活性形式，来研究阻断ET-1产生的治疗价值。在新西兰白兔中诱导SAH后，静脉注射内皮素转化酶（ECE）抑制剂CGS 26303。CGS 26303的注射在SAH后1小时（预防方案）或SAH后24小时（逆转方案）开始。三种浓度（3、10或30mg/kg）的CGS 26303之一每天注射两次，所有动物在SAH发生后48小时通过灌注固定处死。取出基底动脉并切片，使用计算机辅助视频显微镜以盲法测量其横截面积。在预防和逆转方案中，CGS 26303治疗均减轻了SAH后的动脉狭窄。在预防方案中，CGS 26303的保护作用在所有剂量下均具有统计学意义，在逆转方案中，30mg/kg剂量时具有统计学意义。这些发现表明，通过静脉注射ECE抑制剂抑制大ET-1向ET-1的转化可能是限制SAH后血管造影血管痉挛的有效策略。此外，结果表明，即使在动脉狭窄过程开始后开始使用ECE抑制剂治疗，也能够减轻血管痉挛。最后，结果为ET在脑血管痉挛形成中的作用提供了进一步支持。因此，ECE抑制剂CGS 26303是治疗动脉瘤性SAH后脑血管痉挛的一种有前景的治疗药物。
