Systemic administration of an inhibitor of endothelin-converting enzyme for attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage
Systemic administration of an inhibitor of endothelin-converting enzyme for attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage
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DOI：
10.3171/jns.1996.85.5.0917
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发表时间：
1996-11-01
影响因子：
4.1
通讯作者：
Lee, KS
中科院分区：
文献类型：
--
作者：
Caner, HH;Kwan, AL;Lee, KS
有效的血管收缩肽，内皮素-1（ET-1），已被牵连在蛛网膜下腔出血（SAH）后发生的脑血管痉挛的病理生理学。该肽被合成为大的前原肽，其需要一系列修饰步骤以使其活化。这些步骤中的最后一个涉及相对无活性的前肽Big ET-1的蛋白水解转化。转化为21个氨基酸的活性肽。负责将大ET-1转化为ET-1的酶是一种称为内皮素转化酶（ECE）的金属蛋白酶。在本研究中，作者研究了一种新开发的ECE抑制剂对正常基底动脉中ET肽的反应和SAH.In第一系列的实验中，作者研究了正常的基底动脉在兔，这是暴露translivally和使用视频显微镜在线测量的痉挛性基底动脉的病理生理收缩的影响。静脉给药或局部应用的活性抑制剂ECE，CGS 26303，阻断血管收缩反应局部应用大ET-1，但不ET-1。相反，局部应用不抑制ECE的结构相关化合物CGS 24592在阻断由局部应用大ET-1引起的血管收缩方面无效。这些发现表明，CGS 26303在全身给药时能够阻断基底动脉中大ET-1向ET-1的转化，而不影响血管对ET-1的反应能力。在第二系列实验中，作者研究了ECE抑制剂对实验性SAH后脑血管痉挛的影响。CGS 26303通过渗透压微型泵腹膜内给药显著减弱了脑池内注射自体blood.This研究提供了第一个证据表明，ECE抑制剂的全身给药能够预防SAH后脑血管痉挛的基底动脉的延迟痉挛反应。这些结果进一步证实了越来越多的证据表明，蛛网膜下腔出血后痉挛性收缩的发展中起着至关重要的作用。此外，研究结果表明，使用CGS 26303阻断大ET-1向其活性ET-1形式的转化可能是改善脑血管痉挛的可行策略。
The potent vasoconstrictor peptide, endothelin-1 (ET-1), has been implicated in the pathophysiology of cerebral vasospasm that occurs after subarachnoid hemorrhage (SAH). This peptide is synthesized as a large prepropeptide that requires a series of modifying steps for its activation. The last of these steps involves the proteolytic conversion of a relatively inactive propeptide, Big ET-1. to its active, 21-amino acid peptide form. The enzyme responsible for converting Big ET-1 to ET-1 is a metalloprotease called endothelin-converting enzyme (ECE). In the present study the authors examined the effects of a newly developed inhibitor of ECE on responses to ET peptides in the normal basilar artery and on pathophysiological constriction in the spastic basilar artery after SAH.In the first series of experiments the authors examined normal basilar arteries in the rabbit, which were exposed transclivally and measured on-line using videomicroscopy. Intravenous administration or topical application of an active inhibitor of ECE, CGS 26303, blocked vasoconstrictor responses to topically applied Big ET-1 but not to ET-1. In contrast, topical application of a structurally related compound that does not inhibit ECE, CGS 24592, was ineffective in blocking vasoconstriction that was elicited by a topical application of Big ET-1. These findings indicate that CGS 26303 when administered systemically is capable of blocking the conversion of Big ET-1 to ET-1 in the basilar artery without affecting the ability of the vessel to respond to ET-1. In the second series of experiments the authors examined the effects of the ECE inhibitor on cerebral vasospasm after experimental SAH. Intraperitoneal administration of CGS 26303 via osmotic minipumps significantly attenuated the delayed spastic response of the basilar artery to an intracisternal injection of autologous blood.This study provides the first evidence that systemic administration of an inhibitor of ECE is capable of preventing cerebral vasospasm after SAH. The results reinforce a growing body of evidence that ETs play a critical role in the development of spastic constriction after SAH. Moreover, the findings indicate that blocking the conversion of Big ET-1 to its active ET-1 form using CGS 26303 may represent a feasible strategy for ameliorating cerebral vasospasm.