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首页> 外文期刊>Neurosurgery >Continuous intravenous infusion of CGS 26303, an endothelin-converting enzyme inhibitor, prevents and reverses cerebral vasospasm after experimental subarachnoid hemorrhage.
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Continuous intravenous infusion of CGS 26303, an endothelin-converting enzyme inhibitor, prevents and reverses cerebral vasospasm after experimental subarachnoid hemorrhage.

机译：连续静脉输注CGS 26303（一种内皮素转化酶抑制剂）可预防和逆转实验性蛛网膜下腔出血后的脑血管痉挛。

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OBJECTIVE: Endothelin-mediated vasoconstriction has been implicated in the pathophysiology of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Endothelin-1, the most potent vasoconstrictor peptide of the endothelin family, is synthesized initially as a large prepropeptide that requires multiple steps of post-translational processing for activation. The final step of this processing involves the proteolytic cleavage of a relatively inactive precursor, big endothelin-1, by the metalloprotease endothelin-converting enzyme. Previous findings have demonstrated that intravenous bolus injections of an endothelin-converting enzyme inhibitor (CGS 26303) administered twice daily can prevent and reverse arterial narrowing in a rabbit model of SAH. However, attenuation of vasospastic response was incomplete and required relatively high doses to be effective in reversing vasospasm. Therefore, the present study evaluated an alternative protocol for administration of CGS 26303 to optimize the antispastic influence of this compound. METHODS: Continuous intravenous infusion of CGS 26303 at doses of 2.4, 8.0, or 24.0 mg/kg/d was initiated either 1 hour (prevention paradigm) or 24 hours (reversal paradigm) after experimental SAH in New Zealand White rabbits. All animals were killed by perfusion-fixation 48 hours after SAH. Basilar arteries were then removed and sectioned, and their cross-sectional areas were measured by use of computer-assisted video microscopy. RESULTS: Continuous intravenous infusion of CGS 26303 attenuated SAH-induced cerebral vasospasm in a dose-dependent manner in both the prevention and the reversal groups. These effects achieved statistical significance at all doses as compared with the SAH-only or SAH-plus-vehicle groups. Furthermore, the attenuation of vasospasm after continuous infusion of CGS 26303 was more efficacious than that obtained with bolus injections. CONCLUSION: These findings provide further support for the use of endothelin-converting enzyme inhibition as a therapeutic strategy for reduction of cerebral vasospasm, and they also support the effectiveness of this strategy even when initiated after arterial narrowing has been established. The findings also indicate that continuous intravenous infusion of CGS 26303 is a more effective approach for attenuation of vasospasm than bolus intravenous administration.
机译：目的：内皮素介导的血管收缩与动脉瘤性蛛网膜下腔出血（SAH）后脑血管痉挛的病理生理学有关。内皮素-1是内皮素家族中最有效的血管收缩肽，最初合成为大的前肽，需要大量翻译后加工步骤才能激活。该过程的最后一步涉及通过金属蛋白酶内皮素转化酶对相对失活的前体大内皮素1进行蛋白水解切割。先前的研究结果表明，每天两次静脉推注内皮素转化酶抑制剂（CGS 26303）可以预防和逆转SAH兔模型中的动脉狭窄。然而，血管痉挛反应的减弱是不完全的，需要相对较高的剂量才能有效地逆转血管痉挛。因此，本研究评估了CGS 26303的替代给药方案，以优化该化合物的抗痉挛作用。方法：在新西兰白兔实验性SAH后1小时（预防范式）或24小时（逆向范式）开始以2.4、8.0或24.0 mg / kg / d的剂量连续静脉输注CGS 26303。 SAH后48小时，通过灌注固定杀死所有动物。然后切除并切开基底动脉，并使用计算机辅助视频显微镜测量其横截面积。结果：在预防组和逆转组中，持续静脉内输注CGS 26303均以剂量依赖的方式减弱了SAH诱导的脑血管痉挛。与仅使用SAH或添加SAH的车辆组相比，这些效果在所有剂量下均具有统计学意义。此外，连续推注CGS 26303后对血管痉挛的减弱作用比推注法更有效。结论：这些发现为使用内皮素转化酶抑制作为减少脑血管痉挛的治疗策略提供了进一步的支持，并且即使在动脉狭窄建立后就开始使用该策略也有效。这些发现还表明，与推注静脉内给药相比，连续静脉内输注CGS 26303是减轻血管痉挛的更有效方法。

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