Department of Neurosurgery, Kantonsspital Aarau, Tellstrasse 25, 5001 Aarau, Switzerland.
Cerebrovascular Research Group, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland.
Int J Mol Sci. 2020 Sep 5;21(18):6496. doi: 10.3390/ijms21186496.
Cerebral vasospasm (CVS) remains a major cause of delayed cerebral ischaemia following aneurysmal subarachnoid haemorrhage (SAH), making it a life-threatening type of stroke with high morbidity and mortality. Endothelin-1 is known as key player mediating a strong vasocontractile effect. Interestingly, losartan restores the impaired vasorelaxative ET(B) receptor function in a non-competitive direct fashion. With this study, we aimed to investigate a potential losartan-dependent vasodilatory effect vice versa by inhibiting NO release through L-NAME, thus pushing forward concepts to alleviate vasospasm and possibly prevent ischaemia and neurodegeneration.
Cerebral vasospasm was induced by the use of an established double-injection rat model. Sprague-Dawley rats were culled on Day 3 after the ictus, and the vasospastic basilar artery was harvested for isometric investigations of the vessel tone. Ring segments were preincubated with and without L-NAME and/or losartan.
Preincubation with L-NAME induced dose-dependent vasoconstriction via endothelin-1 in the non-SAH cohort, which was dose-dependently reduced by losartan. After SAH and dose-dependent endothelin-1 administration, maximal contraction was achieved in the control group without losartan. Furthermore, this maximal contraction was significantly decreased in the losartan group and was reversed by L-NAME.
After SAH, losartan was shown to positively influence the ET(B) receptor pathway in a non-competitive direct agonistic and indirect fashion. Losartan alleviated the maximum contraction triggered by endothelin-1. This effect was resolved due to NO inhibition by L-NAME. Considering this spasmolytic effect of losartan besides its already well-known effects (attenuating cerebral inflammation, restoring cerebral autoregulation and reducing epileptogenic activity) and alleviating early brain injury, losartan seems to have potential as a promising pharmacological agent after SAH.
蛛网膜下腔出血（SAH）后迟发性脑缺血仍然是脑血管痉挛（CVS）的主要原因，这使得它成为一种具有高发病率和死亡率的危及生命的中风类型。内皮素-1 被认为是介导强烈血管收缩作用的关键因子。有趣的是，氯沙坦以非竞争性直接方式恢复受损的血管舒张性 ET(B)受体功能。通过这项研究，我们旨在通过 L-NAME 抑制 NO 释放来研究潜在的氯沙坦依赖性血管扩张作用，从而推动减轻血管痉挛和预防缺血和神经退行性变的概念。
通过使用已建立的大鼠双注射模型诱导脑血管痉挛。在中风后第 3 天处死 Sprague-Dawley 大鼠，并收获痉挛性基底动脉进行血管张力等离体研究。环段在有无 L-NAME 和/或氯沙坦的情况下进行预孵育。
在非 SAH 队列中，L-NAME 诱导的内皮素-1 依赖性剂量依赖性血管收缩，氯沙坦呈剂量依赖性降低。在 SAH 和剂量依赖性内皮素-1 给药后，无氯沙坦的对照组达到最大收缩。此外，这种最大收缩在氯沙坦组显著降低，并被 L-NAME 逆转。
SAH 后，氯沙坦以非竞争性直接激动剂和间接方式对 ET(B)受体途径产生积极影响。氯沙坦缓解了内皮素-1 引发的最大收缩。这种作用由于 L-NAME 对 NO 的抑制而得到解决。考虑到氯沙坦除了已经众所周知的作用（减轻脑炎症、恢复脑自动调节和减少致癫痫活性）之外，还具有这种痉挛缓解作用，并减轻早期脑损伤，氯沙坦似乎有潜力成为 SAH 后的一种有前途的药物。
