Wanderer Stefan, Mrosek Jan, Vatter Hartmut, Seifert Volker, Konczalla Juergen
Department of Neurosurgery, Kantonsspital Aarau, Aarau, Switzerland.
Department of Neurosurgery, Goethe-University Hospital, Frankfurt am Main, Germany.
Neurosurg Rev. 2018 Apr;41(2):539-548. doi: 10.1007/s10143-017-0887-z. Epub 2017 Jul 29.
Under physiologic conditions, losartan showed a dose-dependent antagonistic effect to the endothelin-1 (ET-1)-mediated vasoconstriction. This reduced vasoconstriction was abolished after preincubation with an endothelin B receptor (ET(B)-receptor) antagonist. Also, an increased ET(B)-receptor-dependent relaxation to sarafotoxin S6c (S6c; an ET(B)-receptor agonist) was detected by preincubation with losartan. Investigations after experimental induced subarachnoid hemorrhage (SAH) are still missing. Therefore, we analyzed losartan in a further pathological setup. Cerebral vasospasm was induced by a modified double hemorrhage model. Rats were sacrificed on day 3 and isometric force of basilar artery ring segments was measured. Parallel to physiological conditions, after SAH, the ET-1-induced vasoconstriction was decreased by preincubation with losartan. This reduced contraction has been abolished after preincubation with BQ-788, an ET(B)-receptor antagonist. In precontracted vessels, ET-1 induced a higher vasorelaxation under losartan and the endothelin A receptor (ET(A)-receptor) antagonist BQ-123. After SAH, losartan caused a modulatory effect on the ET(B)-receptor-dependent vasorelaxation. It further induced an upregulation of the NO pathway. Under losartan, the formerly known loss of the ET(B)-receptor vasomotor function was abolished and a significantly increased relaxation, accompanied with an enhanced sensitivity of the ET(B)-receptor, has been detected. Also, the dose-dependent antagonistic effect to the ET-1-induced contraction can be effected by angiotensin II type 1 receptor (AT-receptor) antagonism due to losartan directly via the ET(B)-receptor.
在生理条件下，氯沙坦对内皮素-1（ET-1）介导的血管收缩呈现剂量依赖性拮抗作用。在用内皮素B受体（ET(B)受体）拮抗剂预孵育后，这种血管收缩减弱的现象消失。此外，通过用氯沙坦预孵育，检测到对沙拉毒素S6c（S6c；一种ET(B)受体激动剂）的ET(B)受体依赖性舒张增强。目前仍缺乏实验性诱导蛛网膜下腔出血（SAH）后的相关研究。因此，我们在另一种病理模型中分析了氯沙坦。采用改良的双次出血模型诱导脑血管痉挛。在第3天处死大鼠，并测量基底动脉环段的等长张力。与生理条件相似，SAH后，用氯沙坦预孵育可降低ET-1诱导的血管收缩。在用ET(B)受体拮抗剂BQ-788预孵育后，这种收缩减弱的现象消失。在预收缩的血管中，ET-1在氯沙坦和内皮素A受体（ET(A)受体）拮抗剂BQ-123作用下诱导更高的血管舒张。SAH后，氯沙坦对ET(B)受体依赖性血管舒张产生调节作用。它进一步诱导了一氧化氮途径的上调。在氯沙坦作用下，先前已知的ET(B)受体血管舒缩功能丧失被消除，并且检测到舒张显著增加，同时伴有ET(B)受体敏感性增强。此外，由于氯沙坦可直接通过ET(B)受体拮抗血管紧张素II 1型受体（AT受体），从而对ET-1诱导的收缩产生剂量依赖性拮抗作用。
