Xyloketal B (Xyl-B) is a novel marine compound isolated from mangrove fungus Xylaria sp. (No 2508). We previously showed that Xyl-B promoted endothelial NO release and protected against atherosclerosis through the Akt/eNOS pathway. Vascular NO production regulates vasoconstriction in central and peripheral arteries and plays an important role in blood pressure control. In this study, we examined whether Xyl-B exerted an antihypertensive effect in a hypertensive rat model, and further explored the possible mechanisms underlying its antihypertensive action. Administration of Xyl-B (20 mg·kg^-1·d^-1, ip, for 12 weeks) significantly decreased the systolic and diastolic blood pressure in a two-kidney, two-clip (2K2C) renovascular hypertensive rats. In endothelium-intact and endothelium-denuded thoracic aortic rings, pretreatment with Xyl-B (20 μmol/L) significantly suppressed phenylephrine (Phe)-induced contractions, suggesting that its vasorelaxant effect was attributed to both endothelial-dependent and endothelial-independent mechanisms. We used SNP, methylene blue (MB, guanylate cyclase inhibitor) and indomethacin (IMC, cyclooxygenase inhibitor) to examine which endothelial pathway was involved, and found that MB, but not IMC, reversed the inhibitory effects of Xyl-B on Phe-induced vasocontraction. Moreover, Xyl-B increased the endothelial NO bioactivity and smooth muscle cGMP level, revealing that the NO-sGC-cGMP pathway, rather than PGI₂, mediated the anti-hypertensive effect of Xyl-B. We further showed that Xyl-B significantly attenuated KCl-induced Ca²⁺ entry in smooth muscle cells in vitro, which was supposed to be mediated by voltage-dependent Ca²⁺ channels (VDCCs), and reduced ryanodine-induced aortic contractions, which may be associated with store-operated Ca²⁺ entry (SOCE). Taken together, these findings demonstrate that Xyl-B exerts significant antihypertensive effects not only through the endothelial NO-sGC-cGMP pathway but also through smooth muscle calcium signaling, including VDCCs and SOCE.

中文翻译：

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Xyloketal B通过NO-sGC-cGMP途径和钙信号传导在肾血管性高血压大鼠中发挥降压作用。

Xyloketal B（Xyl-B）是一种从红树林真菌Xylaria sp。分离的新型海洋化合物。（第2508号）。我们以前显示Xyl-B促进内皮细胞NO释放并通过Akt / eNOS途径保护其免受动脉粥样硬化的侵害。血管NO的产生调节中央和周围动脉的血管收缩，并在血压控制中起重要作用。在这项研究中，我们检查了Xyl-B是否在高血压大鼠模型中发挥降压作用，并进一步探讨了其降压作用的可能机制。给予Xyl-B（20 mg·kg ^-1 ·d ^-1，ip，持续12周）显着降低了两肾两夹（2K2C）肾血管性高血压大鼠的收缩压和舒张压。在内皮完好和内皮剥脱的胸主动脉环中，用Xyl-B（20μmol/ L）预处理可显着抑制去氧肾上腺素（Phe）引起的收缩，表明其血管舒张作用归因于内皮依赖性和内皮依赖性机制。我们使用SNP，亚甲基蓝（MB，鸟苷酸环化酶抑制剂）和消炎痛（IMC，环加氧酶抑制剂）检查了涉及的内皮途径，发现MB（而非IMC）逆转了Xyl-B对Phe诱导的抑制作用血管收缩。此外，Xyl-B增加了内皮一氧化氮的生物活性和平滑肌cGMP水平，表明NO-sGC-cGMP途径而非PGI₂，介导Xyl-B的抗高血压作用。我们进一步表明，Xyl-B在体外显着减弱了KCl诱导的平滑肌细胞中Ca ^2+的进入，这可能是由电压依赖性Ca ²⁺通道（VDCCs）介导的，并减少了由ryanodine引起的主动脉收缩，可能与存储操作的Ca ²⁺条目（SOCE）相关联。综上所述，这些发现表明，Xyl-B不仅通过内皮NO-sGC-cGMP途径，而且还通过包括VDCCs和SOCE在内的平滑肌钙信号传导发挥重要的降压作用。