Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
Acta Pharmacol Sin. 2018 May;39(5):875-884. doi: 10.1038/aps.2018.12. Epub 2018 Mar 29.
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·d, 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 PGI, mediated the anti-hypertensive effect of Xyl-B. We further showed that Xyl-B significantly attenuated KCl-induced Ca entry in smooth muscle cells in vitro, which was supposed to be mediated by voltage-dependent Ca channels (VDCCs), and reduced ryanodine-induced aortic contractions, which may be associated with store-operated Ca 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.
木栓酮 B（Xyl-B）是一种从红树林真菌 Xylaria sp.（No 2508）中分离得到的新型海洋化合物。我们之前的研究表明，Xyl-B 通过 Akt/eNOS 通路促进内皮一氧化氮释放并预防动脉粥样硬化。血管一氧化氮的产生调节中枢和外周动脉的血管收缩，在血压控制中发挥重要作用。在这项研究中，我们研究了 Xyl-B 是否在高血压大鼠模型中具有降压作用，并进一步探讨了其降压作用的可能机制。给予 Xyl-B（20mg·kg·d，ip，12 周）可显著降低两肾两夹（2K2C）肾血管性高血压大鼠的收缩压和舒张压。在完整内皮和去内皮的胸主动脉环中，Xyl-B（20μmol/L）预处理显著抑制了去甲肾上腺素（Phe）诱导的收缩，表明其血管舒张作用归因于内皮依赖性和非内皮依赖性机制。我们使用 SNP、亚甲蓝（MB，鸟苷酸环化酶抑制剂）和吲哚美辛（IMC，环氧化酶抑制剂）来研究涉及的内皮途径，发现只有 MB，而不是 IMC，逆转了 Xyl-B 对 Phe 诱导的血管收缩的抑制作用。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 通路而不是 PGI 介导了 Xyl-B 的抗高血压作用。我们进一步表明，Xyl-B 显著减弱了平滑肌细胞中 KCl 诱导的 Ca 内流，这可能是通过电压依赖性 Ca 通道（VDCCs）介导的，并减轻了 Ryanodine 诱导的主动脉收缩，这可能与储存操作 Ca 内流（SOCE）有关。综上所述，这些发现表明，Xyl-B 不仅通过内皮一氧化氮-sGC-cGMP 通路，而且通过平滑肌钙信号转导，包括 VDCCs 和 SOCE，发挥显著的降压作用。
