Xyloketal B exerts antihypertensive effect in renovascular hypertensive rats via the NO-sGC-cGMP pathway and calcium signaling

Abstract

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.

CFTR deficiency aggravates Ang II induced vasoconstriction and hypertension by regulating Ca𝟐+ influx and RhoA/Rock pathway in VSMCs

“…Vascular rings of thoracic aorta and basilar artery were prepared and isometric tension measurement experiments were performed as previously described [25]. Briefly, mice were euthanized and then thoracic aortas or basilar arteries were quickly removed and placed into icecold Krebs-Henseleit Modified Buffer containing 2.5 mM Ca 2+ (Krebs buffer), and detached from fatty and connective tissues.…”

Marine Compound Xyloketal B as a Potential Drug Development Target for Neuroprotection

“…In the most recent xyloketal B study, Zhao and colleagues (2018) have proven xyloketal B’s ability in the reduction of blood pressure and relaxation of aortic rings in 2K2C renovascular hypertensive rats [50]. As hypertension is one of the major risk factors for ischemic stroke, these findings further validate the beneficial effects of xyloketal B in cardiovascular patients.…”

Xyloketal B Reverses Nutritional Hepatic Steatosis, Steatohepatitis, and Liver Fibrosis through Activation of the PPARα/PGC1α Signaling Pathway

“…On the other hand, our results may also explain some previously reported findings. For instance, a series of publications reported that Xyl-B could enhance the activity of endothelial nitric oxide synthase (eNOS) and thus attenuate atherosclerotic plaque formation; ,, these effects might be also essentially mediated by the PPARα/PGC1α signaling pathway, as the close correlations between PPARα agonism and eNOS activation had been expounded . Nonetheless, sufficient evidence was required to support these inferences.…”