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

Authors: Li-yan ZHAO1, Jie LI2, Xiong-qing HUANG3, Guo-hao WANG4, Xiao-fei LV5, Wei-feng MENG5, Wen-liang CHEN6, Ji-yan PANG7, Yong-cheng LIN7, Hong-shuo SUN8, Guan-lei WANG5,9, Yao-min DU10
1 Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
2 Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China
3 Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
4 Department of Computer Engineering, Engineering Institute in Lishui University, Lishui 323000, China
5 Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
6 6Department of Pharmacology, School of Pharmaceutical Sciences, and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
7 Department of Applied Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510080, China
8 Departments of Surgery and Physiology, Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON M5G 1G6, Canada
9 Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China
10 Departments of Geriatrics, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou 510080, China
Corresponding to: Guan-lei WANG:, Yao-min DU:,
DOI: 10.1038/aps.2018.12
Received: 4 November 2017
Accepted: 12 January 2018
Advance online: 29 March 2018


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 endotheliumdenuded 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-sGCcGMP 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-sGCcGMP pathway but also through smooth muscle calcium signaling, including VDCCs and SOCE.
Keywords: hypertension; two-kidney two-clip renovascular hypertensive rats; aortic rings; smooth muscle cells; xyloketal B; NO-sGCcGMP pathway; SNP methylene blue; indomethacin; KCl; ryanodine