Objective: The aim of this study was to determine the vasorelaxant effect of semisynthetic derivatives of ursolic acid, establish the mode of action, and determine the antihypertensive effect of the most active compound.
Methods: Isolated aorta rat rings (ex vivo assay), with and without endothelium, were used to determine the vasorelaxant effect of seven semisynthetic derivatives of ursolic acid (UA-01 to UA-07). Then, the effect of the most active compound was studied in ex vivo assay using L-NAME, ODQ and indomethacin to determine its mode action. Finally, the in vivo cardiovascular effect and molecular docking of the most active compound were determined.
Results: UA-07 was the most potent compound of the derivatives, since UA-07 induced significant relaxant effect in concentration- and endothelium-dependent manners (Emax = 79.09% and EC50 = 110 μM) on aortic rat rings pre-contracted with noradrenaline (NA, 0.1 μM). Also, endothelium-derived nitric oxide seems to be involved in the mechanism of action of UA-07, because pre-incubation with L-NAME (a NOS inhibitor) and ODQ (a soluble guanylate cyclase inhibitor) significantly reduced its vasorelaxant effect. Further, UA-07 showed a similar binding affinity as ursolic acid on eNOS C1 binding pocket in in silico studies. Finally, treatment with UA-07 (50 mg/Kg) on spontaneously hypertensive rats (SHR) significantly decreased diastolic blood pressure for seven hours.
Conclusion: These results demonstrate the significant antihypertensive effect of UA-07, possibly through the NO/cGMP system.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.115.018912] [PMID: 27502908]
[http://dx.doi.org/10.7326/0003-4819-139-9-200311040-00011] [PMID: 14597461]
[http://dx.doi.org/10.3389/fphar.2020.00422] [PMID: 32317975]
[http://dx.doi.org/10.1016/j.fitote.2012.05.014] [PMID: 22659049]
[http://dx.doi.org/10.1016/j.lfs.2006.03.006] [PMID: 16630635]
[http://dx.doi.org/10.1016/j.pbb.2014.05.015] [PMID: 24887451]
[http://dx.doi.org/10.1002/ddr.21422] [PMID: 29380400]
[http://dx.doi.org/10.1080/13880209.2016.1184690] [PMID: 27252080]
[http://dx.doi.org/10.1016/j.cbi.2010.04.024] [PMID: 20433815]
[http://dx.doi.org/10.1021/jm030301u] [PMID: 14667223]
[http://dx.doi.org/10.1016/j.jep.2021.113948] [PMID: 33610712]
[http://dx.doi.org/10.1016/j.ejmech.2016.07.045] [PMID: 27484517]
[http://dx.doi.org/10.1038/s41598-017-00557-2] [PMID: 28352125]
[http://dx.doi.org/10.1016/j.cbi.2021.109576] [PMID: 34252406]
[http://dx.doi.org/10.1016/j.phymed.2013.06.011] [PMID: 23880329]