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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Vasorelaxant and Antihypertensive Effects of (3β)-ursen-12-en-3,28-diol by NO/cGMP System

Author(s): Ricardo Guzmán-Ávila, Samuel Estrada-Soto*, Luis Arias-Durán, César Millán-Pacheco, Jaime Escalante-García, Maria Yolanda Rios, Virginia Flores-Morales, Rafael Villalobos-Molina and Gabriela Pérez-Barrón*

Volume 20, Issue 12, 2023

Published on: 27 September, 2022

Page: [1959 - 1969] Pages: 11

DOI: 10.2174/1570180819666220704111424

Price: $65

Abstract

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.

Keywords: Antihypertensive, vasorelaxant, ursolic acid derivatives, SHR, eNOS, hypertensive rats.

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[1]
Mills, K.T.; Stefanescu, A.; He, J. The global epidemiology of hypertension. Nat. Rev. Nephrol., 2020, 16(4), 223-237.
[http://dx.doi.org/10.1038/s41581-019-0244-2] [PMID: 32024986]
[2]
Demir, Y. The behaviour of some antihypertension drugs on human serum paraoxonase-1: an important protector enzyme against atherosclerosis. J. Pharm. Pharmacol., 2019, 71(10), 1576-1583.
[http://dx.doi.org/10.1111/jphp.13144] [PMID: 31347707]
[3]
Demir, Y. Naphthoquinones, benzoquinones, and anthraquinones: Molecular docking, ADME and inhibition studies on human serum paraoxonase-1 associated with cardiovascular diseases. Drug Dev. Res., 2020, 81(5), 628-636.
[http://dx.doi.org/10.1002/ddr.21667] [PMID: 32232985]
[4]
Mills, K.T.; Bundy, J.D.; Kelly, T.N.; Reed, J.E.; Kearney, P.M.; Reynolds, K.; Chen, J.; He, J. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation, 2016, 134(6), 441-450.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.115.018912] [PMID: 27502908]
[5]
Oparil, S.; Zaman, M.A.; Calhoun, D.A. Pathogenesis of hypertension. Ann. Intern. Med., 2003, 139(9), 761-776.
[http://dx.doi.org/10.7326/0003-4819-139-9-200311040-00011] [PMID: 14597461]
[6]
Campos-Nonato, I.; Hernández-Barrera, L.; Pedroza-Tobías, A.; Medina, C.; Barquera, S. [Hypertension in Mexican adults: prevalence, diagnosis and type of treatment. Ensanut MC 2016]. Sal. Pub. Mex., 2018, 60(3), 233-243.
[http://dx.doi.org/10.21149/8813] [PMID: 29746740]
[7]
Arredondo, A.; Avilés, R. Hypertension and its effects on the economy of the health system for patients and society: suggestions for developing countries. Am. J. Hypertens., 2014, 27(4), 635-636.
[http://dx.doi.org/10.1093/ajh/hpu010] [PMID: 24610899]
[8]
Dickerson, L.M.; Gibson, M.V. Management of hypertension in older persons. Am. Fam. Physician, 2005, 71(3), 469-476.
[PMID: 15712622]
[9]
Mlala, S.; Oyedeji, A.O.; Gondwe, M.; Oyedeji, O.O. Ursolic acid and its derivatives as bioactive agents. Molecules, 2019, 24(15), 2751.
[http://dx.doi.org/10.3390/molecules24152751] [PMID: 31362424]
[10]
Badran, A.; Baydoun, E.; Samaha, A.; Pintus, G.; Mesmar, J.; Iratni, R.; Issa, K.; Eid, A.H. Marjoram relaxes rat thoracic aorta via a PI3-K/eNOS/cGMP Pathway. Biomolecules, 2019, 9(6), 227.
[http://dx.doi.org/10.3390/biom9060227] [PMID: 31212721]
[11]
Samaha, A.A.; Fawaz, M.; Salami, A.; Baydoun, S.; Eid, A.H. Antihypertensive indigenous lebanese plants: ethnopharmacology and a clinical trial. Biomolecules, 2019, 9(7), 292.
[http://dx.doi.org/10.3390/biom9070292] [PMID: 31330767]
[12]
Kamyab, R.; Namdar, H.; Torbati, M.; Ghojazadeh, M.; Araj-Khodaei, M.; Fazljou, S.M.B. Medicinal plants in the treatment of hypertension: a review. Adv. Pharm. Bull., 2021, 11(4), 601-617.
[http://dx.doi.org/10.34172/apb.2021.090] [PMID: 34888207]
[13]
Al Disi, S.S.; Anwar, M.A.; Eid, A.H. Anti-hypertensive Herbs and their mechanisms of action: part I. Front. Pharmacol., 2016, 6, 323.
[http://dx.doi.org/10.3389/fphar.2015.00323] [PMID: 26834637]
[14]
Chen, C.; Wang, J.; Sun, M.; Li, J.; Wang, H.D. Toward the next-generation phyto-nanomedicines: cell-derived nanovesicles (CDNs) for natural product delivery. Biomed. Pharmacother., 2022, 145, 112416.
[http://dx.doi.org/10.1016/j.biopha.2021.112416] [PMID: 34781147]
[15]
Shaito, A.; Thuan, D.T.B.; Phu, H.T.; Nguyen, T.H.D.; Hasan, H.; Halabi, S.; Abdelhady, S.; Nasrallah, G.K.; Eid, A.H.; Pintus, G. Herbal medicine for cardiovascular diseases: efficacy, mechanisms, and safety. Front. Pharmacol., 2020, 11, 422.
[http://dx.doi.org/10.3389/fphar.2020.00422] [PMID: 32317975]
[16]
Rios, M.Y.; López-Martínez, S.; López-Vallejo, F.; Medina-Franco, J.L.; Villalobos-Molina, R.; Ibarra-Barajas, M.; Navarrete-Vazquez, G.; Hidalgo-Figueroa, S.; Hernández-Abreu, O.; Estrada-Soto, S. Vasorelaxant activity of some structurally related triterpenic acids from Phoradendron reichenbachianum (Viscaceae) mainly by NO production: Ex vivo and in silico studies. Fitoterapia, 2012, 83(6), 1023-1029. ss
[http://dx.doi.org/10.1016/j.fitote.2012.05.014] [PMID: 22659049]
[17]
Sheng, H.; Sun, H. Synthesis, biology and clinical significance of pentacyclic triterpenes: a multi-target approach to prevention and treatment of metabolic and vascular diseases. Nat. Prod. Rep., 2011, 28(3), 543-593.
[http://dx.doi.org/10.1039/c0np00059k] [PMID: 21290067]
[18]
Aguirre-Crespo, F.; Vergara-Galicia, J.; Villalobos-Molina, R.; Javier López-Guerrero, J.; Navarrete-Vázquez, G.; Estrada-Soto, S. Ursolic acid mediates the vasorelaxant activity of Lepechinia caulescens via NO release in isolated rat thoracic aorta. Life Sci., 2006, 79(11), 1062-1068.
[http://dx.doi.org/10.1016/j.lfs.2006.03.006] [PMID: 16630635]
[19]
Allouche, Y.; Beltrán, G.; Gaforio, J.J.; Uceda, M.; Mesa, M.D. Antioxidant and antiatherogenic activities of pentacyclic triterpenic diols and acids. Food Chem. Toxicol., 2010, 48(10), 2885-2890.
[http://dx.doi.org/10.1016/j.fct.2010.07.022] [PMID: 20650302]
[20]
Colla, A.R.S.; Oliveira, A.; Pazini, F.L.; Rosa, J.M.; Manosso, L.M.; Cunha, M.P.; Rodrigues, A.L.S. Serotonergic and noradrenergic systems are implicated in the antidepressant-like effect of ursolic acid in mice. Pharmacol. Biochem. Behav., 2014, 124, 108-116.
[http://dx.doi.org/10.1016/j.pbb.2014.05.015] [PMID: 24887451]
[21]
Chen, H.; Gao, Y.; Wang, A.; Zhou, X.; Zheng, Y.; Zhou, J. Evolution in medicinal chemistry of ursolic acid derivatives as anticancer agents. Eur. J. Med. Chem., 2015, 92, 648-655.
[http://dx.doi.org/10.1016/j.ejmech.2015.01.031] [PMID: 25617694]
[22]
Guzmán-Ávila, R.; Flores-Morales, V.; Paoli, P.; Camici, G.; Ramírez-Espinosa, J.J.; Cerón-Romero, L.; Navarrete-Vázquez, G.; Hidalgo-Figueroa, S.; Yolanda Rios, M.; Villalobos-Molina, R.; Estrada-Soto, S. Ursolic acid derivatives as potential antidiabetic agents: In vitro, in vivo and in silico studies. Drug Dev. Res., 2018, 79(2), 70-80.
[http://dx.doi.org/10.1002/ddr.21422] [PMID: 29380400]
[23]
Flores-Flores, A.; Hernández-Abreu, O.; Rios, M.Y.; León-Rivera, I.; Aguilar-Guadarrama, B.; Castillo-España, P.; Perea-Arango, I.; Estrada-Soto, S. Vasorelaxant mode of action of dichloromethanesoluble extract from Agastache mexicana and its main bioactive compounds. Pharm. Biol., 2016, 54(12), 2807-2813.
[http://dx.doi.org/10.1080/13880209.2016.1184690] [PMID: 27252080]
[24]
Suzuki, A.; Yamamoto, M.; Jokura, H.; Fujii, A.; Tokimitsu, I.; Hase, T.; Saito, I. Ferulic acid restores endothelium-dependent vasodilation in aortas of spontaneously hypertensive rats. Am. J. Hypertens., 2007, 20(5), 508-513.
[http://dx.doi.org/10.1016/j.amjhyper.2006.11.008] [PMID: 17485012]
[25]
Xu, Z.; Wang, X.; Dai, Y.; Kong, L.; Wang, F.; Xu, H.; Lu, D.; Song, J.; Hou, Z. (+/-)-Praeruptorin A enantiomers exert distinct relaxant effects on isolated rat aorta rings dependent on endothelium and nitric oxide synthesis. Chem. Biol. Interact., 2010, 186(2), 239-246.
[http://dx.doi.org/10.1016/j.cbi.2010.04.024] [PMID: 20433815]
[26]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[27]
Ji, H.; Li, H.; Flinspach, M.; Poulos, T.L.; Silverman, R.B. Computer modeling of selective regions in the active site of nitric oxide synthases: implication for the design of isoform-selective inhibitors. J. Med. Chem., 2003, 46(26), 5700-5711.
[http://dx.doi.org/10.1021/jm030301u] [PMID: 14667223]
[28]
Raman, C.S.; Li, H.; Martásek, P.; Southan, G.; Masters, B.S.; Poulos, T.L. Crystal structure of nitric oxide synthase bound to nitro indazole reveals a novel inactivation mechanism. Biochemistry, 2001, 40(45), 13448-13455.
[http://dx.doi.org/10.1021/bi010957u] [PMID: 11695891]
[29]
Arias-Durán, L.; Estrada-Soto, S.; Hernández-Morales, M.; Millán-Pacheco, C.; Navarrete-Vázquez, G.; Villalobos-Molina, R.; Ibarra-Barajas, M.; Almanza-Pérez, J.C. Antihypertensive and vasorelaxant effect of leucodin and achillin isolated from Achillea millefolium through calcium channel blockade and NO production: In vivo, functional ex vivo and in silico studies. J. Ethnopharmacol., 2021, 273, 113948.
[http://dx.doi.org/10.1016/j.jep.2021.113948] [PMID: 33610712]
[30]
Russell, J.C.; Proctor, S.D. Small animal models of cardiovascular disease: tools for the study of the roles of metabolic syndrome, dyslipidemia, and atherosclerosis. Cardiovasc. Pathol., 2006, 15(6), 318-330.
[http://dx.doi.org/10.1016/j.carpath.2006.09.001] [PMID: 17113010]
[31]
Mendes, V.I.S.; Bartholomeusz, G.A.; Ayres, M.; Gandhi, V.; Salvador, J.A.R. Synthesis and cytotoxic activity of novel A-ring cleaved ursolic acid derivatives in human non-small cell lung cancer cells. Eur. J. Med. Chem., 2016, 123, 317-331.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.045] [PMID: 27484517]
[32]
Wu, P.P.; Zhang, B.J.; Cui, X.P.; Yang, Y.; Jiang, Z.Y.; Zhou, Z.H.; Zhong, Y.Y.; Mai, Y.Y.; Ouyang, Z.; Chen, H.S.; Zheng, J.; Zhao, S.Q.; Zhang, K. Synthesis and biological evaluation of novel ursolic acid analogues as potential-glucosidase inhibitors. Sci. Rep., 2017, 7, 455-478.
[http://dx.doi.org/10.1038/s41598-017-00557-2] [PMID: 28352125]
[33]
Ormazabal, V.; Nair, S.; Elfeky, O.; Aguayo, C.; Salomon, C.; Zuñiga, F.A. Association between insulin resistance and the development of cardiovascular disease. Cardiovasc. Diabetol., 2018, 17(1), 122.
[http://dx.doi.org/10.1186/s12933-018-0762-4] [PMID: 30170598]
[34]
Sever, B.; Altıntop, M.D.; Demir, Y.; Yılmaz, N.; Akalın Çiftçi, G.; Beydemir, Ş.; Özdemir, A. Identification of a new class of potent aldose reductase inhibitors: Design, microwave-assisted synthesis, in vitro and in silico evaluation of 2-pyrazolines. Chem. Biol. Interact., 2021, 345, 109576.
[http://dx.doi.org/10.1016/j.cbi.2021.109576] [PMID: 34252406]
[35]
Rodriguez-Rodriguez, R.; Perona, J.S.; Herrera, M.D.; Ruiz-Gutierrez, V. Triterpenic compounds from “orujo” olive oil elicit vasorelaxation in aorta from spontaneously hypertensive rats. J. Agric. Food Chem., 2006, 54(6), 2096-2102.
[http://dx.doi.org/10.1021/jf0528512] [PMID: 16536581]
[36]
Avila-Villarreal, G.; Hernández-Abreu, O.; Hidalgo-Figueroa, S.; Navarrete-Vázquez, G.; Escalante-Erosa, F.; Peña-Rodríguez, L.M.; Villalobos-Molina, R.; Estrada-Soto, S. Antihypertensive and vasorelaxant effects of dihydrospinochalcone-A isolated from Lonchocarpus xuul Lundell by NO production: computational and ex vivo approaches. Phytomedicine, 2013, 20(14), 1241-1246.
[http://dx.doi.org/10.1016/j.phymed.2013.06.011] [PMID: 23880329]
[37]
Aguirre-Crespo, F.A.; Castillo-España, P.; Villalobos-Molina, R.; López-Guerrero, J.J.; Estrada-Soto, S. Vasorelaxant effect of Mexican medicinal plants on isolated rat aorta. Pharm. Biol., 2005, 43, 540-546.
[http://dx.doi.org/10.1080/13880200500220839]

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