Isolated Natural Antioxidants as a new Possible Therapeutic Alternative
for the Treatment of Hypertension

Matheus   Vinicius Barbosa   da Silva; Maria   Alessandra   da Silva Lima; Lizandra   Henrique   de Farias; Vanessa   Maria   dos Santos; Thyago   Moreira   de Queiroz
doi:10.2174/1573402118666221003095317
Abstract

Oxidative stress is one of the main mechanisms involved in the pathophysiology of arterial hypertension, inducing direct effects on the vasculature, and contributing to endothelial dysfunction and consequent impairment of vascular relaxation. Despite a large number of pharmacological treatments available, intolerable side effects are reported, which makes the use of natural antioxidants a promising and complementary alternative for the prevention and treatment of hypertension. From this perspective, the current review aims to investigate and characterize the main antioxidants of natural origin for the treatment of hypertension. Antioxidants act in the inhibition or extinction of chemical reactions involving free radicals and consequently reduce the occurrence of damage caused by these cellular components. The main natural antioxidants for treating hypertension include caffeic acid, ferulic acid, curcumin, apocynin, quercetin, lipoic acid, and lycopene. The effects associated with these antioxidants, which make them therapeutic targets for decreasing high blood pressure, include increased activation of antioxidant enzymes, stimulation of nitric oxide bioavailability, and reduction in angiotensin-converting enzyme activity, arginase, and NADPH oxidase, whose effects contribute to reducing oxidative stress, improving endothelial function, and preventing cardiovascular dysfunctions. Thus, several products with antioxidant properties that are available in nature and their application in the treatment of hypertension are described in the literature. The therapeutic effects of these products seem to regulate several parameters related to arterial hypertension, in addition to combating and preventing the deleterious effects related to the disease.
Keywords: Hypertension, oxidative stress, phenolic compounds, caffeic acid, carotenoids, curcumin, apocynin, lipoic acid
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Graphical Abstract

[1]
World Health Organization. A global brief on hypertension: Silent killer, global public health crisis: World Health Day 2013. Whoint 2013. Available from: https://apps.who.int/iris/handle/10665/79059 (Accessed on: 2021 Dec 27).

[2]
Montezano AC, Touyz RM. Molecular mechanisms of hypertension-reactive oxygen species and antioxidants: A basic science update for the clinician. Can J Cardiol  2012; 28(3): 288-95.
 [http://dx.doi.org/10.1016/j.cjca.2012.01.017] [PMID:  22445098]

[3]
Togliatto G, Lombardo G, Brizzi MF. The future challenge of Reactive Oxygen Species (ROS) in hypertension: From bench to bed side. Int J Mol Sci  2017; 18(9): 1988.
 [http://dx.doi.org/10.3390/ijms18091988] [PMID:  28914782]

[4]
Hirooka Y, Sagara Y, Kishi T, Sunagawa K. Oxidative stress and central cardiovascular regulation. - Pathogenesis of hypertension and therapeutic aspects -. Circ J  2010; 74(5): 827-35.
 [http://dx.doi.org/10.1253/circj.CJ-10-0153] [PMID:  20424336]

[5]
Ahmad KA, Yuan YD, Nawaz W, et al. Antioxidant therapy for management of oxidative stress induced hypertension. Free Radic Res  2017; 51(4): 428-38.
 [http://dx.doi.org/10.1080/10715762.2017.1322205] [PMID:  28427291]

[6]
Bose KSC, Agrawal BK. Effect of lycopene from tomatoes (cooked) on plasma antioxidant enzymes, lipid peroxidation rate and lipid profile in grade-I hypertension. Ann Nutr Metab  2007; 51(5): 477-81.
 [http://dx.doi.org/10.1159/000111170] [PMID:  18025823]

[7]
Cogolludo A, Pérez VF, Tamargo J. New insights in the pharmacological therapy of arterial hypertension. Curr Opin Nephrol Hypertens  2005; 14(5): 423-7.
 [http://dx.doi.org/10.1097/01.mnh.0000168334.09454.1c] [PMID:  16046899]

[8]
Kizhakekuttu TJ, Widlansky ME. Natural antioxidants and hypertension: Promises and challenges. Cardiovasc Ther  2010; 28(4): e20-32.

[9]
Zampelas A, Micha R. Antioxidants in health and disease. In: Antioxidants Heal Dis.  Florida: CRC Press 2015; pp. 1-302.

[10]
Pereira ALF, Vidal TF, Constant PBL. Antioxidantes alimentares: Importância química e biológica. Nutr Rev Soc Bras Aliment Nutr  2009; 34(3): 231-47.

[11]
Cardoso S, Fazio A. The antioxidant capacities of natural products 2019. Molecules  2020; 25(23): 5676.
 [http://dx.doi.org/10.3390/molecules25235676] [PMID:  33271992]

[12]
Rajendran P, Nandakumar N, Rengarajan T, et al. Antioxidants and human diseases. Clin Chim Acta  2014; 436: 332-47.
 [http://dx.doi.org/10.1016/j.cca.2014.06.004] [PMID:  24933428]

[13]
Manning RD Jr, Tian N, Meng S. Oxidative stress and antioxidant treatment in hypertension and the associated renal damage. Am J Nephrol  2005; 25(4): 311-7.
 [http://dx.doi.org/10.1159/000086411] [PMID:  15956781]

[14]
Briones AM, Touyz RM. Oxidative stress and hypertension: Current concepts. Curr Hypertens Rep  2010; 12(2): 135-42.
 [http://dx.doi.org/10.1007/s11906-010-0100-z] [PMID:  20424957]

[15]
Guzik TJ, Korbut R, Adamek GT. Nitric oxide and superoxide in inflammation and immune regulation. J Physiol Pharmacol  2003; 54(4): 469-87.
 [PMID:  14726604]

[16]
Dubois DE, Peugnet V, Turkieh A, Pinet F. Oxidative stress in cardiovascular diseases. Antioxidants  2020; 9(9): 864.
 [http://dx.doi.org/10.3390/antiox9090864] [PMID:  32937950]

[17]
Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology: Implications in hypertension. Histochem Cell Biol  2004; 122(4): 339-52.
 [http://dx.doi.org/10.1007/s00418-004-0696-7] [PMID:  15338229]

[18]
Wassmann S, Wassmann K, Nickenig G. Modulation of oxidant and antioxidant enzyme expression and function in vascular cells. Hypertension  2004; 44(4): 381-6.
 [http://dx.doi.org/10.1161/01.HYP.0000142232.29764.a7] [PMID:  15337734]

[19]
Chocry M, Leloup L. The NADPH oxidase family and its inhibitors. Antioxid Redox Signal  2020; 33(5): 332-53.
 [http://dx.doi.org/10.1089/ars.2019.7915] [PMID:  31826639]

[20]
Schulz E, Gori T, Münzel T. Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res  2011; 34(6): 665-73.
 [http://dx.doi.org/10.1038/hr.2011.39] [PMID:  21512515]

[21]
Sun HJ, Hou B, Wang X, Zhu XX, Li KX, Qiu LY. Endothelial dysfunction and cardiometabolic diseases: Role of long non-coding RNAs. Life Sci  2016; 167: 6-11.
 [http://dx.doi.org/10.1016/j.lfs.2016.11.005] [PMID:  27838210]

[22]
Blascke de Mello MM, Parente JM, Schulz R, Castro MM. Matrix Metalloproteinase (MMP)-2 activation by oxidative stress decreases aortic calponin-1 levels during hypertrophic remodeling in early hypertension. Vascul Pharmacol  2019; 116: 36-44.
 [http://dx.doi.org/10.1016/j.vph.2018.10.002] [PMID:  30339939]

[23]
Matsuoka H. Endothelial dysfunction associated with oxidative stress in human. Diabetes Res Clin Pract  2001; 54 (SUPPL. 2): S65-72.
 [http://dx.doi.org/10.1016/S0168-8227(01)00337-0]

[24]
Montezano AC, Dulak LM, Tsiropoulou S, Harvey A, Briones AM, Touyz RM. Oxidative stress and human hypertension: Vascular mechanisms, biomarkers, and novel therapies. Can J Cardiol  2015; 31(5): 631-41.
 [http://dx.doi.org/10.1016/j.cjca.2015.02.008] [PMID:  25936489]

[25]
Portaluppi F, Boari B, Manfredini R. Oxidative stress in essential hypertension. Curr Pharm Des  2004; 10(14): 1695-8.
 [http://dx.doi.org/10.2174/1381612043384619] [PMID:  15134566]

[26]
Luscher TF. The endothelium and cardiovascular disease a complex relation. N Eng J Med  1994; 330(15): 1081-3.

[27]
Simic DV, Mimic OJ, Pljesa EM, et al. Byproducts of oxidative protein damage and antioxidant enzyme activities in plasma of patients with different degrees of essential hypertension. J Hum Hypertens  2006; 20(2): 149-55.
 [http://dx.doi.org/10.1038/sj.jhh.1001945] [PMID:  16341053]

[28]
Ahmad A, Singhal U, Hossain MM, Islam N, Rizvi I. The role of the endogenous antioxidant enzymes and malondialdehyde in essential hypertension. J Clin Diagn Res  2013; 7(6): 987-90.
 [http://dx.doi.org/10.7860/JCDR/2013/5829.3091] [PMID:  23905086]

[29]
Niki E. Assessment of antioxidant capacity in vitro and in vivo. Free Radic Biol Med  2010; 49(4): 503-15.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2010.04.016] [PMID:  20416370]

[30]
Xu DP, Li Y, Meng X, et al. Natural antioxidants in foods and medicinal plants: Extraction, assessment and resources. Int J Mol Sci  2017; 18(1): 96.
 [http://dx.doi.org/10.3390/ijms18010096] [PMID:  28067795]

[31]
Neha K, Haider MR, Pathak A, Yar MS. Medicinal prospects of antioxidants: A review. Eur J Med Chem  2019; 178: 687-704.
 [http://dx.doi.org/10.1016/j.ejmech.2019.06.010] [PMID:  31228811]

[32]
Koppenol H, Koppenol H. Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and the ugly. Am J Physiol  1996; 271: C1424-37.

[33]
Russo G, Curcio F, Bulli G, et al. Oxidative Stress and Diseases. Clin Interv Aging  2018; 13: 757-72.

[34]
Massaro M, Scoditti E, Carluccio MA, De Caterina R. Oxidative stress and vascular stiffness in hypertension: A renewed interest for antioxidant therapies? Vascul Pharmacol  2019; 116(April): 45-50.
 [http://dx.doi.org/10.1016/j.vph.2019.03.004] [PMID:  30946986]

[35]
Rodrigo R, Prat H, Passalacqua W, Araya J, Guichard C, Bächler JP. Relationship between oxidative stress and essential hypertension. Hypertens Res  2007; 30(12): 1159-67.
 [http://dx.doi.org/10.1291/hypres.30.1159] [PMID:  18344620]

[36]
Levonen AL, Vähäkangas E, Koponen JK, Ylä HS. Antioxidant gene therapy for cardiovascular disease: Current status and future perspectives. Circulation  2008; 117(16): 2142-50.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.107.718585] [PMID:  18427144]

[37]
Larson A, Symons JD, Jalili T. Quercetin: A treatment for hypertension? - A review of efficacy and mechanisms. Pharmaceuticals (Basel)  2010; 3(1): 237-50.
 [http://dx.doi.org/10.3390/ph3010237] [PMID:  27713250]

[38]
Maarman GJ. Natural antioxidants as potential therapy, and a promising role for melatonin against pulmonary hypertension. Adv Exp Med Biol  2017; 967: 161-78.
 [http://dx.doi.org/10.1007/978-3-319-63245-2_10] [PMID:  29047086]

[39]
Pechanova O, Simko F. Chronic antioxidant therapy fails to ameliorate hypertension: Potential mechanisms behind. J Hypertens  2009; 27(6) (Suppl. 6): S32-6.
 [http://dx.doi.org/10.1097/01.hjh.0000358835.25934.5e] [PMID:  19633449]

[40]
Casas-Agustench P, López UP, Ros E, Bulló M, Salas SJ. Nuts, hypertension and endothelial function. Nutr Metab Cardiovasc Dis  2011; 21 (Suppl. 1): S21-33.
 [http://dx.doi.org/10.1016/j.numecd.2011.01.009]

[41]
John JH, Ziebland S, Yudkin P, Roe LS, Neil HAW. Effects of fruit and vegetable consumption on plasma antioxidant concentrations and blood pressure: A randomised controlled trial. Lancet  2002; 359(9322): 1969-74.
 [http://dx.doi.org/10.1016/S0140-6736(02)98858-6] [PMID:  12076551]

[42]
Conlin PR, Chow D, Miller ER III, et al. The effect of dietary patterns on blood pressure control in hypertensive patients: Results from the Dietary Approaches To Stop Hypertension (DASH) trial. Am J Hypertens  2000; 13(9): 949-55.
 [http://dx.doi.org/10.1016/S0895-7061(99)00284-8] [PMID:  10981543]

[43]
Graf E. Antioxidant potential of ferulic acid. Free Rad Bio Med  1992; 13(4): 435-48.

[44]
Alam MA. Anti-hypertensive effect of cereal antioxidant ferulic acid and its mechanism of action. Front Nutr  2019; 6: 121.
 [http://dx.doi.org/10.3389/fnut.2019.00121] [PMID:  31448280]

[45]
Zduńska K, Dana A, Kolodziejczak A, Rotsztejn H. Antioxidant properties of ferulic acid and its possible application. Skin Pharmacol Physiol  2018; 31(6): 332-6.
 [http://dx.doi.org/10.1159/000491755] [PMID:  30235459]

[46]
Alam MA, Sernia C, Brown L. Ferulic acid improves cardiovascular and kidney structure and function in hypertensive rats. J Cardiovasc Pharmacol  2013; 61(3): 240-9.
 [http://dx.doi.org/10.1097/FJC.0b013e31827cb600] [PMID:  23188120]

[47]
Suzuki A, Kagawa D, Fujii A, Ochiai R, Tokimitsu I, Saito I. Short and long-term effects of ferulic acid on blood pressure in spontaneously hypertensive rats. Am J Hypertens  2002; 15(4): 351-7.
 [http://dx.doi.org/10.1016/S0895-7061(01)02337-8] [PMID:  11991222]

[48]
Bumrungpert A, Lilitchan S, Tuntipopipat S, Tirawanchai N, Komindr S. Ferulic acid supplementation improves lipid profiles, oxidative stress, and inflammatory status in hyperlipidemic subjects: A randomized, double-blind, placebo-controlled clinical trial. Nutrients  2018; 10(6): 713.
 [http://dx.doi.org/10.3390/nu10060713] [PMID:  29865227]

[49]
Kwon EY, Do GM, Cho YY, Park YB, Jeon SM, Choi MS. Antiatherogenic property of ferulic acid in apolipoprotein E-deficient mice fed Western diet: Comparison with clofibrate. Food Chem Toxicol  2010; 48(8-9): 2298-303.
 [http://dx.doi.org/10.1016/j.fct.2010.05.063] [PMID:  20573577]

[50]
Qiao Y, He H, Zhang Z, et al. Long-term sodium ferulate supplementation scavenges oxygen radicals and reverses liver damage induced by iron overloading. Molecules  2016; 21(9): 1219.
 [http://dx.doi.org/10.3390/molecules21091219] [PMID:  27649133]

[51]
Cao Y, Zhang Y, Qi J, Liu R, Zhang H, He L. Ferulic acid inhibits H2O2-induced oxidative stress and inflammation in rat vascular smooth muscle cells via inhibition of the NADPH oxidase and NF-κB pathway. Int Immunopharmacol  2015; 28(2): 1018-25.
 [http://dx.doi.org/10.1016/j.intimp.2015.07.037] [PMID:  26330101]

[52]
Choi S, Il KH, Hag PS, et al. Endothelium-dependent vasodilation by ferulic acid in aorta from chronic renal hypertensive rats. Kidney Res Clin Pract  2012; 31(4): 227-33.
 [http://dx.doi.org/10.1016/j.krcp.2012.09.001] [PMID:  26889426]

[53]
Linz D, Hohl M, Schütze J, et al. Progression of kidney injury and cardiac remodeling in obese spontaneously hypertensive rats: The role of renal sympathetic innervation. Am J Hypertens  2015; 28(2): 256-65.
 [http://dx.doi.org/10.1093/ajh/hpu123] [PMID:  25023205]

[54]
Jiang RW, Lau KM, Hon PM, Mak T, Woo KS, Fung KP. Chemistry and biological activities of caffeic acid derivatives from Salvia miltiorrhiza. Curr Med Chem  2005; 12(2): 237-46.
 [http://dx.doi.org/10.2174/0929867053363397] [PMID:  15638738]

[55]
Effenberger F, Kiefer G. Stereochemistry of the Cycloaddition of Sulfonyl Isocyanates and N-Sulfinylsulfonamides to Enol Ethers. Angew Chemie Int Ed  2021; 6(11): 951-2. Available from: [https://onlinelibrary.wiley.com/toc/15213773a/1967/6/11].

[56]
Koga M, Nakagawa S, Kato A, Kusumi I. Caffeic acid reduces oxidative stress and microglial activation in the mouse hippocampus. Tissue Cell  2019; 60(July): 14-20.
 [http://dx.doi.org/10.1016/j.tice.2019.07.006] [PMID:  31582013]

[57]
Sato Y, Itagaki S, Kurokawa T, et al. In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid. Int J Pharm  2011; 403(1-2): 136-8.
 [http://dx.doi.org/10.1016/j.ijpharm.2010.09.035] [PMID:  20933071]

[58]
Gonthier MP, Verny MA, Besson C, Rémésy C, Scalbert A. Chlorogenic acid bioavailability largely depends on its metabolism by the gut microflora in rats. J Nutr  2003; 133(6): 1853-9.
 [http://dx.doi.org/10.1093/jn/133.6.1853] [PMID:  12771329]

[59]
Gülçin I. Antioxidant activity of caffeic acid (3,4-dihydroxycinnamic acid). Toxicology  2006; 217(2-3): 213-20.
 [http://dx.doi.org/10.1016/j.tox.2005.09.011] [PMID:  16243424]

[60]
De Alencar SA, De Morais PL, Da Silva RRE, et al. Pharmacological screening of the phenolic compound caffeic acid using rat aorta, uterus and ileum smooth muscle. Chem Biol Interact  2020; 332: 109269.
 [http://dx.doi.org/10.1016/j.cbi.2020.109269] [PMID:  32991861]

[61]
Li PG, Xu JW, Ikeda K, et al. Caffeic acid inhibits vascular smooth muscle cell proliferation induced by angiotensin II in stroke-prone spontaneously hypertensive rats. Hypertens Res  2005; 28(4): 369-77.
 [http://dx.doi.org/10.1291/hypres.28.369] [PMID:  16138568]

[62]
Bhullar KS, Lassalle CG, Touaibia M, Rupasinghe HPV. Antihypertensive effect of caffeic acid and its analogs through dual renin–angiotensin–aldosterone system inhibition. Eur J Pharmacol  2014; 730(1): 125-32.
 [http://dx.doi.org/10.1016/j.ejphar.2014.02.038] [PMID:  24631256]

[63]
Oboh G, Ojueromi OO, Ademosun AO, et al. Effects of caffeine and caffeic acid on selected biochemical parameters in L‐NAME‐induced hypertensive rats. J Food Biochem  2021; 45(3): e13384.
 [http://dx.doi.org/10.1111/jfbc.13384] [PMID:  32725646]

[64]
Agunloye OM, Oboh G, Ademiluyi AO, et al. Cardio-protective and antioxidant properties of caffeic acid and chlorogenic acid: Mechanistic role of angiotensin converting enzyme, cholinesterase and arginase activities in cyclosporine induced hypertensive rats. Biomed Pharmacother  2019; 109(109): 450-8.
 [http://dx.doi.org/10.1016/j.biopha.2018.10.044] [PMID:  30399581]

[65]
Akinyemi AJ, Oboh G, Ademiluyi AO, Boligon AA, Athayde ML. Effect of two ginger varieties on arginase activity in hypercholesterolemic rats. J Acupunct Meridian Stud  2016; 9(2): 80-7.
 [http://dx.doi.org/10.1016/j.jams.2015.03.003] [PMID:  27079229]

[66]
Berk BC. Angiotensin II signal transduction in vascular smooth muscle: Pathways activated by specific tyrosine kinases. J Am Soc Nephrol  1999; 10(1) (Suppl. 11): S62-8.
 [PMID:  9892142]

[67]
Jiang N, Zhang M, Meng X, Sun B. Effects of curcumin on the pharmacokinetics of amlodipine in rats and its potential mechanism. Pharm Biol  2020; 58(1): 465-8.
 [http://dx.doi.org/10.1080/13880209.2020.1764060] [PMID:  32432949]

[68]
Shabbir U, Rubab M, Daliri EB, Chelliah R, Javed A, Oh D. The role of gut microbiota. Nutrients  2021; 13(1): 206.

[69]
Kotha RR, Luthria DL. Curcumin: Biological, pharmaceutical, nutraceutical, and analytical aspects. Molecules  2019; 24(16): 2930.
 [http://dx.doi.org/10.3390/molecules24162930] [PMID:  31412624]

[70]
Chainoglou E, Hadjipavlou LD. Curcumin analogues and derivatives with anti-proliferative and anti-inflammatory activity: Structural characteristics and molecular targets. Expert Opin Drug Discov  2019; 14(8): 821-42.
 [http://dx.doi.org/10.1080/17460441.2019.1614560] [PMID:  31094233]

[71]
Sundar DKS, Houreld N, Abrahamse H. Therapeutic potential and recent advances of curcumin in the treatment of aging-associated diseases. Molecules  2018; 23(4): 835.
 [http://dx.doi.org/10.3390/molecules23040835] [PMID:  29621160]

[72]
Filardi T, Varì R, Ferretti E, Zicari A, Morano S, Santangelo C. Curcumin: Could this compound be useful in pregnancy and pregnancy-related complications? Nutrients  2020; 12(10): 3179.
 [http://dx.doi.org/10.3390/nu12103179] [PMID:  33080891]

[73]
Alidadi M, Liberale L, Montecucco F, et al. Protective effects of curcumin on endothelium: An updated review. Adv Exp Med Biol  2021; 1291: 103-19.
 [PMID:  34331686]

[74]
Nakmareong S, Kukongviriyapan U, Pakdeechote P, et al. Antioxidant and vascular protective effects of curcumin and tetrahydrocurcumin in rats with l-NAME-induced hypertension. Naunyn Schmiedebergs Arch Pharmacol  2011; 383(5): 519-29.
 [http://dx.doi.org/10.1007/s00210-011-0624-z] [PMID:  21448566]

[75]
Hlavačková L, Janegová A, Uličná O, Janega P, Černá A, Babál P. Spice up the hypertension diet - curcumin and piperine prevent remodeling of aorta in experimental L-NAME induced hypertension. Nutr Metab (L  2011  8(1): 72.
 [http://dx.doi.org/10.1186/1743-7075-8-72] [PMID: 22005253]

[76]
Kunchandy E, Rao MNA. Oxygen radical scavenging activity of curcumin. Int J Pharm  1990; 58(3): 237-40.
 [http://dx.doi.org/10.1016/0378-5173(90)90201-E]

[77]
Rachmawati H, Soraya IS, Kurniati NF, Rahma A. In vitro study on antihypertensive and antihypercholesterolemic effects of a curcumin nanoemulsion. Sci Pharm  2016; 84(1): 131-40.
 [http://dx.doi.org/10.3797/scipharm.ISP.2015.05] [PMID:  27110504]

[78]
Shome S, Talukdar AD, Choudhury MD, Bhattacharya MK, Upadhyaya H. Curcumin as potential therapeutic natural product: A nanobiotechnological perspective. J Pharm Pharmacol  2016; 68(12): 1481-500.
 [http://dx.doi.org/10.1111/jphp.12611] [PMID:  27747859]

[79]
Boonla O, Kukongviriyapan U, Pakdeechote P, et al. Curcumin improves endothelial dysfunction and vascular remodeling in 2K-1C hypertensive rats by raising nitric oxide availability and reducing oxidative stress. Nitric Oxide - Biol Chem  2014; 42: 44-53.
 [http://dx.doi.org/10.1016/j.niox.2014.09.001]

[80]
Li HB, Xu ML, Du MM, et al. Curcumin ameliorates hypertension via gut-brain communication in spontaneously hypertensive rat. Toxicol Appl Pharmacol  2021; 429(June): 115701.
 [http://dx.doi.org/10.1016/j.taap.2021.115701] [PMID:  34453990]

[81]
Han Y, Sun HJ, Tong Y, et al. Curcumin attenuates migration of vascular smooth muscle cells via inhibiting NFκB-mediated NLRP3 expression in spontaneously hypertensive rats. J Nutr Biochem  2019; 72: 108212.
 [http://dx.doi.org/10.1016/j.jnutbio.2019.07.003] [PMID:  31473513]

[82]
Tubsakul A, Sangartit W, Pakdeechote P, Kukongviriyapan V, Apaijit K, Kukongviriyapan U. Curcumin mitigates hypertension, endothelial dysfunction and oxidative stress in rats with chronic exposure to lead and cadmium. Tohoku J Exp Med  2021; 253(1): 69-76.
 [http://dx.doi.org/10.1620/tjem.253.69] [PMID:  33473064]

[83]
Santos PJR, Strahler TR, Bassett CJ, Bispham NZ, Chonchol MB, Seals DR. Curcumin older adults by increasing nitric oxide bioavailability and reducing oxidative stress. Aging-Us  2017; 9(1): 187-208.
 [http://dx.doi.org/10.18632/aging.101149] [PMID:  28070018]

[84]
Sunagawa Y, Funamoto M, Shimizu K, et al. Curcumin, an inhibitor of p300-hat activity, suppresses the development of hypertension-induced left ventricular hypertrophy with preserved ejection fraction in dahl rats. Nutrients  2021; 13(8): 2608.
 [http://dx.doi.org/10.3390/nu13082608] [PMID:  34444769]

[85]
Su Q, Liu JJ, Cui W, et al. Alpha lipoic acid supplementation attenuates reactive oxygen species in hypothalamic paraventricular nucleus and sympathoexcitation in high salt-induced hypertension. Toxicol Lett  2016; 241: 152-8.
 [http://dx.doi.org/10.1016/j.toxlet.2015.10.019] [PMID:  26518973]

[86]
Yao Y, Wang W, Li M, et al. Curcumin exerts its anti-hypertensive effect by down-regulating the at1 receptor in vascular smooth muscle cells. Sci Rep  2016; 6(1): 25579.
 [http://dx.doi.org/10.1038/srep25579] [PMID:  27146402]

[87]
Gradman AH. AT1-receptor blockers: Differences that matter. J Hum Hypertens  2002; 16(S3) (Suppl. 3): S9-S16.
 [http://dx.doi.org/10.1038/sj.jhh.1001434] [PMID:  12140723]

[88]
Unger T. Pharmacology of AT 1-receptor Blockers. Blood Press  2001; 10(3): 5-10.
 [http://dx.doi.org/10.1080/08037050152518302] [PMID:  11683476]

[89]
Stefanska J, Pawliczak R. Apocynin: Molecular aptitudes. Mediators Inflamm  2008; 2008: 106507.

[90]
Virdis A, Gesi M, Taddei S. Impact of apocynin on vascular disease in hypertension. Vascul Pharmacol  2016; 87: 1-5.
 [http://dx.doi.org/10.1016/j.vph.2016.08.006] [PMID:  27569106]

[91]
Kovacevic S, Ivanov M, Zivotic M, et al. Immunohistochemical analysis of 4-hne, ngal, and ho-1 tissue expression after apocynin treatment and hbo preconditioning in postischemic acute kidney injury induced in spontaneously hypertensive rats. Antioxidants  2021; 10(8): 1163.
 [http://dx.doi.org/10.3390/antiox10081163] [PMID:  34439411]

[92]
Savla SR, Laddha AP, Kulkarni YA. Pharmacology of apocynin: A natural acetophenone. Drug Metab Rev  2021; 53(4): 542-62.
 [http://dx.doi.org/10.1080/03602532.2021.1895203] [PMID:  33689526]

[93]
Bäumer AT, Krüger CA, Falkenberg J, et al. The NAD(P)H oxidase inhibitor apocynin improves endothelial NO/superoxide balance and lowers effectively blood pressure in spontaneously hypertensive rats: Comparison to calcium channel blockade. Clin Exp Hypertens  2007; 29(5): 287-99.
 [http://dx.doi.org/10.1080/10641960701500398] [PMID:  17653964]

[94]
Liu F, Fan LM, Michael N, Li JM. In vivo and in silico characterization of apocynin in reducing organ oxidative stress: A pharmacokinetic and pharmacodynamic study. Pharmacol Res Perspect  2020; 8(4): e00635.
 [http://dx.doi.org/10.1002/prp2.635] [PMID:  32761799]

[95]
Hu L, Zhang Y, Lim P, et al. Apocynin but not L-arginine prevents and reverses dexamethasone-induced hypertension in the rat. Am J Hypertens  2006; 19(4): 413-8.
 [http://dx.doi.org/10.1016/j.amjhyper.2005.09.023] [PMID:  16580579]

[96]
Tain YL, Hsu CN, Huang LT, Lau YT. Apocynin attenuates oxidative stress and hypertension in young spontaneously hypertensive rats independent of ADMA/NO pathway. Free Radic Res  2012; 46(1): 68-76.
 [http://dx.doi.org/10.3109/10715762.2011.639069] [PMID:  22070348]

[97]
Perassa LA, Graton ME, Potje SR, et al. Apocynin reduces blood pressure and restores the proper function of vascular endothelium in SHR. Vascul Pharmacol  2016; 87: 38-48.
 [http://dx.doi.org/10.1016/j.vph.2016.06.005] [PMID:  27353052]

[98]
Costa CA, Amaral TAS, Carvalho LCRM, et al. Antioxidant treatment with tempol and apocynin prevents endothelial dysfunction and development of renovascular hypertension. Am J Hypertens  2009; 22(12): 1242-9.
 [http://dx.doi.org/10.1038/ajh.2009.186] [PMID:  19779472]

[99]
Li Y, Li X, Guo S, et al. Apocynin attenuates oxidative stress and cardiac fibrosis in angiotensin II-induced cardiac diastolic dysfunction in mice. Acta Pharmacol Sin  2013; 34(3): 352-9.
 [http://dx.doi.org/10.1038/aps.2012.164] [PMID:  23334241]

[100]
Nwokocha CR, Baker A, Douglas D, McCalla G, Nwokocha M, Brown PD. Apocynin ameliorates cadmium-induced hypertension through elevation of endothelium nitric oxide synthase. Cardiovasc Toxicol  2013; 13(4): 357-63.
 [http://dx.doi.org/10.1007/s12012-013-9216-0] [PMID:  23703608]

[101]
Patil BM, Unger BS. Apocynin improves endothelial function and prevents the development of hypertension in fructose fed rat. Indian J Pharmacol  2009; 41(5): 208-12.
 [http://dx.doi.org/10.4103/0253-7613.58508] [PMID:  20177490]

[102]
Duarte J, Jiménez R, O’Valle F, et al. Protective effects of the flavonoid quercetin in chronic nitric oxide deficient rats. J Hypertens  2002; 20(9): 1843-54.
 [http://dx.doi.org/10.1097/00004872-200209000-00031] [PMID:  12195128]

[103]
Ibarra M, Moreno L, Vera R, et al. Effects of the flavonoid quercetin and its methylated metabolite isorhamnetin in isolated arteries from spontaneously hypertensive rats. Planta Med  2003; 69(11): 995-1000.
 [http://dx.doi.org/10.1055/s-2003-45144] [PMID:  14735435]

[104]
Shah PM, Vishnu Priya V, Gayathri R. Quercetin – A flavonoid:A systematic review. 2016. Available from: https://www.researchgate. net/publication/308097976_Quercetin_-_A_flavonoidA_systematic_review (Accessed on: 2021 Dec 27).

[105]
Andres S, Pevny S, Ziegenhagen R, et al. Safety aspects of the use of quercetin as a dietary supplement. Mol Nutr Food Res  2018; 62(1): 1700447.
 [http://dx.doi.org/10.1002/mnfr.201700447] [PMID:  29127724]

[106]
Serban MC, Sahebkar A, Zanchetti A, et al. Effects of quercetin on blood pressure: A systematic review and meta‐analysis of randomized controlled trials. J Am Heart Assoc  2016; 5(7): e002713.
 [http://dx.doi.org/10.1161/JAHA.115.002713] [PMID:  27405810]

[107]
Mackraj I, Govender T, Ramesar S. The antihypertensive effects of quercetin in a salt-sensitive model of hypertension. J Cardiovasc Pharmacol  2008; 51(3): 239-45.
 [http://dx.doi.org/10.1097/FJC.0b013e318162011f] [PMID:  18356687]

[108]
García SMF, Galisteo M, Villar IC, et al. Effects of chronic quercetin treatment in experimental renovascular hypertension. Mol Cell Biochem  2005; 270(1-2): 147-55.
 [http://dx.doi.org/10.1007/s11010-005-4503-0] [PMID:  15792364]

[109]
Duarte J, Pérez PR, Vargas F, et al. Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats. Br J Pharmacol  2001; 133(1): 117-24.
 [http://dx.doi.org/10.1038/sj.bjp.0704064] [PMID:  11325801]

[110]
Sedeek M, Hébert RL, Kennedy CR, Burns KD, Touyz RM. Molecular mechanisms of hypertension: Role of Nox family NADPH oxidases. Curr Opin Nephrol Hypertens  2009; 18(2): 122-7.
 [http://dx.doi.org/10.1097/MNH.0b013e32832923c3] [PMID:  19430333]

[111]
Montenegro MF, Neto NEM, Dias Jr CA, et al. Quercetin restores plasma nitrite and nitroso species levels in renovascular hypertension. Naunyn Schmiedebergs Arch Pharmacol  2010; 382(4): 293-301.
 [http://dx.doi.org/10.1007/s00210-010-0546-1] [PMID:  20694791]

[112]
Choi S, Ryu KH, Park SH, et al. Direct vascular actions of quercetin in aorta from renal hypertensive rats. Kidney Res Clin Pract  2016; 35(1): 15-21.
 [http://dx.doi.org/10.1016/j.krcp.2015.12.003] [PMID:  27069853]

[113]
Bylund DB. Subtypes of α 1 ‐ and α 2 ‐adrenergic receptors. FASEB J  1992; 6(3): 832-9.
 [http://dx.doi.org/10.1096/fasebj.6.3.1346768] [PMID:  1346768]

[114]
Pereira SC, Parente JM, Belo VA, et al. Quercetin decreases the activity of matrix metalloproteinase-2 and ameliorates vascular remodeling in renovascular hypertension. Atherosclerosis  2018; 270: 146-53.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2018.01.031] [PMID:  29425960]

[115]
Wang X, Ouyang YY, Liu J, Zhao G. Flavonoid intake and risk of CVD: A systematic review and meta-analysis of prospective cohort studies. Br J Nutr  2014; 111(1): 1-11.
 [http://dx.doi.org/10.1017/S000711451300278X] [PMID:  23953879]

[116]
Ożarowski M, Mikołajczak PL, Kujawski R, et al. Pharmacological effect of quercetin in hypertension and its potential application in pregnancy-induced hypertension: Review of in vitro, in vivo, and clinical studies. Evidence-based Complement Altern Med  2018; 2018: 7421489.

[117]
Patel RV, Mistry BM, Shinde SK, Syed R, Singh V, Shin HS. Therapeutic potential of quercetin as a cardiovascular agent. Eur J Med Chem  2018; 155: 889-904.
 [http://dx.doi.org/10.1016/j.ejmech.2018.06.053] [PMID:  29966915]

[118]
Mendes Jr LG, Monteiro MMO, Carvalho AS, Queiroz TM, Braga VA. Oral supplementation with the rutin improves cardiovagal baroreflex sensitivity and vascular reactivity in hypertensive rats. Appl Physiol Nutr Metab  2013; 38(11): 1099-106.
 [http://dx.doi.org/10.1139/apnm-2013-0091] [PMID:  24053516]

[119]
Monteiro M, França SM, Alves N, Porpino S, Braga V. Quercetin improves baroreflex sensitivity in spontaneously hypertensive rats. Molecules  2012; 17(11): 12997-3008.
 [http://dx.doi.org/10.3390/molecules171112997] [PMID:  23117438]

[120]
Fogacci F, Rizzo M, Krogager C, et al. Safety evaluation of α‐lipoic acid supplementation: A systematic review and meta‐analysis of randomized placebo‐controlled clinical studies. Antioxidants  2020; 9(10): 1011.
 [http://dx.doi.org/10.3390/antiox9101011] [PMID:  33086555]

[121]
Wollin SD, Jones PJH. Recent advances in nutritional sciences. alpha -lipoic acid and cardiovascular. J Nutr  2003; 133: 3327-30.
 [http://dx.doi.org/10.1093/jn/133.11.3327] [PMID:  14608040]

[122]
Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alphalipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential. Biochim Biophys Acta, Gen Subj  2009; 1790(10): 1149-60.
 [http://dx.doi.org/10.1016/j.bbagen.2009.07.026] [PMID:  19664690]

[123]
Salinthone S, Yadav V, Bourdette D, Carr D. Lipoic acid: A novel therapeutic approach for multiple sclerosis and other chronic inflammatory diseases of the CNS. Endocrine‚ Metab Immune Disord Targets  2008; 8(2): 132-42.
 [http://dx.doi.org/10.2174/187153008784534303]

[124]
Han D, Handelman G, Marcocci L, et al. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors  1997; 6(3): 321-38.
 [http://dx.doi.org/10.1002/biof.5520060303] [PMID:  9288403]

[125]
Ergür BU, Çilaker Mıcılı S, Yilmaz O, Akokay P. The effects of α-lipoic acid on aortic injury and hypertension in the rat remnant kidney (5/6 nephrectomy) model. Anatol J Cardiol  2015; 15(16): 443-9.
 [http://dx.doi.org/10.5152/akd.2014.5483] [PMID:  25430409]

[126]
Heinisch BB, Francesconi M, Mittermayer F, et al. Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: A placebo-controlled randomized trial. Eur J Clin Invest  2010; 40(2): 148-54.
 [http://dx.doi.org/10.1111/j.1365-2362.2009.02236.x] [PMID:  20050880]

[127]
Kumagai H, Oshima N, Matsuura T, et al. Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure. Hypertens Res  2012; 35(2): 132-41.
 [http://dx.doi.org/10.1038/hr.2011.208] [PMID:  22170390]

[128]
Huang YP, Jin HY, Yu HP. Inhibitory effects of alpha-lipoic acid on oxidative stress in the rostral ventrolateral medulla in rats with salt-induced hypertension. Int J Mol Med  2017; 39(2): 430-6.
 [http://dx.doi.org/10.3892/ijmm.2016.2846] [PMID:  28035366]

[129]
Queiroz T, Guimarães D, Mendes Jr L, Braga V. α-lipoic acid reduces hypertension and increases baroreflex sensitivity in renovascular hypertensive rats. Molecules  2012; 17(11): 13357-67.
 [http://dx.doi.org/10.3390/molecules171113357] [PMID:  23143148]

[130]
Queiroz TM, Xia H, Filipeanu CM, Braga VA, Lazartigues E. α-Lipoic acid reduces neurogenic hypertension by blunting oxidative stress-mediated increase in ADAM17. Am J Physiol - Hear Circ Physiol  2015; 309(5): H926.

[131]
Cheng PY, Lee YM, Chung MT, Shih YC, Yen MH. Role of AMP-activated protein kinase in α-lipoic acid-induced vasodilatation in spontaneously hypertensive rats. Am J Hypertens  2012; 25(2): 152-8.
 [http://dx.doi.org/10.1038/ajh.2011.196] [PMID:  22052076]

[132]
Vasdev S, Gill V, Parai S, Gadag V. Dietary lipoic acid supplementation attenuates hypertension in Dahl salt sensitive rats. Mol Cell Biochem  2005; 275(1-2): 135-41.
 [http://dx.doi.org/10.1007/s11010-005-1095-7] [PMID:  16335793]

[133]
Louhelainen M, Merasto S, Finckenberg P, Lapatto R, Cheng ZJ, Mervaala EMA. Lipoic acid supplementation prevents cyclosporine-induced hypertension and nephrotoxicity in spontaneously hypertensive rats. J Hypertens  2006; 24(5): 947-56.
 [http://dx.doi.org/10.1097/01.hjh.0000222766.37971.9f] [PMID:  16612258]

[134]
Martinelli I, Tomassoni D, Roy P, Di Cesare ML, Amenta F, Tayebati SK. Antioxidant properties of alpha-lipoic (Thioctic) acid treatment on renal and heart parenchyma in a rat model of hypertension. Antioxidants  2021; 10(7): 1006.
 [http://dx.doi.org/10.3390/antiox10071006] [PMID:  34201726]

[135]
Ong SLH, Vohra H, Zhang Y, Sutton M, Whitworth JA. The effect of alpha-lipoic acid on mitochondrial superoxide and glucocorticoid-induced hypertension. Oxid Med Cell Longev  2013; 2013: 51704.
 [http://dx.doi.org/10.1155/2013/517045]

[136]
Tayebati SK, Tomassoni D, Di Cesare Mannelli L, Amenta F. Effect of treatment with the antioxidant alpha-lipoic (thioctic) acid on heart and kidney microvasculature in spontaneously hypertensive rats. Clin Exp Hypertens  2016; 38(1): 30-8.
 [http://dx.doi.org/10.3109/10641963.2015.1047950] [PMID:  26207883]

[137]
Burton FBM, Sesso HD. Whole food versus supplement: Comparing the clinical evidence of tomato intake and lycopene supplementation on cardiovascular risk factors. Adv Nutr  2014; 5(5): 457-85.
 [http://dx.doi.org/10.3945/an.114.005231] [PMID:  25469376]

[138]
Mozos I, Stoian D, Caraba A, Malainer C, Horbańczuk JO, Atanasov AG. Lycopene and vascular health. Front Pharmacol  2018; 9: 521.
 [http://dx.doi.org/10.3389/fphar.2018.00521] [PMID:  29875663]

[139]
Kim JY, Paik JK, Kim OY, et al. Effects of lycopene supplementation on oxidative stress and markers of endothelial function in healthy men. Atherosclerosis  2011; 215(1): 189-95.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2010.11.036] [PMID:  21194693]

[140]
Paran E, Novack V, Engelhard YN, Hazan-Halevy I. The effects of natural antioxidants from tomato extract in treated but uncontrolled hypertensive patients. Cardiovasc Drugs Ther  2009; 23(2): 145-51.
 [http://dx.doi.org/10.1007/s10557-008-6155-2] [PMID:  19052855]

[141]
Khan NI, Noori S, Mahboob T. Efficacy of lycopene on modulation of renal antioxidant enzymes, ACE and ACE gene expression in hyperlipidaemic rats. J Renin Angiotensin Aldosterone Syst  2016; 17(3): 1470320316664611.
 [http://dx.doi.org/10.1177/1470320316664611] [PMID:  27678388]

[142]
Ferreira SP, Aparicio R, Carrón R, Sevilla MÁ, Monroy RJ, Montero MJ. Lycopene-supplemented diet ameliorates cardiovascular remodeling and oxidative stress in rats with hypertension induced by Angiotensin II. J Funct Foods  2018; 47: 279-87.
 [http://dx.doi.org/10.1016/j.jff.2018.06.002]

[143]
Zeng J, Zhao J, Dong B, et al. Lycopene protects against pressure overload-induced cardiac hypertrophy by attenuating oxidative stress. J Nutr Biochem  2019; 66: 70-8.
 [http://dx.doi.org/10.1016/j.jnutbio.2019.01.002] [PMID:  30772766]

[144]
Ferreira SP, Carrón R, Montero MJ, Sevilla MÁ. The antihypertensive and antihypertrophic effect of lycopene is not affected by and is independent of age. J Funct Foods  2021; 85: 104656.
 [http://dx.doi.org/10.1016/j.jff.2021.104656]
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DOI https://dx.doi.org/10.2174/1573402118666221003095317	Print ISSN 1573-4021
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Isolated Natural Antioxidants as a new Possible Therapeutic Alternative for the Treatment of Hypertension

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