Phytotherapy of Hypertension: An Updated Overview

Mohammed       Ajebli; Mohamed       Eddouks
doi:10.2174/1871530320666191227104648
Abstract

Background: Cardiovascular disorders are the leading cause of morbidity and mortality throughout the globe. Hypertension is the main risk factor that contributes to the development of many diseases. The use of herbal therapies, medicinal plants and their derivatives for the remedy and management of hypertension is well-recognized and popular among a wide part of the world population.
Methods: The aim of the current review was to collect, treat, and critically analyze the published research studies relative to experimental and clinical investigations which have studied the blood pressure lowering abilities of medicinal plant derivatives in the last decade. This review was organized into three principal axes; the first axis was attributed to the in vivo and in vitro experimental studies; the second treated the clinical trials; while, the last one is devoted to analyze the mechanisms of action underlying the therapeutic antihypertensive effectiveness of phytochemicals.
Results: Different types of extracts and isolated molecules obtained from a large variety of species demonstrated their efficiency in improving the increase of blood pressure either experimentally or clinically. Medicinal species such as garlic (Allium sativum), celery (Apium graveolens), Black Cumin (Nigella sativa) and Ginseng (Panax) are among the most common and therapeutically used plant derivatives for controlling hypertension while Asteraceae, Apiaceae and Rosaceae are among the botanical families which were frequently studied in the last decade. Isolated compounds such as allicin and apigenin have received more interest in this field. Recent evidence from clinical trials suggests that a wide variety of herbal preparations and plant extracts or natural isolated compounds have a favorable therapeutic impact on blood flow. Interestingly, phytochemicals can either act directly on blood vessels via a vasorelaxant effect involving a variety of signaling cascades or indirectly through inhibiting or stimulating diversity of systems such as angiotensin-converting enzyme (ACE), renin-angiotensin system (RAS) or the diuretic activity. Hence, based on the findings of the present review medicinal plant derivatives could be used as preventive and curative agents in the case of cardiovascular disorders, particularly hypertension and could play a promoting function for the discovery of new antihypertensive agents.
Conclusion: The analysis of the published data shows that a great effort remains to be done to investigate the medicinal plants cited as antihypertensive through published ethnopharmacological surveys. The analysis of the literature in this field shows the lack of standardization at the level of experimental study methods as well as the need to study purified molecules. Moreover, the mechanistic studies when they exist remain in the whole partial. On the other hand, few advanced clinical studies have been conducted. Finally, the determination of the efficacy/safety ratio remains absent in almost all studies.
Keywords: Hypertension, blood pressure, medicinal plants, phytochemicals, mechanisms of action, angiotensin-converting enzyme.
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[1] 
Lawrence, R.K. Definition and Classification of Arterial Pressure Phenotypes. Disorders of blood pressure regulation: Phenotypes, Mechanisms, Therapeutic Options; Adel, E.; Berbari, G.M; ., Eds.;Springer Nature:: Cham, Switzerland, 2018, pp. 1-9.
[2] 
World Health Organization. Available at:, who.int/features/qa/82/en/ (Accessed on July 23,2018)
[3] 
Rawat, P.S.; Pawan, K.; Kumar, V. Antihypertensive medicinal plants and their mode of action. J. Herb. Med.,  2016, 6(3), 107-118.
[http://dx.doi.org/10.1016/j.hermed.2016.06.001] 
[4] 
Lawrence, J.; Epstein, M.D.; Steven, M. The Harvard medical school guide to lowering your blood pressure; McGraw Hill, 2006. 
[5] 
Van Zwieten, P.A. Handbook of Hypertension: Pharmacology of Antihypertensive Drugs; Elsevier: Amsterdam, New York, Oxford, 1984. 
[6] 
Calixto, J.B. Twenty-five years of research on medicinal plants in Latin America: a personal view. J. Ethnopharmacol.,  2005, 100(1-2), 131-134.
[http://dx.doi.org/10.1016/j.jep.2005.06.004] [PMID: 16006081] 
[7] 
World Health Organization. Traditional Medicine (CVDs); World Health Organization: Geneva, 2014. 
[8] 
Stoclet, J.C.; Chataigneau, T.; Ndiaye, M.; Oak, M.H.; El Bedoui, J.; Chataigneau, M.; Schini-Kerth, V.B. Vascular protection by dietary polyphenols. Eur. J. Pharmacol.,  2004, 500(1-3), 299-313.
[http://dx.doi.org/10.1016/j.ejphar.2004.07.034] [PMID: 15464042] 
[9] 
Coffey, D.S.; Isaacs, J.T. Requirements for an idealized animal model in prostatic cancer. Models for prostate cancer; Murphy,, G.P.; Liss, A.R., Eds.; Progress in Clinical and Biological Research: New York, 1980, pp. 379-411.
[10] 
Gross, D.R. Animal models in cardiovascular research, 3rd ed; Springer Dordrecht: New York, 2009. 
[http://dx.doi.org/10.1007/978-0-387-95962-7] 
[11] 
Gonzalez-Nicolini, V.; Fussenegger, M. In vitro assays for anticancer drug discovery--a novel approach based on engineered mammalian cell lines. Anticancer Drugs,  2005, 16(3), 223-228.
[http://dx.doi.org/10.1097/00001813-200503000-00001] [PMID: 15711174] 
[12] 
Chandrashekhar, H. Pooja, R.K.; Sunil, D. In vitro Bioassay Techniques for Anticancer Drug Discovery and Development; CRC Press, 2017. 
[13] 
Gross, R.D. Animal Models.Cardiovascular Research, 3rd ed; Gross, R.D., Ed.; Springer: New York, 2009, pp. 45-52.
[http://dx.doi.org/10.1007/978-0-387-95962-7] 
[14] 
La Clair, J.J. Natural product mode of action (MOA) studies: a link between natural and synthetic worlds. Nat. Prod. Rep.,  2010, 27(7), 969-995.
[http://dx.doi.org/10.1039/b909989c] [PMID: 20422068] 
[15] 
Clark, J.L.; Zahradka, P.; Taylor, C.G. Efficacy of flavonoids in the management of high blood pressure. Nutr. Rev.,  2015, 73(12), 799-822.
[http://dx.doi.org/10.1093/nutrit/nuv048] [PMID: 26491142] 
[16] 
Menezes, I.A.C.; Barreto, C.M.N.; Antoniolli, A.R.; Santos, M.R.V.; de Sousa, D.P. Hypotensive activity of terpenes found in essential oils. Z. Natforsch. C J. Biosci.,  2010, 65(9-10), 562-566.
[http://dx.doi.org/10.1515/znc-2010-9-1005] [PMID: 21138056] 
[17] 
Santos, M.R.V.; Moreira, F.V.; Fraga, B.P.; Souza, D.P.; Bonjardim, L.R.; Quintans-Junior, L.J. Cardiovascular effects of monoterpenes: a review. Rev. Bras. Farmacogn.,  2011, 21, 764-771.
[http://dx.doi.org/10.1590/S0102-695X2011005000119] 
[18] 
Patwardhan, B. Ayurveda: the “designer” medicine: A review of ethnopharmacology and bioprospecting research. Indian. Drugs,  2000, 14, 213-227.
[19] 
Patwardhan, B.; Chaguturu, R. Innovative approaches in drug discovery: Ethnopharmacology, systems biology, and holistic targeting; Elsevier/Academic Press: Amsterdam, 2017. 
[20] 
Kinghorn, A.D.; Carcache de Blanco, E.J.; Chai, H.B.; Orjala, J.; Farnsworth, N.R.; Soejarto, D.D.; Oberlies, N.H.; Wani, M.C.; Kroll, D.J.; Pearce, C.J.; Swanson, S.M.; Kramer, R.A.; Rose, W.C.; Fairchild, C.R.; Vite, G.D.; Emanuel, S.; Jarjoura, D.; Cope, F.O. Discovery of anticancer agents of diverse natural origin. Pure Appl. Chem.,  2009, 81(6), 1051-1063.
[http://dx.doi.org/10.1351/PAC-CON-08-10-16] [PMID: 20046887] 
[21] 
Gurib-Fakim, A. Medicinal plants: traditions of yesterday and drugs of tomorrow. Mol. Aspects Med.,  2006, 27(1), 1-93.
[http://dx.doi.org/10.1016/j.mam.2005.07.008] [PMID: 16105678] 
[22] 
Shah, B.N.; Seth, A.K. Textbook of pharmacognosy and phytochemistry; Elsevier: New Delhi, 2010. 
[23] 
Zhu, Y.; Anand, R.; Geng, X.; Ding, Y. A mini review: Garlic extract and vascular diseases. Neurol. Res.,  2018, 40(6), 421-425.
[http://dx.doi.org/10.1080/01616412.2018.1451269] [PMID: 29557277] 
[24] 
Skidmore-Roth, L. Mosby’s handbook of herbs & natural supplements; Mosby: St. Louis, Mo, 2012. 
[25] 
Zhou, X.; Wang, F.; Zhou, R.; Song, X.; Xie, M. Apigenin: A current review on its beneficial biological activities. Food. Biochem.,  2017, 41,e12376.
[26] 
Jin, B.H.; Qian, L.B.; Chen, S.; Li, J.; Wang, H.P.; Bruce, I.C.; Lin, J.; Xia, Q. Apigenin protects endothelium-dependent relaxation of rat aorta against oxidative stress. Eur. J. Pharmacol.,  2009, 616(1-3), 200-205.
[http://dx.doi.org/10.1016/j.ejphar.2009.06.020] [PMID: 19549516] 
[27] 
Salah, A.M.; Dongmo, A.B.; Kamanyi, A.; Bopelet, M.; Wagner, H. Angiotensin-conventing enzyme-inhibitory effect by Ruellia praetermissa. Pharm. Biol.,  2001, 39, 16-19.
[http://dx.doi.org/10.1076/phbi.39.1.16.5942] 
[28] 
Zhou, X.; Gao, T.; Jiang, X.G.; Xie, M.L. Protective effect of apigenin on bleomycin-induced pulmonary fibrosis in mice by increments of lung antioxidant ability and PPAR gamma expression. J. Funct. Foods,  2016, 24, 382-389.
[http://dx.doi.org/10.1016/j.jff.2016.04.039] 
[29] 
Turner, J.M.; Spatz, E.S. Nutritional supplements for the treatment of hypertension: a practical guide for clinicians. Curr. Cardiol. Rep.,  2016, 18(12), 126.
[http://dx.doi.org/10.1007/s11886-016-0806-x] [PMID: 27796863] 
[30] 
Tang, G.Y.; Meng, X.; Li, Y.; Zhao, C.N.; Liu, Q.; Li, H.B. Effects of vegetables on cardiovascular diseases and related mechanisms. Nutrients,  2017, 9(8), 857.
[http://dx.doi.org/10.3390/nu9080857] [PMID: 28796173] 
[31] 
Threapleton, D.E.; Greenwood, D.C.; Evans, C.E.L.; Cleghorn, C.L.; Nykjaer, C.; Woodhead, C.; Cade, J.E.; Gale, C.P.; Burley, V.J. Dietary fibre intake and risk of cardiovascular disease: systematic review and meta-analysis. BMJ,  2013, 347, f6879.
[http://dx.doi.org/10.1136/bmj.f6879] [PMID: 24355537] 
[32] 
Honarbakhsh, S.; Schachter, M. Vitamins and cardiovascular disease. Br. J. Nutr.,  2009, 101(8), 1113-1131.
[http://dx.doi.org/10.1017/S000711450809123X] [PMID: 18826726] 
[33] 
Cam, A.; de Mejia, E.G. Role of dietary proteins and peptides in cardiovascular disease. Mol. Nutr. Food Res.,  2012, 56(1), 53-66.
[http://dx.doi.org/10.1002/mnfr.201100535] [PMID: 22121103] 
[34] 
Xiong, X.; Yang, X.; Liu, Y.; Zhang, Y.; Wang, P.; Wang, J. Chinese herbal formulas for treating hypertension in traditional Chinese medicine: perspective of modern science. Hypertens. Res.,  2013, 36(7), 570-579.
[http://dx.doi.org/10.1038/hr.2013.18] [PMID: 23552514] 
[35] 
Cheung, B.M.; Li, C. Diabetes and hypertension: is there a common metabolic pathway? Curr. Atheroscler. Rep.,  2012, 14(2), 160-166.
[http://dx.doi.org/10.1007/s11883-012-0227-2] [PMID: 22281657] 
[36] 
Mullane, K.; Enna, S.J.; Piette, J.; Williams, M. Guidelines for manuscript submission in the peer-reviewed pharmacological literature. Biochem. Pharmacol.,  2015, 97(3), 225-235.
[http://dx.doi.org/10.1016/j.bcp.2015.06.023] [PMID: 26208784] 
[37] 
Mullane, K.; Williams, M. Unknown unknowns in biomedical research: Does an inability to deal with ambiguity contribute to issues of irreproducibility? Biochem. Pharmacol.,  2015, 97(2), 133-136.
[http://dx.doi.org/10.1016/j.bcp.2015.07.002] [PMID: 26239804] 
[38] 
Laine, C.; De Angelis, C.; Delamothe, T.; Drazen, J.M.; Frizelle, F.A.; Haug, C.; Hébert, P.C.; Horton, R.; Kotzin, S.; Marusic, A.; Sahni, P.; Schroeder, T.V.; Sox, H.C.; Van der Weyden, M.B.; Verheugt, F.W. Clinical trial registration: looking back and moving ahead. Ann. Intern. Med.,  2007, 147(4), 275-277.
[http://dx.doi.org/10.7326/0003-4819-147-4-200708210-00166] [PMID: 17548404] 
[39] 
World Health Organization. International Clinical Trials Registry Platform  Available at:,., http://www.who.int/ictrp/about/details/en/ index.html (Accessed on September 6, 2018).
[40] 
Research Guidelines for Evaluating the Safety and Efficacy of Herbal Medicines. http://apps.who.int/medicinedocs/en/d/Jh2946e/2.html#Jh2946e
[41] 
Dehkordi, F.R.; Kamkhah, A.F. Antihypertensive effect of Nigella sativa seed extract in patients with mild hypertension. Fundam. Clin. Pharmacol.,  2008, 22(4), 447-452.
[http://dx.doi.org/10.1111/j.1472-8206.2008.00607.x] [PMID: 18705755] 
[42] 
Fallah, H.  Seed Oil in Healthy Volunteers: A Randomized, Double‐Blind, Placebo‐controlled Clinical Trial - Phytotherapy Research Wiley Online Library, 2013. Available at: , https://onlinelibrary.wiley. com/doi/abs/10.1002/ptr.4944  (Accessed on September 6, 2018).
[43] 
Rizka, A.; Setiati, S.; Lydia, A.; Dewiasty, E. Effect of Nigella sativa Seed Extract for Hypertension in Elderly: a Double-blind, Randomized Controlled Trial. Acta Med. Indones.,  2017, 49(4), 307-313.
[PMID: 29348380] 
[44] 
Miyawaki, T.; Aono, H.; Toyoda-Ono, Y.; Maeda, H.; Kiso, Y.; Moriyama, K. Antihypertensive effects of sesamin in humans. J. Nutr. Sci. Vitaminol. (Tokyo),  2009, 55(1), 87-91.
[http://dx.doi.org/10.3177/jnsv.55.87] [PMID: 19352068] 
[45] 
Wichitsranoi, J.; Weerapreeyakul, N.; Boonsiri, P.; Settasatian, C.; Settasatian, N.; Komanasin, N.; Sirijaichingkul, S.; Teerajetgul, Y.; Rangkadilok, N.; Leelayuwat, N. Antihypertensive and antioxidant effects of dietary black sesame meal in pre-hypertensive humans. Nutr. J.,  2011, 10, 82.
[http://dx.doi.org/10.1186/1475-2891-10-82] [PMID: 21827664] 
[46] 
Roghani-Dehkordi, F.; Kamkhah, A.F. Artichoke leaf juice contains antihypertensive effect in patients with mild hypertension. J. Diet. Suppl.,  2009, 6(4), 328-341.
[http://dx.doi.org/10.3109/19390210903280207] [PMID: 22435514] 
[47] 
Awaad, A.A.; El-Meligy, R.M.; Zain, G.M.; Safhi, A.A.; Al Qurain, N.A.; Almoqren, S.S.; Zain, Y.M.; Sesh Adri, V.D.; Al-Saikhan, F.I. Experimental and clinical antihypertensive activity of Matricaria chamomilla extracts and their angiotensin-converting enzyme inhibitory activity. Phytother. Res.,  2018, 32(8), 1564-1573.
[http://dx.doi.org/10.1002/ptr.6086] [PMID: 29656575] 
[48] 
Rhee, M.Y.; Cho, B.; Kim, K.I.; Kim, J.; Kim, M.K.; Lee, E.K.; Kim, H.J.; Kim, C.H. Blood pressure lowering effect of Korea ginseng derived ginseol K-g1. Am. J. Chin. Med.,  2014, 42(3), 605-618.
[http://dx.doi.org/10.1142/S0192415X14500396] [PMID: 24871654] 
[49] 
Hobbs, D.A.; Kaffa, N.; George, T.W.; Methven, L.; Lovegrove, J.A. Blood pressure-lowering effects of beetroot juice and novel beetrootenriched bread products in normotensive male subjects. Br. J. Nutr.,  2012, 108(11), 2066-2074.
[http://dx.doi.org/10.1017/S0007114512000190] [PMID: 22414688] 
[50] 
Ried, K.; Frank, O.R.; Stocks, N.P. Aged garlic extract reduces blood pressure in hypertensives: A dose-response trial. Eur. J. Clin. Nutr.,  2013, 67(1), 64-70.
[http://dx.doi.org/10.1038/ejcn.2012.178] [PMID: 23169470] 
[51] 
Asgary, S.; Sahebkar, A.; Afshani, M.R.; Keshvari, M.; Haghjooyjavanmard, S.; Rafieian-Kopaei, M. Clinical evaluation of blood pressure lowering, endothelial function improving, hypolipidemic and anti-inflammatory effects of pomegranate juice in hypertensive subjects. Phytother. Res.,  2014, 28(2), 193-199.
[http://dx.doi.org/10.1002/ptr.4977] [PMID: 23519910] 
[52] 
Hobbs, D.A.; Goulding, M.G.; Nguyen, A.; Malaver, T.; Walker, C.F.; George, T.W.; Methven, L.; Lovegrove, J.A. Acute ingestion of beetroot bread increases endothelium-independent vasodilation and lowers diastolic blood pressure in healthy men: a randomized controlled trial. J. Nutr.,  2013, 143(9), 1399-1405.
[http://dx.doi.org/10.3945/jn.113.175778] [PMID: 23884387] 
[53] 
Madhavi, D.; Kagan, D.; Rao, V.; Murray, M.T. A pilot study to evaluate the antihypertensive effect of a celery extract in mild to moderate hypertensive patients. Nat. Med. J.,  2013, 4, 1-3.
[54] 
Greenway, F.; Liu, Z.; Yu, Y.; Gupta, A. A clinical trial testing the safety and efficacy of a standardized Eucommia ulmoides Oliver bark extract to treat hypertension. Altern. Med. Rev.,  2011, 16(4), 338-347.
[PMID: 22214253] 
[55] 
Yuan, X.; Li, X.; Ji, Z.; Xiao, J.; Zhang, L.; Zhang, W.; Su, H.; Kaliannan, K.; Long, Y.; Shao, Z. Effects of vitamin C supplementation on blood pressure and hypertension control in response to ambient temperature changes in patients with essential hypertension. Clin. Exp. Hypertens.,  2018, 1993, 1-8.
[PMID: 30183398] 
[56] 
Lockyer, S.; Rowland, I.; Spencer, J.P.E.; Yaqoob, P.; Stonehouse, W. Impact of phenolic-rich olive leaf extract on blood pressure, plasma lipids and inflammatory markers: a randomised controlled trial. Eur. J. Nutr.,  2017, 56(4), 1421-1432.
[http://dx.doi.org/10.1007/s00394-016-1188-y] [PMID: 26951205] 
[57] 
Ajebli, M.; Eddouks, M. The promising role of plant tannins as bioactive antidiabetic agents. Curr. Med. Chem.,  2019, 26(25), 4852-4884.
[http://dx.doi.org/10.2174/0929867325666180605124256] [PMID: 29874989] 
[58] 
Macready, A.L.; George, T.W.; Chong, M.F.; Alimbetov, D.S.; Jin, Y.; Vidal, A.; Spencer, J.P.; Kennedy, O.B.; Tuohy, K.M.; Minihane, A.M.; Gordon, M.H.; Lovegrove, J.A. FLAVURS Study Group. Flavonoid-rich fruit and vegetables improve microvascular reactivity and inflammatory status in men at risk of cardiovascular disease--FLAVURS: a randomized controlled trial. Am. J. Clin. Nutr.,  2014, 99(3), 479-489.
[http://dx.doi.org/10.3945/ajcn.113.074237] [PMID: 24452238] 
[59] 
Heinrich, M. Fundamentals of pharmacognosy and phytotherapy, 2nd ed; Elsevier: Edinburgh, 2012. 
[60] 
Rates, S.M. Plants as source of drugs. Toxicon,  2001, 39(5), 603-613.
[http://dx.doi.org/10.1016/S0041-0101(00)00154-9] [PMID: 11072038] 
[61] 
Agrawal, M.; Nandini, D.; Sharma, V.; Chauhan, N.J.I.J.P.S. Res. Herbal remedies for treatment of hypertension. Int. J. Pharm. Sci. Res.,  2010, 1, 1-21.
[62] 
Davids, D.; Gibson, D.; Johnson, Q. Ethnobotanical survey of medicinal plants used to manage high blood pressure and type 2 diabetes mellitus in Bitterfontein, Western Cape Province, South Africa. J. Ethnopharmacol.,  2016, 194, 755-766.
[http://dx.doi.org/10.1016/j.jep.2016.10.063] [PMID: 27780752] 
[63] 
Malik, K.; Ahmad, M.; Bussmann, R.W.; Tariq, A.; Ullah, R.; Alqahtani, A.S.; Shahat, A.A.; Rashid, N.; Zafar, M.; Sultana, S.; Shah, S.N. Ethnobotany of anti-hypertensive plants used in northern Pakistan. Front. Pharmacol.,  2018, 9, 789.
[http://dx.doi.org/10.3389/fphar.2018.00789] [PMID: 30087613] 
[64] 
Gbekley, H.E.; Karou, S.D.; Katawa, G.; Tchacondo, T.; Batawila, K.; Ameyapoh, Y.; Simpore, J. Ethnobotanical survey of medicinal plants used in the management of hypertension in the maritime region of Togo. Afr. J. Tradit. Complement. Altern. Med.,  2018, 15, 85-97.
[http://dx.doi.org/10.21010/ajtcam.v15i1.9] 
[65] 
Ekar, T.; Kreft, S. Common risks of adulterated and mislabeled herbal preparations. Food Chem. Toxicol.,  2019, 123, 288-297.
[http://dx.doi.org/10.1016/j.fct.2018.10.043] [PMID: 30339960] 
[66] 
Newman, D.J. Natural products as leads to potential drugs: an old process or the new hope for drug discovery? J. Med. Chem.,  2008, 51(9), 2589-2599.
[http://dx.doi.org/10.1021/jm0704090] [PMID: 18393402] 
[67] 
Zaid, H.; Rayan, J.; Nasser, A.; Saad, B.; Rayan, A. Physicochemical properties of natural based products versus synthetic chemicals. Open Nutr. J.,  2010, 3, 194-202.
[68] 
Saad, B.; Zaid, H.; Shanak, S.; Kadan, S. Anti-diabetes and Anti-obesity Medicinal Plants and Phytochemicals; Springer International Publishing: Cham, 2017. 
[http://dx.doi.org/10.1007/978-3-319-54102-0] 
[69] 
Cong, F.; Cheung, A.K.; Huang, S.M. Chemical genetics-based target identification in drug discovery. Annu. Rev. Pharmacol. Toxicol.,  2012, 52, 57-78.
[http://dx.doi.org/10.1146/annurev-pharmtox-010611-134639] [PMID: 21819237] 
[70] 
Hurko, O. Target-based drug discovery, genetic diseases, and biologics. Neurochem. Int.,  2012, 61(6), 892-898.
[http://dx.doi.org/10.1016/j.neuint.2012.01.016] [PMID: 22306775] 
[71] 
Spainhour, C.B. Drug discovery handbook; Wiley-Interscience: Hoboken, 2005. 
[72] 
Salvador-Reyes, L.A.; Luesch, H. Biological targets and mechanisms of action of natural products from marine cyanobacteria. Nat. Prod. Rep.,  2015, 32(3), 478-503.
[http://dx.doi.org/10.1039/C4NP00104D] [PMID: 25571978] 
[73] 
Rovati, G.E.; Capra, V. Drug-receptor interactions: quantitative and qualitative aspects.General and Molecular Pharmacology : Principles of Drug Action,1st ed; Clementi, F.; Fumagalli, G.,   Eds.; John Wiley & Sons, Inc.::  Hoboken, New Jersey,,  2015,; pp. 93- 108.
[74] 
Hopkins, A.L.; Groom, C.R. The druggable genome. Nat. Rev. Drug Discov.,  2002, 1(9), 727-730.
[http://dx.doi.org/10.1038/nrd892] [PMID: 12209152] 
[75] 
Palozi, R.A.C.; Schaedler, M.I.; Tirloni, C.A.S.; Silva, A.O.; Lívero, F.A.D.R.; Souza, R.I.C.; Dos Santos, A.C.; Prando, T.B.L.; de Souza, L.M.; Gasparotto Junior, A.; Gasparotto, A. junior roles of nitric oxide and prostaglandins in the sustained antihypertensive effects of acanthospermum hispidum dc. on ovariectomized rats with renovascular hypertension. Evid. Based Complement. Alternat. Med.,  2017, 2017,2492483.
[http://dx.doi.org/10.1155/2017/2492483] [PMID: 29234376] 
[76] 
Konukogl, D.; Uzun, H. Endothelial Dysfunction and Hypertension,  2017, 511-540.
[77] 
Godfraind, T. Calcium Channel Blockers; Birkhäuser: Basel, Switzerland, 2004. 
[http://dx.doi.org/10.1007/978-3-0348-7859-3] 
[78] 
Opie, L.H. Calcium channel antagonists in the treatment of coronary artery disease: Fundamental pharmacological properties relevant to clinical use. Prog. Cardiovasc. Dis.,  1996, 38(4), 273-290.
[http://dx.doi.org/10.1016/S0033-0620(96)80014-4] [PMID: 8552787] 
[79] 
Karthik, D.; Viswanathan, P.; Anuradha, C.V. Administration of rosmarinic acid reduces cardiopathology and blood pressure through inhibition of p22phox NADPH oxidase in fructose-fed hypertensive rats. J. Cardiovasc. Pharmacol.,  2011, 58(5), 514-521.
[http://dx.doi.org/10.1097/FJC.0b013e31822c265d] [PMID: 21795992] 
[80] 
Sowbhagya, H.B. Chemistry, technology, and nutraceutical functions of celery (Apium graveolens L.): An overview. Crit. Rev. Food Sci. Nutr.,  2014, 54(3), 389-398.
[http://dx.doi.org/10.1080/10408398.2011.586740] [PMID: 24188309] 
[81] 
Tsi, D.; Tan, B.K.H. Cardiovascular pharmacology of 3-n-butylphthalide in spontaneously hypertensive rats. Phytother. Res.,  1997, 11, 576-582.
[http://dx.doi.org/10.1002/(SICI)1099-1573(199712)11:8<576::AIDPTR174>3.0.CO;2-7] 
[82] 
Zhu, Z.Y.; Gao, T.; Huang, Y.; Xue, J.; Xie, M.L. Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lα in rats. Food Funct.,  2016, 7(4), 1992-1998.
[http://dx.doi.org/10.1039/C5FO01464F] [PMID: 26987380] 
[83] 
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] 
[84] 
Anwar, M.A.; Al Disi, S.S.; Eid, A.H. Anti-hypertensive herbs and their mechanisms of action: part II. Front. Pharmacol.,  2016, 7, 50.
[http://dx.doi.org/10.3389/fphar.2016.00050] [PMID: 27014064] 
[85] 
Sakat, S.S.; Wankhede, S.S.; Juvekar, A.R.; Mali, V.R.; Bodhankar, S.L. Antihypertensive effect of aqueous extract of Elaeocarpus ganitrus Roxb. seeds in renal artery occluded hypertensive rats. Int. J. Pharm. Tech. Res.,  2009, 1, 779-782.
[86] 
Brasil, G.A.; Ronchi, S.N.; do Nascimento, A.M.; de Lima, E.M.; Romão, W.; da Costa, H.B.; Scherer, R.; Ventura, J.A.; Lenz, D.; Bissoli, N.S.; Endringer, D.C.; de Andrade, T.U. Antihypertensive effect of Carica papaya via a reduction in ACE activity and improved baroreflex. Planta Med.,  2014, 80(17), 1580-1587.
[http://dx.doi.org/10.1055/s-0034-1383122] [PMID: 25295669] 
[87] 
Nwokocha, C.R.; Ozolua, R.I.; Owu, D.U.; Nwokocha, M.I.; Ugwu, A.C. Antihypertensive properties of Allium sativum (garlic) on normotensive and two kidney one clip hypertensive rats. Niger. J. Physiol. Sci.,  2011, 26(2), 213-218.
[PMID: 22547193] 
[88] 
Anonymous,  The Mechanism for Garlic’s(Allium sativum) Ability to Lower Blood Pressure . https://www.ebmconsult.com/articles/garlic-lowers-blood-pressure-hypertension2015.
[89] 
Sharifi, A.M.; Darabi, R.; Akbarloo, N. Investigation of antihypertensive mechanism of garlic in 2K1C hypertensive rat. J. Ethnopharmacol.,  2003, 86(2-3), 219-224.
[http://dx.doi.org/10.1016/S0378-8741(03)00080-1] [PMID: 12738090] 
[90] 
Bnouham, M.; Benalla, W.; Bellahcen, S.; Hakkou, Z.; Ziyyat, A.; Mekhfi, H.; Aziz, M.; Legssyer, A. Antidiabetic and antihypertensive effect of a polyphenol-rich fraction of Thymelaea hirsuta L. in a model of neonatal streptozotocin-diabetic and N(G) -nitro-l-arginine methyl ester-hypertensive rats. J. Diabetes,  2012, 4(3), 307-313.
[http://dx.doi.org/10.1111/j.1753-0407.2012.00202.x] [PMID: 22519949] 
[91] 
de Paula Vasconcelos, P.C.; Tirloni, C.A.S.; Palozi, R.A.C.; Leitão, M.M.; Carneiro, M.T.S.; Schaedler, M.I.; Silva, A.O.; Souza, R.I.C.; Salvador, M.J.; Junior, A.G.; Kassuya, C.A.L. Diuretic herb Gomphrena celosioides Mart. (Amaranthaceae) promotes sustained arterial pressure reduction and protection from cardiac remodeling on rats with renovascular hypertension. J. Ethnopharmacol.,  2018, 224, 126-133.
[http://dx.doi.org/10.1016/j.jep.2018.05.036] [PMID: 29842964] 
[92] 
Xie, Y.; Zhang, W. Antihypertensive activity of Rosa rugosa Thunb. flowers: angiotensin I converting enzyme inhibitor. J. Ethnopharmacol.,  2012, 144(3), 562-566.
[http://dx.doi.org/10.1016/j.jep.2012.09.038] [PMID: 23063753] 
[93] 
Belmokhtar, M.; Bouanani, N.E.; Ziyyat, A.; Mekhfi, H.; Bnouham, M.; Aziz, M.; Matéo, P.; Fischmeister, R.; Legssyer, A. Antihypertensive and endothelium-dependent vasodilator effects of aqueous extract of Cistus ladaniferus. Biochem. Biophys. Res. Commun.,  2009, 389(1), 145-149.
[http://dx.doi.org/10.1016/j.bbrc.2009.08.113] [PMID: 19715668] 
[94] 
Hakkou, Z.; Maciuk, A.; Leblais, V.; Bouanani, N.E.; Mekhfi, H.; Bnouham, M.; Aziz, M.; Ziyyat, A.; Rauf, A.; Hadda, T.B.; Shaheen, U.; Patel, S.; Fischmeister, R.; Legssyer, A. Antihypertensive and vasodilator effects of methanolic extract of Inula viscosa: Biological evaluation and POM analysis of cynarin, chlorogenic acid as potential hypertensive. Biomed. Pharmacother.,  2017, 93, 62-69.
[http://dx.doi.org/10.1016/j.biopha.2017.06.015] [PMID: 28623784] 
[95] 
Vergara-Galicia, J.; Ortiz-Andrade, R.; Castillo-España, P.; Ibarra-Barajas, M.; Gallardo-Ortiz, I.; Villalobos-Molina, R.; Estrada-Soto, S. Antihypertensive and vasorelaxant activities of Laelia autumnalis are mainly through calcium channel blockade. Vascul. Pharmacol.,  2008, 49(1), 26-31.
[http://dx.doi.org/10.1016/j.vph.2008.04.002] [PMID: 18534917] 
[96] 
Ch’ng, Y.S.; Loh, Y.C.; Tan, C.S.; Ahmad, M.; Asmawi, M.Z.; Wan Omar, W.M.; Yam, M.F. Vasodilation and Antihypertensive Activities of Swietenia macrophylla (Mahogany) Seed Extract. J. Med. Food,  2018, 21(3), 289-301.
[http://dx.doi.org/10.1089/jmf.2017.4008] [PMID: 29420109] 
[97] 
Yoshimura, M.; Toyoshi, T.; Sano, A.; Izumi, T.; Fujii, T.; Konishi, C.; Inai, S.; Matsukura, C.; Fukuda, N.; Ezura, H.; Obata, A. Antihypertensive effect of a γ-aminobutyric acid rich tomato cultivar ‘DG03-9’ in spontaneously hypertensive rats. J. Agric. Food Chem.,  2010, 58(1), 615-619.
[http://dx.doi.org/10.1021/jf903008t] [PMID: 20050705] 
[98] 
Patel, S.S.; Verma, N.K.; Ravi, V.; Gauthaman, K.; Soni, N. Antihypertensive Effect of an Aqueous Extract of Passiflora nepalensis Wall. Int. J. Appl. Res. Nat. Prod.,  2011, 3, 22-27.
[99] 
Moghadam, M.H.; Imenshahidi, M.; Mohajeri, S.A. Antihypertensive effect of celery seed on rat blood pressure in chronic administration. J. Med. Food,  2013, 16(6), 558-563.
[http://dx.doi.org/10.1089/jmf.2012.2664] [PMID: 23735001] 
[100] 
Luo, L.F.; Wu, W.H.; Zhou, Y.J.; Yan, J.; Yang, G.P.; Ouyang, D.S. Antihypertensive effect of Eucommia ulmoides Oliv. extracts in spontaneously hypertensive rats. J. Ethnopharmacol.,  2010, 129(2), 238-243.
[http://dx.doi.org/10.1016/j.jep.2010.03.019] [PMID: 20347950] 
[101] 
Veeramani, C.; Al-Numair, K.S.; Chandramohan, G.; Alsaif, M.A.; Alhamdan, A.A.; Pugalendi, K.V. Antihypertensive effect of Melothria maderaspatana leaf fractions on DOCA-salt-induced hypertensive rats and identification of compounds by GC-MS analysis. J. Nat. Med.,  2012, 66(2), 302-310.
[http://dx.doi.org/10.1007/s11418-011-0590-2] [PMID: 21964566] 
[102] 
Yang, N.C.; Jhou, K.Y.; Tseng, C.Y. Antihypertensive effect of mulberry leaf aqueous extract containing γ-aminobutyric acid in spontaneously hypertensive rats. Food Chem.,  2012, 132, 1796-1801.
[http://dx.doi.org/10.1016/j.foodchem.2011.11.143] 
[103] 
Patel, P.; Vaghasiya, J.; Thakor, A.; Jariwala, J. Antihypertensive effect of rhizome part of Acorus calamus on renal artery occlusion induced hypertension in rats. Asian Pac. J. Trop. Dis.,  2012, 2, S6-S10.
[http://dx.doi.org/10.1016/S2222-1808(12)60114-5] 
[104] 
Cai, R.L.; Li, M.; Xie, S.H.; Song, Y.; Zou, Z.M.; Zhu, C.Y.; Qi, Y. Antihypertensive effect of total flavone extracts from Puerariae Radix. J. Ethnopharmacol.,  2011, 133(1), 177-183.
[http://dx.doi.org/10.1016/j.jep.2010.09.013] [PMID: 20933075] 
[105] 
Ikarashi, N.; Toda, T.; Hatakeyama, Y.; Kusunoki, Y.; Kon, R.; Mizukami, N.; Kaneko, M.; Ogawa, S.; Sugiyama, K. Anti-hypertensive effects of acacia polyphenol in spontaneously hypertensive rats. Int. J. Mol. Sci.,  2018, 19(3), 700.
[http://dx.doi.org/10.3390/ijms19030700] [PMID: 29494506] 
[106] 
Bhatia, J.; Tabassum, F.; Sharma, A.K.; Bharti, S.; Golechha, M.; Joshi, S.; Sayeed Akhatar, M.; Srivastava, A.K.; Arya, D.S. Emblica officinalis exerts antihypertensive effect in a rat model of DOCA-salt-induced hypertension: role of (p) eNOS, NO and oxidative stress. Cardiovasc. Toxicol.,  2011, 11(3), 272-279.
[http://dx.doi.org/10.1007/s12012-011-9122-2] [PMID: 21748534] 
[107] 
Jabeen, Q.; Bashir, S.; Lyoussi, B.; Gilani, A.H. Coriander fruit exhibits gut modulatory, blood pressure lowering and diuretic activities. J. Ethnopharmacol.,  2009, 122(1), 123-130.
[http://dx.doi.org/10.1016/j.jep.2008.12.016] [PMID: 19146935] 
[108] 
Syed, A.A.; Lahiri, S.; Mohan, D.; Valicherla, G.R.; Gupta, A.P.; Riyazuddin, M.; Kumar, S.; Maurya, R.; Hanif, K.; Gayen, J.R. Evaluation of anti-hypertensive activity of Ulmus wallichiana extract and fraction in SHR, DOCA-salt- and L-NAME-induced hypertensive rats. J. Ethnopharmacol.,  2016, 193, 555-565.
[http://dx.doi.org/10.1016/j.jep.2016.10.008] [PMID: 27720848] 
[109] 
Quiñones, M.; Guerrero, L.; Suarez, M.; Pons, Z.; Aleixandre, A.; Arola, L.; Muguerza, B. Low-molecular procyanidin rich grape seed extract exerts antihypertensive effect in males spontaneously hypertensive rats. Food Res. Int.,  2013, 51, 587-595.
[http://dx.doi.org/10.1016/j.foodres.2013.01.023] 
[110] 
Nworgu, Z.A.M.; Onwukaeme, D.N.; Afolayan, A.J.; Ameachina, F.C.; Ayinde, B. Preliminary studies of blood pressure lowering effect of Nauclea latifolia in rats.  . Afr. J. Pharm. Pharmacol,,   2008,,  2,,  037- 041..
[111] 
Maneesai, P.; Prasarttong, P.; Bunbupha, S.; Kukongviriyapan, U.; Kukongviriyapan, V.; Tangsucharit, P.; Prachaney, P.; Pakdeechote, P. Synergistic Antihypertensive Effect of Carthamus tinctorius L. Extract and Captopril in L-NAME-Induced Hypertensive Rats via Restoration of eNOS and AT1R Expression. Nutrients,  2016, 8(3), 122.
[http://dx.doi.org/10.3390/nu8030122] [PMID: 26938552] 
[112] 
Jia, H.; Liu, J.W.; Ufur, H.; He, G.S.; Liqian, H.; Chen, P. The antihypertensive effect of ethyl acetate extract from red raspberry fruit in hypertensive rats. Pharmacogn. Mag.,  2011, 7(25), 19-24.
[http://dx.doi.org/10.4103/0973-1296.75885] [PMID: 21472074] 
[113] 
Chung, D.H.; Kim, S.H.; Myung, N.; Cho, K.J.; Chang, M.J. The antihypertensive effect of ethyl acetate extract of radish leaves in spontaneously hypertensive rats. Nutr. Res. Pract.,  2012, 6(4), 308-314.
[http://dx.doi.org/10.4162/nrp.2012.6.4.308] [PMID: 22977684] 
[114] 
Bankar, G.R.; Nayak, P.G.; Bansal, P.; Paul, P.; Pai, K.S.R.; Singla, R.K.; Bhat, V.G. Vasorelaxant and antihypertensive effect of Cocos nucifera Linn. endocarp on isolated rat thoracic aorta and DOCA salt-induced hypertensive rats. J. Ethnopharmacol.,  2011, 134(1), 50-54.
[http://dx.doi.org/10.1016/j.jep.2010.11.047] [PMID: 21129472] 
[115] 
Hellstrom, J.K.; Shikov, A.N.; Makarova, M.N.; Pihlanto, A.M.; Pozharitskaya, O.N.; Ryhanen, E-L.; Kivijarvi, P.; Makarov, V.G.; Mattila, P.H. Blood pressure-lowering properties of chokeberry (Aronia mitchurinii, var. Viking). J. Funct. Foods,  2010, 2, 163-169.
[http://dx.doi.org/10.1016/j.jff.2010.04.004] 
[116] 
Bahgat, A.; Abdel-Aziz, H.; Raafat, M.; Mahdy, A.; El-Khatib, A.S.; Ismail, A.; Khayyal, M.T. Solanum indicum ssp. distichum extract is effective against L-NAME-induced hypertension in rats. Fundam. Clin. Pharmacol.,  2008, 22(6), 693-699.
[http://dx.doi.org/10.1111/j.1472-8206.2008.00627.x] [PMID: 19049674] 
[117] 
Shah, A.J.; Gilani, A.H. Blood pressure-lowering and vascular modulator effects of Acorus calamus extract are mediated through multiple pathways. J. Cardiovasc. Pharmacol.,  2009, 54(1), 38-46.
[http://dx.doi.org/10.1097/FJC.0b013e3181aa5781] [PMID: 19528816] 
[118] 
Nakamura, K.; Naramoto, K.; Koyama, M. Blood-pressure-lowering effect of fermented buckwheat sprouts in spontaneously hypertensive rats. J. Funct. Foods,  2013, 5, 406-415.
[http://dx.doi.org/10.1016/j.jff.2012.11.013] 
[119] 
Khan, A.U.; Gilani, A.H. Blood pressure lowering, cardiovascular inhibitory and bronchodilatory actions of Achillea millefolium. Phytother. Res.,  2011, 25(4), 577-583.
[http://dx.doi.org/10.1002/ptr.3303] [PMID: 20857434] 
[120] 
Vajic, U.J.; Grujic-Milanovic, J.; Miloradovic, Z.; Jovovic, D.; Ivanov, M.; Karanovic, D.; Savikin, K.; Bugarski, B.; Mihailovic-Stanojevic, N. Urtica dioica L. leaf extract modulates blood pressure and oxidative stress in spontaneously hypertensive rats. Phytomedicine,  2018, 46, 39-45.
[http://dx.doi.org/10.1016/j.phymed.2018.04.037] [PMID: 30097121] 
[121] 
Jung, I.H.; Kim, S.E.; Lee, Y.G.; Kim, D.H.; Kim, H.; Kim, G-S.; Baek, N-I.; Lee, D.Y. Antihypertensive effect from ethanolic extract of Acanthopanax sessiliflorus fruits and quality control of active Compounds. Oxid. Med. Cell. Longev, 2018,,   1-14. ID 5158243
[http://dx.doi.org/10.1155/2018/5158243] 
[122] 
Bhullar, K.S.; Lassalle-Claux, G.; Touaibia, M.; Rupasinghe, H.P.V. Antihypertensive effect of caffeic acid and its analogs through dual renin-angiotensin-aldosterone system inhibition. Eur. J. Pharmacol.,  2014, 730, 125-132.
[http://dx.doi.org/10.1016/j.ejphar.2014.02.038] [PMID: 24631256] 
[123] 
Hernández-Abreu, O.; Castillo-España, P.; León-Rivera, I.; Ibarra Barajas, M.; Villalobos-Molina, R.; González-Christen, J.; Vergara-Galicia, J.; Estrada-Soto, S. Antihypertensive and vasorelaxant effects of tilianin isolated from Agastache mexicana are mediated by NO/cGMP pathway and potassium channel opening. Biochem. Pharmacol.,  2009, 78(1), 54-61.
[http://dx.doi.org/10.1016/j.bcp.2009.03.016] [PMID: 19447223] 
[124] 
Zhang, L.; Yang, M.; Song, Y.; Sun, Z.; Peng, Y.; Qu, K.; Zhu, H. Antihypertensive effect of 3,3,5,5-tetramethyl-4-piperidone, a new compound extracted from Marasmius androsaceus. J. Ethnopharmacol.,  2009, 123(1), 34-39.
[http://dx.doi.org/10.1016/j.jep.2009.02.033] [PMID: 19429336] 
[125] 
Ferreira, L.G.; Evora, P.R.B.; Capellini, V.K.; Albuquerque, A.A.; Carvalho, M.T.M.; Gomes, R.A.D.S.; Parolini, M.T.; Celotto, A.C. Effect of rosmarinic acid on the arterial blood pressure in normotensive and hypertensive rats: Role of ACE. Phytomedicine,  2018, 38, 158-165.
[http://dx.doi.org/10.1016/j.phymed.2017.02.006] [PMID: 29425648] 
[126] 
Imenshahidi, M.; Eghbal, M.; Sahebkar, A.; Iranshahi, M. Hypotensive activity of auraptene, a monoterpene coumarin from Citrus spp. Pharm. Biol.,  2013, 51(5), 545-549.
[http://dx.doi.org/10.3109/13880209.2012.747546] [PMID: 23368941] 
[127] 
Camargo, S.B.; Simões, L.O.; Medeiros, C.F.A.; de Melo Jesus, A.; Fregoneze, J.B.; Evangelista, A.; Villarreal, C.F.; Araújo, A.A.S.; Quintans-Júnior, L.J.; Silva, D.F. Antihypertensive potential of linalool and linalool complexed with β-cyclodextrin: Effects of subchronic treatment on blood pressure and vascular reactivity. Biochem. Pharmacol.,  2018, 151, 38-46.
[http://dx.doi.org/10.1016/j.bcp.2018.02.014] [PMID: 29454617] 
[128] 
Lin, S.Y.; Wang, C.C.; Lu, Y.L.; Wu, W.C.; Hou, W.C. Antioxidant, anti-semicarbazide-sensitive amine oxidase, and anti-hypertensive activities of geraniin isolated from Phyllanthus urinaria. Food Chem. Toxicol.,  2008, 46(7), 2485-2492.
[http://dx.doi.org/10.1016/j.fct.2008.04.007] [PMID: 18495318] 
[129] 
Litterio, M.C.; Jaggers, G.; Sagdicoglu Celep, G.; Adamo, A.M.; Costa, M.A.; Oteiza, P.I.; Fraga, C.G.; Galleano, M. Blood pressure-lowering effect of dietary (-)-epicatechin administration in L-NAME-treated rats is associated with restored nitric oxide levels. Free Radic. Biol. Med.,  2012, 53(10), 1894-1902.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.08.585] [PMID: 22985936] 
[130] 
Kang, N.; Lee, J-H.; Lee, W.; Ko, J.Y.; Kim, E.A.; Kim, J.S.; Heu, M.S.; Kim, G.H.; Jeon, Y.J. Gallic acid isolated from Spirogyra sp. improves cardiovascular disease through a vasorelaxant and antihypertensive effect. Environ. Toxicol. Pharmacol.,  2015, 39(2), 764-772.
[http://dx.doi.org/10.1016/j.etap.2015.02.006] [PMID: 25727171] 
[131] 
Fu, S.; Li, Y.L.; Wu, Y.T.; Yue, Y.; Qian, Z.Q.; Yang, D.L. Icariside II attenuates myocardial fibrosis by inhibiting nuclear factor-κB and the TGF-β1/Smad2 signalling pathway in spontaneously hypertensive rats. Biomed. Pharmacother.,  2018, 100, 64-71.
[http://dx.doi.org/10.1016/j.biopha.2018.01.138] [PMID: 29421583] 
[132] 
Dubey, H.; Singh, A.; Patole, A.M.; Tenpe, C.R. Antihypertensive effect of allicin in dexamethasone-induced hypertensive rats. Integr. Med. Res.,  2017, 6(1), 60-65.
[http://dx.doi.org/10.1016/j.imr.2016.12.002] [PMID: 28462145] 
[133] 
Dasgupta, A.; Agarwal, S.S.; Basu, D.K. Anticonvulsant activity of the mixed fatty acids of Elaeocarpus ganitrus roxb. (Rudraksh). Indian J. Physiol. Pharmacol.,  1984, 28(3), 245-246.
[PMID: 6519771] 
[134] 
Hule, A.K.; Shah, A.S.; Gambhire, M.N.; Juvekar, A.R. An evaluation of the antidiabetic effects of Elaeocarpus ganitrus in experimental animals. Indian J. Pharmacol.,  2011, 43(1), 56-59.
[http://dx.doi.org/10.4103/0253-7613.75671] [PMID: 21455423] 
[135] 
Sripanidkulchai, B.; Wongpanich, V.; Laupattarakasem, P.; Suwansaksri, J.; Jirakulsomchok, D. Diuretic effects of selected Thai indigenous medicinal plants in rats. J. Ethnopharmacol.,  2001, 75(2-3), 185-190.
[http://dx.doi.org/10.1016/S0378-8741(01)00173-8] [PMID: 11297849] 
[136] 
Ismail, Z.; Halim, S.Z.; Abdullah, N.R.; Afzan, A.; Abdul Rashid, B.A.; Jantan, I. Safety Evaluation of Oral Toxicity of Carica papaya Linn. Leaves: A Subchronic Toxicity Study in Sprague Dawley Rats. Evid. based. Complementary. Altern. Med.,  2014, 74, 14-70.
[137] 
Gruenwald, J.; Brendler, T.; Jaenicke, C. PDR for herbal medicines, 4th ed; Medical Economics Company, Inc.: Montvale, 2000. 
[138] 
Fowotade, A.A.; Fowotade, A.; Enaibe, B.U.; Avwioro, G.O. Evaluating Toxicity Profile of Garlic (Allium sativum) on the Liver, Kidney and Heart Using Wistar Rat Model. Int. J. Trop. Dis. Health,  2017, 26, 1-12.
[http://dx.doi.org/10.9734/IJTDH/2017/36282] 
[139] 
Azza, Z.; Marnissi, F.; Naya, A.; Benjelloun, N.; Zamyati, S.; Amrani, M.; Oudghiri, M. Toxicological evaluation of Thymelaea hirsuta and protective effect against CCl4-induced hepatic injury in rats. Int. J. Biol. Chem. Sci.,  2012, 6, 379-393.
[http://dx.doi.org/10.4314/ijbcs.v6i1.33] 
[140] 
de Paula Vasconcelos, P.C.; Spessotto, D.R.; Marinho, J.V.; Salvador, M.J.; Junior, A.G.O.; Kassuya, C.A.L. Mechanisms underlying the diuretic effect of Gomphrena celosioides Mart. (Amaranthaceae). J. Ethnopharmacol.,  2017, 202, 85-91.
[http://dx.doi.org/10.1016/j.jep.2017.03.007] [PMID: 28315456] 
[141] 
Boudjelal, A.; Henchiri, C.; Sari, M.; Sarri, D.; Hendel, N.; Benkhaled, A.; Ruberto, G. Herbalists and wild medicinal plants in M’Sila (North Algeria): an ethnopharmacology survey. J. Ethnopharmacol.,  2013, 148(2), 395-402.
[http://dx.doi.org/10.1016/j.jep.2013.03.082] [PMID: 23643544] 
[142] 
Souleymane, M.; Konan, G.; Houphouet, F.Y. Antioxidant in vivo, in vitro activity assessment and acute toxicity of aqueous extract of gomphrena celosioides (Amaranthaceae). Experiment.,  2014, 23, 1601-1610.
[143] 
Cheol Park, J.; Chul Kim, S.; Moon Hur, J.; Choi, S.H.; Yeon Lee, K.; Won Choi, J. Anti-hepatotoxic effects of Rosa rugosa root and its compound, rosamultin, in rats intoxicated with bromobenzene. J. Med. Food,  2004, 7(4), 436-441.
[http://dx.doi.org/10.1089/jmf.2004.7.436] [PMID: 15671686] 
[144] 
Eddouks, M.; Ajebli, M.; Hebi, M. Ethnopharmacological survey of medicinal plants used in Daraa-Tafilalet region (Province of Errachidia), Morocco. J. Ethnopharmacol.,  2017, 198, 516-530.
[http://dx.doi.org/10.1016/j.jep.2016.12.017] [PMID: 28003130] 
[145] 
Rowe, A.H. Camomile (Anthemis cotula) as a skin irritant. J. Allergy,  1934, 5, 383.
[http://dx.doi.org/10.1016/S0021-8707(34)90162-3] 
[146] 
Ouahchia, C.; Cherif, H.S.; Hamaidi-Chergui, F.; Marzen, L.; Deradji, S.; Hemma, R.; Saidi, F. Acute and subacute toxicity of Inula viscosa L.(Dittrichia viscosa L.) methanolic extracts. AgroBiologia.,  2017, 7, 562-573.
[147] 
Vergara-Galicia, J.; Aguirre-Crespo, F.; Castillo-España, P.; Arroyo-Mora, A.; López-Escamilla, A.L.; Villalobos-Molina, R.; Estrada-Soto, S. Micropropagation and vasorelaxant activity of Laelia autumnalis (Orchidaceae). Nat. Prod. Res.,  2010, 24(2), 106-114.
[http://dx.doi.org/10.1080/14786410802340820] [PMID: 20077303] 
[148] 
Dharmalingam, K.; Tan, B.K.; Mahmud, M.Z.; Sedek, S.A.M.; Majid, M.I.A.; Kuah, M.K.; Sulaiman, S.F.; Ooi, K.L.; Khan, N.A.; Muhammad, T.S.; Tan, M.W.; Shu-Chien, A.C. Swietenia macrophylla extract promotes the ability of Caenorhabditis elegans to survive Pseudomonas aeruginosa infection. J. Ethnopharmacol.,  2012, 139(2), 657-663.
[http://dx.doi.org/10.1016/j.jep.2011.12.016] [PMID: 22193176] 
[149] 
Balijepalli, M.K.; Suppaiah, V.; Chin, A.M.; Buru, A.S.; Sagineedu, S.R.; Pichika, M.R. Acute oral toxicity studies of Swietenia macrophylla seeds in Sprague Dawley rats. Pharmacognosy Res.,  2015, 7(1), 38-44.
[http://dx.doi.org/10.4103/0974-8490.147197] [PMID: 25598633] 
[150] 
Rao, A.V.; Rao, L.G. Carotenoids and human health. Pharmacol. Res.,  2007, 55(3), 207-216.
[http://dx.doi.org/10.1016/j.phrs.2007.01.012] [PMID: 17349800] 
[151] 
Ali, B.; Adam, S.E.I. Toxicity of Acanthospermum hispidum to mice. J. Comp. Pathol.,  1978, 88(3), 443-448.
[http://dx.doi.org/10.1016/0021-9975(78)90049-X] [PMID: 670443] 
[152] 
Araújo, E.D.L.; Randau, K.P.; Sena-Filho, J.G.; Pimentel, R.M.M.; Xavier, H.S. Acanthospermum hispidum DC (Asteraceae): perspectives for a phytotherapeutic product. Rev. Bras. Farmacogn.,  2008, 18, 777-784.
[http://dx.doi.org/10.1590/S0102-695X2008000500024] 
[153] 
He, X.; Wang, J.; Li, M.; Hao, D.; Yang, Y.; Zhang, C.; He, R.; Tao, R. Eucommia ulmoides Oliv.: ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine. J. Ethnopharmacol.,  2014, 151(1), 78-92.
[http://dx.doi.org/10.1016/j.jep.2013.11.023] [PMID: 24296089] 
[154] 
Zhang, G.H.; Guo, M.F.; Yang, Z.H.; Wu, Z.J.; Liu, X.S.; Song, J.H.; Meng, X.Q.; Ren, L.M. Effect of Du-zhongkangcha on sexual behavior and its acute toxicity. J. Hebei. Med. Univ.,  1999, 20, 140-142.
[155] 
Balaraman, A.K.; Singh, J.; Dash, S.; Maity, T.K. Antihyperglycemic and hypolipidemic effects of Melothria maderaspatana and Coccinia indica in Streptozotocin induced diabetes in rats. Saudi Pharm. J.,  2010, 18(3), 173-178.
[http://dx.doi.org/10.1016/j.jsps.2010.05.009] [PMID: 23964177] 
[156] 
De Oliveira, A.M.;  da Mesquita, M.S.; da Silva, G.C.; de Oliveira Lima, E.; de Medeiros, P.L.; Paiva, P.M.G.;  Souza, I.A. de, Napoleão, T.H. Evaluation of toxicity and antimicrobial activity of an ethanolic extract from leaves of morus alba L. (Moraceae). Evid. Based Complement. Alternat. Med.,  2015, 2015, 1-7.
[http://dx.doi.org/10.1155/2015/513978] 
[157] 
Shah, P.; Deshmukh, P.; Joshi, S.; Ghag, M.; Kulkarni, Y.; Vyas, B.; Shah, D. Toxicity study of ethanolic extract of Acorus calamus rhizome. Int. J. Green Pharm.,  2012, 6, 29.
[http://dx.doi.org/10.4103/0973-8258.97119] 
[158] 
Zhang, Z.; Lam, T-N.; Zuo, Z. Radix Puerariae: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J. Clin. Pharmacol.,  2013, 53(8), 787-811.
[http://dx.doi.org/10.1002/jcph.96] [PMID: 23677886] 
[159] 
Olajuyigbe, O.O.; Afolayan, A.J. Pharmacological assessment of the medicinal potential of Acacia mearnsii De Wild.: antimicrobial and toxicity activities. Int. J. Mol. Sci.,  2012, 13(4), 4255-4267.
[http://dx.doi.org/10.3390/ijms13044255] [PMID: 22605976] 
[160] 
Hasan, M.R.; Islam, M.N.; Islam, M.R. Phytochemistry, pharmacological activities and traditional uses of Emblica officinalis: A review. Int. Curr. Pharm. J.,  2016, 5, 14-21.
[http://dx.doi.org/10.3329/icpj.v5i2.26441] 
[161] 
Burdock, G.A.; Carabin, I.G. Safety assessment of coriander (Coriandrum sativum L.) essential oil as a food ingredient. Food Chem. Toxicol.,  2009, 47(1), 22-34.
[http://dx.doi.org/10.1016/j.fct.2008.11.006] [PMID: 19032971] 
[162] 
Syed, A.A.; Lahiri, S.; Mohan, D.; Valicherla, G.R.; Gupta, A.P.; Kumar, S.; Maurya, R.; Bora, H.K.; Hanif, K.; Gayen, J.R. Cardioprotective Effect of Ulmus wallichiana Planchon in β-Adrenergic Agonist Induced Cardiac Hypertrophy. Front. Pharmacol.,  2016, 7, 510.
[http://dx.doi.org/10.3389/fphar.2016.00510] [PMID: 28066255] 
[163] 
Kouadio, J.; Bleyere, M.; Kone, M.; Dano, S. Acute and sub-acute toxicity of aqueous extract of nauclea latifolia in Swiss mice and in OFA rats. Trop. J. Pharm. Res.,  2014, 13, 109.
[http://dx.doi.org/10.4314/tjpr.v13i1.16] 
[164] 
Mirhoseini, M.; Mohamadpour, M.; Khorsandi, L. Toxic effects of Carthamus tinctorius L. (Safflower) extract on mouse spermatogenesis. J. Assist. Reprod. Genet.,  2012, 29(5), 457-461.
[http://dx.doi.org/10.1007/s10815-012-9734-x] [PMID: 22395857] 
[165] 
Krauze-Baranowska, M.; Glód, D.; Kula, M.; Majdan, M. Ha\lasa, R.; Matkowski, A.; Koz\lowska, W.; Kawiak, A. Chemical composition and biological activity of Rubus idaeus shoots–a traditional herbal remedy of Eastern Europe. BMC Complement. Altern. Med.,  2014, 14, 480.
[http://dx.doi.org/10.1186/1472-6882-14-480] [PMID: 25496130] 
[166] 
Sham, T.T.; Yuen, A.C.Y.; Ng, Y.F.; Chan, C.O.; Mok, D.K.W.; Chan, S.W. A review of the phytochemistry and pharmacological activities of raphani semen. Evid. Based Complement. Alternat. Med.,  2013, 2013,636194.
[http://dx.doi.org/10.1155/2013/636194] [PMID: 23935670] 
[167] 
Sharma, V.; Hem, K.; Seth, A.; Maurya, S.K. Solanum indicum Linn: An ethnopharmacological, phytochemical and pharmacological review. Cur. Res. J. Pharm. Allied. Sci.,  2017, 1, 1-9.
[168] 
Abdel-Aziz, H.; Fawzy, N.; Ismail, A.I.; El-Askary, H. Toxicological studies on a standardized extract of Solanum indicum ssp. distichum. Food Chem. Toxicol.,  2011, 49(4), 903-909.
[http://dx.doi.org/10.1016/j.fct.2010.11.048] [PMID: 21184797] 
[169] 
Karim, M.A.; Rizwani, G.H.; Sidddiqui, A.A.; Khan, M.F. Comparative Toxicities of Hydrastis Canadensis L., Berberis aristata DC. and Achillea millefolium L. Against Brine Shrimps (Artemia salina) Using Dosage Mortality Curve: A Probit Approach. J. Basic Appl. Sci.,  2015, 11, 69-73.
[http://dx.doi.org/10.6000/1927-5129.2015.11.09] 
[170] 
Dar, S.A.; Ganai, F.A.; Yousuf, A.R.; Balkhi, M.U.; Bhat, T.M.; Sharma, P. Pharmacological and toxicological evaluation of Urtica dioica. Pharm. Biol.,  2013, 51(2), 170-180.
[http://dx.doi.org/10.3109/13880209.2012.715172] [PMID: 23036051] 
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DOI https://dx.doi.org/10.2174/1871530320666191227104648	Print ISSN 1871-5303
Publisher Name Bentham Science Publisher	Online ISSN 2212-3873
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