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Wednesday, 13 June 2018

Anti-hypertensive medicinal plants and their mode of action

Volume 6, Issue 3, September 2016, Pages 107-118 Journal of Herbal Medicine Review article Author links open overlay panelPoojaRawatPawan KumarSinghVipinKumar https://doi.org/10.1016/j.hermed.2016.06.001 Get rights and content Highlights • Very few traditionally used plants have been validated scientifically through stringent animal studies and clinical trials. • Different mode of actions has been suggested for traditionally used anti-hypertensive plants. • Systematic validation studies are needed to translate the traditional medications as alternative anti-hypertensive drugs. • Traditional drugs fail to achieve the desired scale due to lack of scientific data on safety, efficacy and mode of action. • Attempt has been made to integrate the clinical studies and mode of action for better understanding of stakeholders. Abstract This review discusses the medicinal plants used in traditional medicine for the treatment of hypertension and their reported mode of action and efficacy. High blood pressure is considered a major risk factor for cardiovascular diseases (CVD) and strokes. Owing to its high prevalence and association with increased morbidity and mortality, it is a major worldwide health problem. According to the data of Global Health Observatory (GHO), in 2014 about 22% of adults aged 18 and above were reported with elevated blood pressure. Between 2010 and 2014 the mean systolic blood pressure of the world’s population has stayed constant at 124 mmHg. Historically, a number of plants and their formulations have been in use for the treatment of hypertension. Awareness of plant based medications and therapeutics are continuously increasing worldwide, hence the acceptance and demand. However, very few of these have been validated scientifically through stringent in vivo animal studies and clinical trials. Most of the available scientific data confirming the antihypertensive potential of traditionally used plants lacks systematic studies on their mode of action, efficacy, stability, toxicity and safety. In-depth scientific validation studies are required to authenticate the traditional medications as alternative and complementary drugs for the treatment of hypertension. Previous article Next article Abbreviations SBPSystolic blood pressure DBPDiastolic blood pressure ACEAngiotensin converting enzyme ECEsET converting enzymes NONitric Oxide SHRSpontaneously Hypertensive Rats 2K1Ctwo-kidney one clip (2K1C) Keywords Hypertension Traditional medicinal plants Angiotensinconverting enzyme Calcium antagonist 1. Introduction In hypertension, the blood flows through the blood vessels with a higher force compared to normal conditions. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) below 120 mmHg and 80 mmHg respectively is defined as normal blood pressure. SBP of 120–139 mmHg or DBP 80–89 mmHg is classified as prehypertension. A person with pre-hypertensive conditions are at higher risk for progression towards hypertension. Hypertension is defined as SBP ≥140 mmHg or DBP ≥90 mmHg. Stage 1 hypertension includes the patients having SBP between 140 and 159 mmHg or DBP ranging from 90 to 99 mmHg whereas stage 2 hypertension includes the patients with SBP ≥160 mmHg or DBP ≥100 mmHg (Liszka et al., 2005). It is evident from various scientific studies that persons with prehypertension are at particular risk of developing recognizable hypertension. Globally, increased blood pressure is estimated to cause about 12.8% of all the deaths, i.e. around 7.5 million deaths annually. In epidemiological studies, about 25% of the urban and 10% of the rural population in India were reported to have hypertension (Gupta, 2004). A positive correlation has been established between high blood pressure (HBP), coronary heart disease and ischemic and haemorrhagic stroke. Other established complications due to HBP are renal damage, heart failure, retinal haemorrhage and visual impairment. The medications suggested for the treatment of hypertension aims to bring SBP and DBP less than 140/90 mmHg which also reduces the associated cardiovascular complications. The most widely used anti-hypertensive chemical drugs are calcium channel blockers, thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and beta blockers. Traditional medicine encompasses knowledge systems that have been established over generations based on the concepts, beliefs and practices native to diverse cultures prior to the modern medicine era. In some Asian and African countries, about 80% of the population depend on the indigenous traditional remedies for their primary health care needs which mainly involves the crude herbal-preparations (Santé, 2005). Though traditional medicines are considered safe, optimization of their appropriate doses and uses are issues worth consideration, as herbal medicines if used incorrectly may also have adverse effects. Detailed research is desirable to establish the safety and effectiveness of practices as well as plants which are used in traditional systems of medicine. Regardless of prevailing uncertainties about safety, efficacy and cost-effectiveness of complementary and alternative medicines, use of traditional plants with rational evidence of efficiency and safety will surely have social, health, and economic benefits (Pandey et al., 2013). Studies suggest that around 20,000 medicinal plants have been documented in India, out of which only 7000–7500 are in use by traditional practitioners for curing different diseases (Samy et al., 2008). Like chemical drugs, traditional or plant based medications interact and affect the functions of molecules, bio-chemicals and invading pathogens present in the human body. Among traditionally used plants, a number of Chinese medicinal plants have also been reported to be anti-hypertensive (Xiong et al., 2013). An understanding of the mechanism of action is essential to recognise the accurate actions, thus predicting and preventing its adverse events. Globally, numerous traditional medicinal plants have been investigated for their anti-hypertensive effects (Tables 1–3). However, very few scientific reports are available regarding their mode of action as summarised in Fig. 1. Table 1. Traditional anti-hypertensive plants with clinical evidence and reported mode of action. S. No. Plant Name Family Part Used Geographical Distribution Mode of Action Reference 1 Achillea wilhelmsii Asteraceae Hydroalcoholic extract of aerial parts Turkey, Caucasus, Syria, Iraq, Iran, Central Asia, Afghanistan, and Pakistan Blockage of receptor operated and voltage dependent calcium channels Asgary et al. (2000), Jagtap et al. (2011) and Niazmand et al. (2014) 2 Allium sativum Liliaceae Bulb China, India, South Korea, Egypt, Russia, Bangladesh, Ethiopia, Myanmar, United States, Ukraine H2S mediated enhancement of the regulation of endothelial NO, induction of smooth muscle cell relaxation, vasodilation, and BP reduction Ried and Fakler (2014a), Al-Qattan et al. (2003), Ashraf et al. (2013), Ried et al. (2008), Nwokocha et al. (2011), Ried et al. (2013), Han et al. (2011) 3 Apium graveolens Apiaceae Hydro-alcoholic Leaf extract, 3-n-butylphthalide (BuPh) North America, Europe Blockage of calcium channel, stimulation of muscarinic receptor Dianat et al. (2015), Chai et al. (2010), Supari (2002), Moghadam et al. (2013), Jorge et al. (2013), Tsi and Tan (1997) and Branković et al. (2010) 4 Avena sativa Poaceae Whole cereal Russia, Canada, Finland, Poland, Australia Direct vasodilation and smooth muscle relaxation Cherksey (1993), Hosseini et al. (2001) and Keenan et al. (2002) 5 Camellia sinensis Theaceae EGCG, Polyphenol from plant China, India, Kenya, Sri Lanka, Turkey Vasodilation in mesenteric vascular beds Potenza et al. (2007), Nagao et al. (2007), Nantz et al. (2009), Negishi et al. (2004), Bogdanski et al. (2012), Peng et al. (2014) and Onakpoya et al. (2014) 6 Cratageus sp. Rosaceae Berry extract North America, Europe Endothelium-dependent, NO-mediated vasorelaxation via eNOS-phosphorylation, a redox-sensitive Src- and Akt-dependent activation of endothelial NO synthase or through inhibition of ACE Brixius et al. (2006), Brixius et al. (2006) and Miller (1998) 7 Crocus Sativus Iridaceae Crocetin Esters, Crocetin and Safranal Iran, Greece, Morocco, India Activation of ß2-adrenoceptors, inhibition of histamine H1 and muscarinic receptors and calcium channels and modulation of nitric oxide (NO) Llorens et al. (2015) and Mokhtari-Zaer et al. (2015) 8 Eucommia ulmoides Eucommiaceae Bark extract Europe, North America NO and renin-angiotensin system (RAS) dependent and direct vasorelaxation Engelhard et al. (2006) and Greenway et al. (2011) 9 Hibiscus sabdariffa Malvaceae Aqueous calyx extract China, Thailand, Mexico, Egypt, Senegal, Tanzania, Mali, Jamaica, India Direct vasorelaxation, decreasing serum Acetylcholinesterase and Na+ levels Mojiminiyi et al. (2013), Nwachukwu et al. (2015), McKay et al. (2010), Mozaffari-Khosravi et al. (2009), Serban et al. (2015), El-Mahmoudy et al. (2014) and Onyenekwe et al. (1999) 10 Linum usitatissimum Linaceae Seeds Canada, China, Russia, India, United Kingdom, United States, Ethiopia, Kazakhstan, Ukraine, Argentina Soluble epoxide hydrolase inhibition Caligiuri et al. (2014), Ursoniu et al. (2016) and Rodriguez-Leyva et al. (2013) 11 Nigella sativa Ranunculaceae Seed extract Southern Europe, Northern Africa, and Southern Asia Calcium channel blockade and diuretic Dehkordi and Kamkhah (2008), Keyhanmanesh et al. (2014), Leong et al. (2013), Mojiminiyi et al. (2013), Nanjmi et al. (2013), Nwachukwu et al. (2015), McKay et al. (2010), Mozaffari-Khosravi et al. (2009), and Onyenekwe et al. (1999) 12 Panax quinquefolius Araliaceae Ginseng Canada, United States Increased synthesis of NO, involvement of calcium channel Han et al. (1998), Sung et al. (2000) and Zhou et al. (2004) 13 Pinus pinaster Pinaceae Pyncogenol from bark extract Algeria, France (Corsica), Gibraltar; Italy (Sardegna, Sicilia), Monaco, Morocco, Portugal, Spain (Baleares), Tunisia NO dependent vasorelaxation Fitzpatrick et al. (1998) and Hosseini et al. (2001) 14 Rauwolfia serpentine Apocynaceae Reserpine alkaloid India, Thialand, Sri Lanka, Burma, and Indonesia, Pacific, South America, Africa Vasodilation mediated through action on vasomotor system Freis and Ari (1954), Sheldon and Kotte (1957), Gawade and Fegade (2012), Shamon and Perez (2009) and Asgary et al. (2000) 15 Theobroma cacao Malvaceae Polyphenols, Bean extract Ivory Coast, Ghana, Indonesia, Nigeria, Brazil, Cameroon, Ecuador, Colombia, Mexico, Papua New Guinea NO dependent vasodilation Cienfuegos-Jovellanos et al. (2009), Dehkordi and Kamkhah (2008), Fisher et al. (2003), Galleano et al. (2010), Grassi et al. (2008), Kozuma et al. (2005), Taubert et al. (2003) and Taubert et al. (2007) 16 Viscum album Santalaceae Aqueous leaf Extract North Africa to southern England and southern Scandinavia, across Central Europe to southwest and east Asia to Japan. α-1-adrenoceptor Antagonist Ofem et al. (2007) and Poruthukaren et al. (2013) Table 2. Traditional anti-hypertensive plants with clinical evidence; mode of action not reported. S. No. Plant Name Family Part Used Geographical Distribution Mode of Action Reference 1 Coleus forskohlii Lamiaceae Root Tablets India, Nepal, Burma, Sri Lanka and Thailand, Egypt, Arabia, Ethiopia, tropical East Africa, Brazil Not investigated Jagtap et al. (2011) 2 Lycopersicon esculentum Solanaceae An encapsulated tomato extract China, India, United States, Turkey, Egypt, Iran, Italy, Spain, Brazil, Mexico Not investigated Engelhard et al. (2006) 3 Psidium guajava Myrtaceae Fruit India, China, Kenya, Thailand, Indonesia Not investigated Singh et al. (1993) Table 3. Traditional anti-hypertensive plants without clinical evidence; with mode of action reported. S. No. Plant Name Family Part Used Geographical Distribution Mode of Action Reference 1 Annona muricata Annonaceae Aqueous leaf extract Caribbean, North America, Central America, South America, Africa Antagonism of Ca2+ Nwokocha et al. (2012a) 2 Artocarpus altilis Moraceae Aqueous leaf extract Central and South America, Africa, India, Southeast Asia, Madagascar, the Maldives, the Seychelles, Indonesia, Sri Lanka, and northern Australia, South Florida. α-adrenoceptor and Ca2⁺ channel antagonism. Nwokocha et al. (2012b) 3 Capparis cartilaginea Capparaceae Ethanolic leaf extract North and Tropical East Africa, Arabia, Israel, Iraq, South Iran, West Pakistan Direct relaxant action on myocardium and blood vessels Gilani and Aftab (1994) 4 Carum copticum Apiaceae Aqueous and Methanolic seed extract, thymol India, Iran, Egypt, Afghanistan Blockade of Calcium channel Gilani et al. (2005) and Aftab and Usmanghani (1995) 5 Cassia occidentalis Caesalpiniaceae Aqueous leaf extract Australia, southern and eastern USA, eastern Africa By inhibition of Ca2+ influx through receptor operated channel and voltage sensitive channel Ajagbonna et al. (2001) 6 Daucus carota Umbelliferae Cumarin glycosides isolated from arial parts Britain, Ireland, Europe and southwest Asia, Australia, North America Blockade of calcium channels Gilani et al. (2000) 7 Desmodium styracifolium Leguminosae Aqueous extracts India, Sri Lanka, Laos, Myanmar, Thailand, Cambodia, Vietnam, Malay Peninsula. Via cholinergic receptor stimulation and by blockades of autonomic ganglion and alpha-adrenoceptor. Ho et al. (1989) 8 Gossypium barbadense Malvaceae Crude leaf decoction Brazil, India, USA, Cuba Involvement of acetylcholine receptors Hasrat et al. (2004) 9 Loranthus micranthus Loranthaceae Leaf extract Nigeria, South Africa NO mediated vasorelaxation Iwalokun et al. (2011) 10 Moringa oleifera Moringaceae Ethanolic leaf extract India, Arabia, the East Indies, tropical Africa, tropical America, Sri Lanka, Mexico, Malabar, Malaysia, Philippine Islands. Via direct vasodilatation and a potential increase in antioxidant activity. Chen et al. (2012) 11 Musanga cecropiodes Cecropiaceae Aqueous Leaf & stem Bark extract Widespread in Africa, from Liberia to Ethiopia, extending south to Angola and the Democratic Republic of Congo Inhibition of sympathetic, cholinergic control of the arterial pressure and through ACE blockade, Release of NO Dongmo et al. (2002), Adeneye et al. (2006), Kamanyi et al. (1996) and Aziba, 2006 12 Ocimum basilicum Lamiaceae Aqueous extract of leaves and stalks Asia, Africa, Middle East, Europe, America An effect on ECEs, Direct relaxation of myocardium Umar et al. (2010) and Aftab (2006) 13 Peganum harmala Nitrariaceae Water or Ethanol Extract of whole plant/Seeds Africa, the Middle East, central Asia, South America, Mexico, and southern USA Inhibition of ACE activity, anti-cholinergic, anti-adrenergic, anti-spasmodic activity Kouchmeshky et al. (2012), Aqel and Hadidi 1991) and Moloudizargari et al. (2013) 14 Phyllanthus amarus Euphorbiaceae Aqueous Leaf extract tropical America, tropical Africa, Indian ocean islands Myocardial depression, muscarinic receptor mediated vascular smooth muscle relaxation and by the calcium channel ion blockade in vascular smooth muscle. Amaechina and Omogbai (2007) 15 Pueraria lobata Fabaceae Aqueous root extract Asia, Africa, North America, Central America, South America, Caribbean, Australia Opening of ATP-sensitive potassium channel (KATP), inward rectifier potassium channel (Kir) and voltage-dependent potassium (Kv) channels. Ng et al. (2011) 16 Punica granatum Lythraceae Fruit Juice Iran, Northern India, Mediterranean region of Asia, Africa and Europe Inhibition of ACE activity Mohan et al. (2010) 17 Raphanus sativus Cruciferae Ethyl acetate extract of leaves South east Asia, Africa, throughout the world By increasing the serum concentration of NO and enhancing antioxidant activities. Chung et al. (2012) 18 Sesamum indicum Pedaliaceae Sesamine, a lignan from sesame oil India, Sudan, Myanmar, China and other tropical and sub-tropical areas Anti-oxidative action Nakano et al. (2002) 19 Uncaria rhynchophylla Rubiaceae Hirsutine, Rhynchophylline and isorhynchophylline China, Japan, Sweden, Viet Nam Blockade of Calcium channel Zhu et al. (2015), Wu et al. (1980), Shi et al. (2003) and Horie et al. (1992) 20 Viola odorata Violaceae Leaf extract South America, Europe Inhibition of Calcium Influx, NO mediated pathway Siddiqi et al., 2012 21 Zingiber officinale Zingiberaceae Crude rhizome extract China, India, West Indies, Jamaica, Africa Blockage of voltage dependent Calcium channel Ojulari et al. (2014) and Elkhishin and Awwad (2009) Fig. 1 Download full-size image Fig. 1. Diagram depicting the mode of action of traditional anti-hypertensive plants (Red colour: Plants with Clinical evidence, Blue Colour: Plants without clinical evidence). Various mechanisms have been suggested for the maintenance of blood pressure in the human body. Irregularity at any of the stages may lead to changes in blood pressure resulting in hypertensive conditions. One such well known system is the renin-angiotensin-aldosterone system. Angiotensin-converting enzyme or “ACE” indirectly escalates the blood pressure and is known to cause constriction in blood vessels. It achieves this by converting angiotensin I to angiotensin II, which has an ability to constrict the blood vessels. ACE inhibitors block angiotensin-converting enzyme which results in widened and relaxed blood vessels and leads to easier blood flow through vessels, which ultimately reduces blood pressure (Atlas, 2007). Blockade of membrane embedded Ca2+ channels is another mechanism for reduction of hypertension. Calcium ion (Ca2+) concentrations outside of cells are about 10000-fold higher than inside of cells. On receipt of certain signals, the opening of Ca2+ channels takes place which results in inward movement of Ca2+ and the associated events. Most of the calcium channel blockers, also called, calcium antagonists preferentially or exclusively block the L-type voltage-gated calcium channel (Yousef et al., 2005). Voltage-dependent calcium channels mediates excitation and contraction of skeletal, smooth and cardiac muscles and also regulates aldosterone and cortisol secretion in endocrine cells of the adrenal cortex (Felizola et al., 2014). In the heart, they mediate the conduction of the pacemaker signals. Calcium channel blockers prevent calcium from entering cells of the heart and blood vessel walls and act by one of the following mechanisms. First is through reducing the contraction of arteries by affecting the muscle cells in arterial walls which causes an increase in arterial diameter and results in lowering of blood pressure. These calcium channel blockers can also act on the cardiac muscles (myocardium) by reducing the force of contraction of the heart. By slowing down the conduction of electrical activity within the heart, they slow down the heartbeat. The calcium signals are blocked on the adrenal cortex cells which directly reduces production of aldosterone steroid hormone and results in lowering of blood pressure. Endothelin converting enzymes (ECEs) play a significant role in maintaining the blood pressure by regulating conversion of endothelins, potent vasoconstrictor peptides, into active form and vasorelaxation via nitric oxide (NO) (Yanagisawa et al., 2000). Another mechanism regulating the blood pressure is through the sympathetic and parasympathetic nervous system. Most blood vessels in the body are innervated by sympathetic adrenergic nerves, which release norepinephrine (NE) as a neurotransmitter. Some blood vessels are innervated by parasympathetic cholinergic or sympathetic cholinergic nerves, both of which releases acetylcholine as their primary neurotransmitter. NE preferentially binds α1 and α2-adrenoceptors to cause smooth muscle contraction and vasoconstriction. ACh, binds to muscarinic receptors on the smooth muscle and/or endothelium and results in vasodilation. Antagonists of norepinephrine and epinephrine at β adrenoceptors by interfering with the sympathetic activity of the heart cause a reduction of heart rate and myocardial contractility, which decrease cardiac output and blood pressure (Brodde and Michel, 1999). A rise in blood pressure has been shown to be correlated with a number of factors, which are either elevated or suppressed in hypertensive patients. On this basis, several functional assays have been developed for diagnosis of hypertension as summarised in Table 4. Table 4. Assays for Diagnosis of Hypertension. S.No. Assay Correlation with hypertension References 1 Plasma Renin Activity Assay Elevated in patients with essential hypertension and suppressed in patients with hypertension due to primary aldosteronism Gunnells et al. (1967) 2 Measurement of Soluble Receptor for Advanced glycation end-products (AGE) in Plasma Plasma sRAGE levels are decreased in patients with essential hypertension Geroldi et al. (2005) 3 Measurement of Plasma aldosterone Elevated in case of renin hypertension Bühler et al. (1973) 4 Optical swelling Assay for Na+ −H+exchange in platelets Increased activity in patients with essential hypertension Rosskopf et al. (1991) 5 Immuno-MALDI (iMALDI) assay for plant Angiotensin-I quantification Measurement of Plasma renin activity Reid et al. (2010) 6 An esterolytic assay for measurement of urinary kallikrein Lower levels in patients with essential hypertension Margolius et al. (1971) 7 Na+,K+ co-transport assay Decrease in the maximal rate of the outward Na+,K+ co-transport in case of essential hypertension Dagher and Garay (1980) 8 Measurement of C-reactive protein (CRP) Associated with increased blood presure Smith et al. 2005 9 Receptor Assay for Digitalis-Like compounds in serum Elevated levels in hypertensive patients Moreth et al. (1987) 10 Platelet Adhesion Assay Increased adhesion to an important coagulation factor (fibrinogen) in the platelets from patients with hypertension Nadar et al. (2005) In the present review three different categories of anti-hypertensive plants that are used traditionally have been reported 1) the plants that have data on clinical studies in humans and have also reported their possible mode of action either in animal models or in vitro conditions 2) the plants which have been validated through clinical studies but have not been studied for their mode of action and 3) the plants that have been reported for their mode of action in animal models and/or in vitro conditions but have not been evaluated through clinical studies. Many of the traditional medications that deserve to be mentioned fail to meet the above criteria due to lack of scientific data on safety, efficacy and mode of action. These herbal formulations have also been unable to get required regulatory clearance due to lack of sufficient data. Therefore, the authors have attempted to integrate the clinical studies and mode of action either studied in animal models or in vitro, for a better understanding by interested parties such as herbal and medical practitioners, researchers and herbal drug companies. 2. Scientific evidence of anti-hypertensive activity of traditional medicinal plants Inclusion and Exclusion criteria: For this review, the research articles published on anti-hypertensive traditional medicinal plants during 1954 to November 2015 were explored through online internet searches, including scientific databases such as Pubmed, Science Direct, Google Scholar and others. The main keywords used for searching included: traditional herbal medicine; clinical studies; mode of action; mechanism; blood pressure and hypertension. Inclusion criteria adapted for this review are given below: a) Clinical studies: Patients/volunteers: More than 10 Study Duration: at least two weeks Outcomes: Clearly indicated in terms of efficacy and safety. Publication language: English b) In Vivo Animal Studies: Outcomes: containing mode of action and efficacy. Protocols: Well-defined in terms of doses and formulation type. Publication language: English The exclusion criteria considered for this review were: a) Studies without scientific data b) Patient/volunteer less than 10 c) Ethnobotanical reports without validation studies d) Language: other than English 3. Traditional medicinal plants with clinical evidence and reported mode of action 3.1. Achillea wilhelmsii (Yarrow) A clinical trial was conducted to check the anti-hypertensive effect of A. wilhelmsii, during which the patients with primary hypertension were treated with a hydroalcoholic extract for more than 6 months. A significant reduction in SBP and DBP was observed at the end of 6 months and 2 months respectively. This data supports the traditional therapeutic use of the plant for high blood pressure (Asgary et al., 2000). The mechanism of action was also investigated and it was found that a vasodilatory effect is mediated through inhibition of calcium influx through receptor operated and voltage dependent calcium channel (Niazmand et al., 2014). 3.2. Allium sativum (Garlic) Garlic tablets showed a significant decrease in systolic and diastolic blood pressures in both a dose and duration dependent manner in patients (n = 210) with stage 1 essential hypertension, after administration of recommended doses (300 mg, 600 mg, 900 mg, 1200 mg and 1500 mg) (Ashraf et al., 2013). In a meta-analysis, a study by Ried et al. (2008) reported a mean decrease of 4.6 ± 2.8 mm Hg for SBP in the group taking garlic (administered as a powder, extract and oil) compared to placebo, while the mean decrease in the hypertensive subgroup was 8.4 ± 2.8 mm Hg for SBP, and 7.3 ± 1.5 mm Hg for DBP. A significant association between blood pressure at the start of the intervention and the level of blood pressure reduction was observed as calculated using regression analysis. Studies are available in humans where the hypotensive effect of garlic has been successfully demonstrated (Ried et al., 2013). Several bioactive constituents such as “S-allyl cysteine” and “allicin” have been identified in garlic as having an anti-hypertensive action. In a clinical study, processed garlic (PG) was tested on spontaneously hypertensive rats (SHR) and hypertensive humans, for its effect on the SBP and DBP. Significant reduction in SBP and DBP was observed. While the lowering of SBP was observed in a time period of 2 weeks, the lowering of DBP took a much longer time of 8 weeks. The amount of active compound in PG was also checked and it was observed that the active compound “S-allyl-l-cysteine” was present at a concentration of about 75.3 mg/100 g in processed garlic (Han et al., 2011). Several ethnobotanical studies have indicated the use of A. sativum for the treatment of hypertension in the central region of Togo, Nigeria, south eastern Morocco, India, Thailand and Vietnam (Karou et al., 2011; Aiyeloja and Bello, 2006; Tahraoui et al., 2007; Kurian, 2012). Recently, the mode of action of garlic has been elucidated whereby it has been shown that garlic-derived polysulfides stimulate the production of vascular gasotransmitter hydrogen sulfide (H2S) that enhance the regulation of endothelial NO, which induces smooth muscle cell relaxation, vasodilation, and BP reduction (Ried and Fakler, 2014b). In another study, an investigation into the mode of action of A. sativum was carried out at molecular level and the possible role of Na/H exchanger isoform-1 was suggested (Al-Qattan et al., 2003). Though different studies have suggested different modes of action for garlic, further studies are needed to completely elucidate the physiological and biochemical mechanism of its anti-hypertensive action. 3.3. Apium graveolens (Celery) For the clinical assessment of the hypotensive potential of A. graveolens, a randomized double blind controlled trial was conducted, where the group receiving A. graveolens (as a formulation Tensigard® comprising of A. graveolens and Orthosiphon stamineus benth) showed significant reduction in blood pressure (Supari, 2002). The vasorelaxant activity of A. graveolens was also observed in an ex vivo study conducted on pre-contracted rat aortic rings with and without endothelium (Jorge et al., 2013). A number of studies have also been conducted on various animal models such as fructose induced hypertension model and two-kidney one clip (2K1C) renal hypertension rat model (Dianat et al., 2015; Chai et al., 2010; Moghadam et al., 2013). An active constituent from A. graveolens, 3-n-butylphthalide (BuPh), was isolated and its mode of action was investigated in SHR. Intraperitoneal administration of BuPh resulted in hypotensive and relaxing effect in the case of contraction induced by phenylephrine and KCl in rat aortic rings, however, no alteration in ACE activity was observed. Blockade of voltage- and receptor-operated Ca2+ channels was suggested to be the probable mechanism (Tsi and Tan, 1997). In another study the hypotensive effect of the plant extract was suggested to be through stimulation of muscarinic receptors (Branković et al., 2010). 3.4. Avena sativa (Green oats) A randomized controlled parallel-group pilot study was conducted to compare the short term effect of oat cereal consumption for a duration of 6 weeks. Significant reduction in both SBP and DBP was observed (Keenan et al., 2002). Avena pyrone, 2H-6-methyltetrahydropyran-2-one, extracted from the plant shows anti-hypertensive activity and the mode of action has been suggested to be through vasodilation and smooth muscle relaxation (Cherksey, 1993). 3.5. Camellia sinensis (Green tea) The anti-oxidant property of green tea has been implicated in the protective effects observed in the case of cardiovascular diseases (Amiri and Joharchi, 2013). A number of studies have been conducted to evaluate the anti-hypertensive effect of green tea (Nagao et al., 2007; Nantz et al., 2009; Negishi et al., 2004). A three month double-blind, placebo-controlled trial was conducted on 56 obese, hypertensive subjects with daily supplementation of green tea extract (GTE) in form of a capsule. A significant decrease of systolic and diastolic blood pressure was observed in the GTE group at a dose of 379 mg of GTE as compared with the placebo group (P < 0.01) (Bogdanski et al., 2012). A meta-analysis of 13 randomized controlled trials was recently performed. The overall outcome of this meta-analysis suggested that green tea consumption significantly decreased SBP level by −1.98 mmHg (P < 0.001). Green tea also exhibited a significant lowering effect on DBP −1.92 mmHg; (P = 0.002) when compared with normal control group (Peng et al., 2014). Another meta-analysis by Onakpoya et al. (2014) also showed the anti-hypertensive effect of green tea consumption. The role of epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea was studied for its protective efficacy against myocardial ischemia-reperfusion (I/R) injury in SHR (Potenza et al., 2007). Ex vivo studies indicated administration of EGCG results in the production of vasodilation in mesenteric vascular beds isolated from SHR in a dose dependent manner. Lowering of SBP was observed in SHR after EGCG therapy. Significant reduction of infarct size was also observed after the therapy along with improved cardiac function in Langendorff-perfused hearts exposed to ischemia-reperfusion (I/R) injury. 3.6. Cratageus sp. (Hawthorn) A number of clinical studies have demonstrated the hypotensive effect of Cratageus sp. (Asgary et al., 2003; Pittler et al., 2003; Tassell et al., 2010). In one such randomized, controlled study, an extract of a Camphor-Crataegus berry combination (Korodin Herz-Kreislauf-Tropfen®) was evaluated for its effect on blood pressure in patients with orthostatic hypertension. Two studies were conducted over a period of 5 and 8 months for evaluating the effect on systolic blood pressure and mean arterial blood pressure respectively. Each of the subjects were treated on four study days with either 5, 20 or 80 drops of the test combination or 20 drops of placebo. After each study day, a wash-out period of 48 h minimum and 2 weeks maximum was observed. A significant dose dependent fall in blood pressure was observed in all the treatment groups (Belz et al., 2002). In another randomized, double blind study conducted by Asgary et al. (2003) a hydroalcoholic extract of leaves and flowers of Crataegus curvisepala was administered over a period of more than 4 months to primary mild hypertensive patients. Significant lowering of SBP and DBP was observed. Vasodilating effects of Cratageus have been investigated in-vitro as well as in-vivo (Walden and Tomlinson Benzie, 2011; Rastogi et al., 2015; Wang et al., 2013). Several mechanisms have been suggested for the observed vasodilating effects such as endothelium-dependent, NO-mediated vasorelaxation via eNOS-phosphorylation (Brixius et al., 2006), a redox-sensitive Src- and Akt-dependent activation of endothelial NO synthase (Brixius et al., 2006) or through inhibition of ACE (Miller, 1998). The role of procyanidins present in Crataegus extract have been implicated in the endothelium-dependent nitric oxide-mediated relaxation in isolated rat aorta through activation of tetraethylammonium-sensitive K+ channels (Kim et al., 2000). 3.7. Crocus sativus (Saffron) A double-blind, placebo-controlled study consisting of treatment with Crocus sativus (saffron) stigma tablets was carried out on 30 healthy volunteers (15 males and 15 females), age ranging from 20 to 50 years to evaluate the safety and efficacy of saffron. Saffron tablets at a dose of 400 mg decreased standing systolic blood pressure (SBP) and standing mean arterial pressures significantly (Modaghegh et al., 2008). In another study, the combined effect of saffron supplementation and resistance training was evaluated in 44 healthy male subjects. Administration of 500 mg of saffron twice daily for a duration of 2 weeks resulted in a significant decrease in the plasma viscosity (Ghanbari-Niaki et al., 2015). Plasma viscosity has been shown to be positively correlated with the blood pressure (Letcher et al., 1981), thereby indicating the role of C. sativus as an anti-hypertensive. Active constituents from C. sativus, crocetin and safranal have been evaluated for their anti-hypertensive potential. The mode of action has been suggested to be via activation of ß2-adrenoceptors; inhibition of histamine H1, muscarinic receptors and calcium channels; via modulation of nitric oxide (NO) (Llorens et al., 2015; Mokhtari-Zaer et al., 2015). 3.8. Eucommia ulmoides (Rubber bark tree) A randomized placebo controlled clinical trial was conducted to evaluate the anti-hypertensive potential of E. ulmoides. The study was conducted using aqueous bark extract of plant administered for a period of 2-weeks to 30 healthy subjects. Treatment with E. ulmoides resulted in significant reduction in blood pressure. The use of E. ulmoides as an intervention for pre-hypertension was suggested in this study (Greenway et al., 2011). Investigation of mode of action shows that the antihypertensive effect is probably associated with regulating NO and renin-angiotensin system (RAS) and directly relaxing artery (Luo et al., 2010). 3.9. Hibiscus sabdariffa (Sorrel) Clinical studies have been conducted by several research groups to assess the hypotensive potential of H. sabdariffa. To examine the anti-hypertensive effects of H. sabdariffa, a randomized, double-blind, placebo-controlled clinical trial was conducted in pre- and mildly hypertensive adults. Intake of hibiscus tea by the individuals resulted in a significant reduction in SBP (McKay et al., 2010). A similar effect was observed in the case of hypertension in patients with type II diabetes (Mozaffari-Khosravi et al., 2009) and mild to moderate hypertensive subjects (Nwachukwu et al., 2015). A recent meta-analysis of randomized controlled trials was conducted by Serban et al. (2015) which showed a significant effect of H. sabdariffa supplementation in lowering both SBP and DBP. Four modes of action have been suggested; via direct relaxation of vascular smooth muscle; decreasing the level of acetylcholinesterase and Na+ in the serum and via decreasing the elevated blood lipid profile (El-Mahmoudy et al., 2014). 3.10. Linum usitatissimum (Flax seed) Various recent clinical studies are available which have evaluated the hypotensive potential of L. usitatissimum. In one of the studies carried out with participants having peripheral arterial disease, it was found that consumption of flaxseed results in significant reduction in both systolic and diastolic blood pressure. To elucidate the mode of action of flaxseed, the study was conducted and analysis of plasma from treated and control groups was carried out using solid phase extraction and high-performance liquid chromatography–mass spectrometry/mass spectrometry analysis. It was observed that consumption of flaxseed (dose of 30 g flaxseed powder per day for a period of 6 months) resulted in a significant decrease in 8 plasma epoxide hydrolase–derived oxylipins as compared to control suggesting that blood pressure lowering effect may be due to soluble epoxide hydrolase inhibition (Caligiuri et al., 2014). In another double-blind, placebo-controlled, randomized trial, an antihypertensive effect was achieved in the group consuming flaxseed (30 g flaxseed powder per day for 6 months) as compared to control. Significant lowering of SBP by ≈ 10 mm Hg, and DBP by ≈ 7 mm Hg was observed in the flaxseed group compared with placebo after 6 months of intake (Rodriguez-Leyva et al., 2013). In one of the recent meta-analysis studies of available randomized controlled trials, the impact of the effects of flaxseed supplements on blood pressure was assessed. The study included 15 trials (comprising 19 treatment arms) with 1302 participants. Significant reductions in both SBP and DBP were observed following the flaxseed supplementation (Ursoniu et al., 2016). Oral administration of the cationic peptides (200 mg/kg body wt.), obtained from flax seeds, to spontaneously hypertensive rats resulted in rapid decrease in systolic blood pressure. Arginine-rich peptides obtained from flaxseed protein was proposed to act as a source of nitric oxide, which has the ability to produce in vivo vasodilatory effects during hypertension (Udenigwe et al., 2012). 3.11. Nigella sativa (Fennel flower/black seed) In a randomized, double-blind, placebo-controlled trial, patients with mild hypertension were treated with 100 mg or 200 mg of N. sativa seed extract and observed for a period of 8 months. Significant lowering of both SBP and DBP in both the treatment groups was observed and the effect was found to be dose dependent (Dehkordi and Kamkhah, 2008). The mode of action of N. sativa has been suggested to be through blockade of calcium channel and through its diuretic action (Keyhanmanesh et al., 2014; Leong et al., 2013; Nanjmi et al., 2013) 3.12. Panax quinquefolius (Ginseng) The effect of Panax quinquefolius on arterial stiffness and blood pressure (BP), in type 2 diabetes patients with concomitant hypertension was accessed through a double-blind, placebo-controlled, parallel design clinical trial. After 12 weeks, compared to placebo, a daily dose of 3 g of extract significantly lowered systolic BP by 11.7% (P < 0.001). No effect was observed with diastolic BP (Mucalo et al., 2013). Cardiovascular effects of ginseng has been suggested to involve calcium channels. Ginsenosides isolated from the plant have been shown to selectively inhibit Ca2+ entry through receptor-mediated channel without affecting the voltage dependent channel or intracellular Ca2+ release (Zhou et al., 2004). In another study, the role of NO has been suggested in mediating anti-hypertensive action (Sung et al., 2000) 3.13. Pinus pinaster (Cluster pine) A randomized, double-blind, placebo-controlled clinical trial carried out on mildly hypertensive individuals was conducted over a period of 16 weeks to assess the anti-hypertensive potential of pycnogenol, the bark extract of P. pinaster. It was observed that administration of the pycogenol at a dose of 200 mg per day resulted in significant lowering of SBP. However, the reduction of DBP was not found to be statistically significant (Hosseini et al., 2001). The investigation of its mode of action indicated an endothelium-dependent relaxing (EDR) effect which was caused by enhanced NO levels (Fitzpatrick et al., 1998). 3.14. Rauwolfia serpentine (Rauwolfia) Several clinical studies have demonstrated the use of reserpine, an alkaloid isolated form R. serpentine as an anti-hypertensive and it is also used clinically for treatment of hypertension (Freis and Ari, 1954; Shamon and Perez, 2009). A 2-year double blind study conducted on patients with essential hypertension showed a significant fall of SBP and DBP in the patients receiving the treatment (Sheldon and Kotte, 1957). The mode of action of reserpine has also been investigated and it was found that the compound acts through control over the vasomotor centre leading to vasodilation (Gawade and Rauwolfia, 2012). 3.15. Theobroma cacao (Chocolate) A number of clinical studies have been conducted showing the attenuating effect of cocoa (administered in the form of beans, powder and chocolate) on the blood pressure of hypertensive individuals (Grassi et al., 2008; Kozuma et al., 2005; Galleano et al., 2010; Cienfuegos-Jovellanos et al., 2009; Taubert et al., 2007, 2003). The anti-hypertensive activity of T. cacao has been shown to be mediated by NO induced vasodilation (Fisher et al., 2003). 3.16. Viscum album (Mistletoe) In a 12-week clinical pilot study on 30 patients with pre-hypertension, the anti-hypertensive activity of V. album mother tincture was assessed. Administration of the tincture for a period of 12 weeks at a dosage of 10 drops 3 times a day resulted in a significant reduction of blood pressure in the treatment group (Poruthukaren et al., 2013). The mode of action was suggested to be through antagonism of α-1-adrenoceptor (Ofem et al., 2007). 4. Traditional medicinal plants with clinical studies, without reported mode of action 4.1. Coleus forskohlii (Indian coleus) In a randomized clinical trial, C. forskohlii preparations as ghana vati (an ayurvedic formulation) or Churna tablet (in two separate test groups) were administered to 49 hypertensive patients (50–80 years) with systolic blood pressure >140 mm of Hg and 90 mm of Hg and

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