Anti-hypertensive Herbs and their Mechanisms of Action: Part I

Traditional medicine has a history extending back to thousands of years, and during the intervening time, man has identified the healing properties of a very broad range of plants. Globally, the use of herbal therapies to treat and manage cardiovascular disease (CVD) is on the rise. This is the second part of our comprehensive review where we discuss the mechanisms of plants and herbs used for the treatment and management of high blood pressure. Similar to the first part, PubMed and ScienceDirect databases were utilized, and the following keywords and phrases were used as inclusion criteria: hypertension, high blood pressure, herbal medicine, complementary and alternative medicine, endothelial cells, nitric oxide (NO), vascular smooth muscle cell (VSMC) proliferation, hydrogen sulfide, nuclear factor kappa-B (NF-κB), oxidative stress, and epigenetics/epigenomics. Each of the aforementioned keywords was co-joined with plant or herb in question, and where possible with its constituent molecule(s). This part deals in particular with plants that are used, albeit less frequently, for the treatment and management of hypertension. We then discuss the interplay between herbs/prescription drugs and herbs/epigenetics in the context of this disease. The review then concludes with a recommendation for more rigorous, well-developed clinical trials to concretely determine the beneficial impact of herbs and plants on hypertension and a disease-free living.


INTRODUCTION
Cardiovascular disease (CVD) remains the leading cause of debility and premature death (WHO, 2013), and hence a major public health problem. Out of the major risk factors, which include diabetes, smoking, and dyslipidemia, hypertension is by far the most prevalent trigger for CVDs, and its comorbidity with other risk factors is even more puissant (Yang et al., 2011;WHO, 2013). Hypertension is responsible for around 16.5% of annual deaths worldwide (WHO, 2013), and is indeed the main cause of morbidity and mortality associated with CVDs (Kizhakekuttu and Widlansky, 2010). By 2030, the annual death toll is estimated to reach 23.5 million people (WHO, 2013). In addition to being a major player in the onset of diseases such as atherosclerosis, stroke, peripheral artery disease, heart failure, and coronary artery disease, hypertension can also lead to kidney damage, dementia, or blindness (August, 2004;Freedman and Cohen, 2016). It is important to note that May 17th of every year has been designated World Hypertension Day by the International Society of Hypertension (ISH), and the theme for 2013 World Health Day (7th April) was Hypertension, and hence a focus of considerable attention.
Hypertension is defined as having a systolic blood pressure (SBP) of ≥140 mmHg and a diastolic blood pressure (DBP) of ≥90 mmHg (≥140/≥90 mmHg; Tabassum and Ahmad, 2011). Every 20/10 (SBP/DBP) mmHg increase indicates a higher risk stage of hypertension; stage 1 (140-159/90-99 mmHg), stage 2 (≥160/≥100 mmHg; Archer, 2000;Weber et al., 2014) with the latter stage requiring immediate medical attention (Weber et al., 2014). Importantly, the American Society of Hypertension and ISH recommend that individuals with blood pressure of 120-139/80-89 mmHg be considered as pre-hypertensives (Weber et al., 2014). For targeted therapeutic interest, it is essential to realize that pre-hypertensive individuals are three times more likely to succumb to hypertension at a later stage of life than their normotensive counterparts (Archer, 2000). It is important to note that according to the Eighth Joint National Committee, it is recommended that for the general population, pharmacologic treatment be started at an SBP of 150 mmHg or DBP of 90 mmHg. However, for patients with Chronic Kidney Disease, treatment shall begin when the values of SBP and DBP reach 140 or 90 mmHg or higher, respectively (James et al., 2014).
Elevated blood pressure is categorized into types: primary (essential) and secondary hypertension. Secondary hypertension, which affects 5-10% of hypertensive individuals, is due to identifiable causes, such as diabetes and renal damage, and thus has a relatively higher chance of being treated. On the other hand, essential hypertension is acquired by multiple factors such as diet, age, lifestyle, neurohumoral activity, and interactions (Tabassum and Ahmad, 2011). Since its etiology may be more difficult to ascertain or establish, essential hypertension is more difficult to manage. Interestingly, the percentage of patients with essential hypertension (90-95%) far exceed those with secondary hypertension (Tabassum and Ahmad, 2011).
Many drugs, ranging from diuretics (Indapamide, Furosemide, Amiloride), sympathoplegic agents (clonidine, reserpine), renin inhibitor (Aliskiren), angiotensin converting enzymes (ACE) inhibitors (Enalapril, Captopril, Quinapril), angiotensin receptors blockers (ARBs-Losartan, Irbesartan, Olmesartan), calcium channel blockers (Nifedipine, Verapamil, Diltiazem), α-adrenergic blockers (Prazosin, Doxazosin), β-adrenergic blockers (Nebivolol, Atenolol) to vasodilators (Minoxidil, sodium nitroprusside), are used to manage blood pressure levels in hypertensive patients (Archer, 2000;Susalit et al., 2011). However, a point of interest to physicians and health-care practitioners is the alarming, and rather unfortunate, reality that high blood pressure is managed in only 34% of hypertensive patients (August, 2004;Wang and Xiong, 2012). The major concerns that often delay treatment allude to higher costs of antihypertensive drugs (Susalit et al., 2011), their availability and accessibility (Wang and Xiong, 2012), the undesired side effects of antihypertensive drugs (Susalit et al., 2011;Wang and Xiong, 2012) and the reduced patient compliance to consume more than a pill per day (August, 2004). Taking this into account, hypertensive patients, especially those dwelling in rural areas, seek alternative approaches such as herbal remedies for their treatment of hypertension and other diseases.

HERBAL REMEDIES
The use of herbal medicine as a treatment modality has significantly increased over the last decade (Frishman et al., 2009). This is due to several factors, principal of which is that herbal medicine is a cheaper alternative with fewer undesired side effects (Frishman et al., 2009;Susalit et al., 2011;Tabassum and Ahmad, 2011). However, the increased desire to use herbal treatment is not a reflection of the economic status of an individual from a certain region or a country. Indeed, 70% of the population in developed nations have resorted to Complementary and Alternative Medicine (CAM) for treatment purposes, and herbal medicine forms a large proportion of its application (WHO, 2008). Further, the usage of CAM in developing countries is becoming even more pronounced (WHO, 2008). Evidently, the rationale for the use of herbal and plant remedies is definitely not surprising, considering the fact that they contain thousands of bioactive components that have known therapeutic applications (Pan et al., 2013). Indeed, plants and herbs have actually provided a starting point for synthesis of over 50% of currently used pharmaceutical drugs (Pan et al., 2013). The pharmacopeia includes ephedrine (from Ephedra sinica), aspirin (from Salix alba), lovastatin (from Monascus purpureus), reserpine (from Rauwolfia serpentina), and taxol (from Taxus brevifolia; Frishman et al., 2009). Remarkably, reserpine (which depletes adrenergic neurotransmitters) still remains an effective treatment for hypertension (Weber et al., 2014).
Importance of plants and herbs, per se, in the medical field must not be overlooked as they have been used throughout human history. Herbal plant-based formulations or drugs are pivotal to Traditional practices in Chinese, Ayurvedic, and Unani Tibb medicine, which is practiced worldwide. Overall, this may explain the increasing interest in panning out the beneficial health effects of various plants and herbs in different diseases including hypertension (Tabassum and Ahmad, 2011). In this review, we focus to provide a summary of different plants that have been reported to exhibit antihypertensive properties, and that can specifically mitigate anti-inflammatory causes in arterial hypertension. Moreover, where information is available, we have discussed botanical-induced improvements in renal biology.

MOLECULAR PATHOGENESIS OF HYPERTENSION
Hypertension is characterized by arterial derangement in the vascular tree, affecting large conduit arteries (such as aorta), small resistance size arteries (150-400 µm), and the microcirculation (arterioles and capillaries). Increased arterial reactivity (sensitivity and potency) due to dysregulation in endothelial nitric oxide synthase (eNOS) and pro-oxidant enzymes, enhanced basal and activated calcium levels due to overactive transmembrane calcium permeability through calcium channels, and/or coexistence of vascular smooth muscle cell (VSMC) hyperplasia and hypertrophy (vascular remodeling) can all lead to increased vasoconstriction. These pathological events lead to an increased ratio of vessel wall thickness as compared to the dimensions of the arterial lumen (Folkow, 1990). It is this increased ratio that plays a major role in precipitating hypertension. Below we discuss some of the major mechanisms implicated in the pathogenesis of hypertension. Then we discuss the most commonly used herbs that ameliorate blood pressure by modulating these mechanisms.
Amongst the several VSMC growth inhibitors are nitric oxide (NO), cyclic guanosine monophosphate (cGMP; Pilz and Casteel, 2003), transforming growth factor-beta (TGFβ; Itoh et al., 1993;Rudijanto, 2007), and adenosine monophosphateactivated protein kinase (AMPK; Song and Zou, 2012). For example, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), a membrane-permeable activator of AMPK, inhibits cell cycle progression, and migration of VSMCs as well as vascular remodeling following injury (Stone et al., 2013). Moreover, rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, acts via protein kinase G (PKG) to exert an anti-proliferative effect on VSMCs in models of angioplasty-induced vascular injury . Contextually, complex regulatory interactions exist between growth factors and the VSMC phenotype (Itoh et al., 1993). The balance between the pro-proliferative and anti-proliferative signals determines, to a large extent, the phenotype of VSMCs. As will be discussed later in this review, many plants and herbs indeed ameliorate increased blood pressure by favorably modulating the VSMC phenotype.

Endothelial Cells
The endothelial cell layer is no longer considered as an inert entity. It rather plays significant roles in many aspects of homeostasis along the cardiovascular network. Endothelial function is regulated and maintained by a variety of cell surface receptors, some of which induce the release of vasoactive substances to regulate vascular tone and smooth muscle cell proliferation (Drexler and Hornig, 1999). Local and circulating cues stimulate the vascular endothelium to release vasodilators (NO, prostacyclin, and endothelial-derived hyperpolarizing factor) and vasoconstrictors (endothelin, thromboxane, and PDGF;Iglarz and Clozel, 2007). When there is an imbalance between these vasoactive agents, an increased production of reactive oxygen species (ROS) may result, which then leads to endothelial dysfunction and eventually hypertension Montezano and Touyz, 2012;Silva et al., 2012; Figure 1).
Endothelial dysfunction anticipates the progression of anatomically overt vascular disease, which robustly correlates with hypertension. However, endothelial derangement could be reversed by modification therapy, such as with herbal remedies. This fact will be highlighted in different sections of this review.

Repertoire of Signaling Molecules
Assuming a homeostatic imbalance, the following signaling molecular entities become integral to the pathogenesis of hypertension (Ong and Whitworth, 2011;Montezano and Touyz, 2012). Fortunately, a diverse range of plant and herbal extracts and their individual metabolites can modulate signaling cascades implicated in the physiology of the cardiovascular system (see Section Herbs and Spices Most Commonly Used for Treatment of Hypertension, below). These herbs are not only vasculoprotective but they could also potentially reverse the changes in hypertension. This particularly applies if the alterations in hypertensive patients are addressed prior to reaching a decompensated state.

Reactive Oxygen Species
In good health, the activity of pro-oxidants is balanced by antioxidative agents. However, when this equilibrium is disturbed, the un-orchestrated milieu leads to pathologic states, such as hypertension, atherosclerosis, and other vascular complications (Figure 1; Montezano and Touyz, 2014). ROS such as superoxide anions (O •− 2 ) and hydroxyl ions (OH − ) play a major role by promoting an environment of oxidative stress, which is a primary cause in the pathogenesis of hypertension (Zeng et al., 2009;Song and Zou, 2012;Montezano et al., 2015). ROS are produced from the reactivity of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and many other enzymatic reactions particularly ones related to the electron transport chain within the mitochondria (Zeng et al., 2009;Dharmashankar and Widlansky, 2010;Drummond et al., 2011;Song and Zou, 2012). The oxidant molecules are inactivated by antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and nonenzymatic substances like reduced glutathione (GSH; Song and Zou, 2012). Recent evidence suggests that AMPK can also suppress the activity of NADPH oxidase (Song and Zou, 2012). An increase in the amount of ROS, and the corresponding fall in intracellular endothelial antioxidant levels (Zeng et al., 2009;Drummond et al., 2011;Song and Zou, 2012), signals an oxidative stress state. The oxidative stress leads to endothelial cell dysfunction and vascular smooth muscle remodeling by reducing NO bioavailability (Zeng et al., 2009;Drummond et al., 2011). ROS are also responsible for the oxidation of low-density lipoprotein (LDL), which results in inflammation and increased proliferation of VSMCs (Slevin et al., 2012). Both inflammation and enhanced proliferation significantly trigger plaque formation (Slevin et al., 2012) which in turn may contribute to increased blood pressure. Interestingly, blocking ROS production by exposure to antioxidants has been shown to reduce blood pressure in rodents (Zeng et al., 2009).

Nitric Oxide
Nitric oxide (NO) is often recognized as an important indicator of vascular health. It plays an important role in blood pressure regulation due to its vasodilating potency (Francis et al., 2010) as well as its ability to inhibit aggregation of platelets and proliferation of VSMCs (Zeng et al., 2009). NO is produced from L-arginine (Francis et al., 2010) by NO synthases (NOS) such as endothelial NOS (eNOS; Francis et al., 2010). After its release, NO translocates into VSMCs and activates soluble guanylate cyclase (sGC), which then catalyzes the conversion and cyclization of guanosine triphosphate (GTP) to cGMP (Francis et al., 2010). cGMP then binds to cGMP-dependent protein kinases (PKGs; Francis et al., 2010) which modulate calcium levels and the consequent contraction of VSMCs (Francis et al., 2010). Within seconds of its production, NO reacts with superoxide anions (Drummond et al., 2011) to produce peroxynitrite (ONOO − ; Drummond et al., 2011). This in itself is a selective oxidant and can precipitate oxidative stress as well as diminish the vasodilatory effect of NO (Drummond et al., 2011). As such, the concentration of ROS has a direct impact on the bioavailability of NO. Interestingly, oxidative stress can also induce eNOS uncoupling, so that eNOS generates free radicals instead of NO. For example, stimulation of NADPH oxidase leads to the generation of superoxide anion (O •− 2 ), which reacts with NO to form the potent oxidizing agent, peroxynitrite. This peroxynitrite then oxidatively degrades the eNOS cofactor tetrahydrobiopterin (BH 4 ) to the inactive dihydrobiopterin (BH 2 ). Effectively, this yields more superoxide anion that eventually depletes BH 4 . Therefore, a shift in balance from NO to superoxide formation ensues; this is referred to as uncoupling of NOS (Michel and Vanhoutte, 2010). As such, the interplay between NO and the regulatory mechanisms governing its bioavailability are thus intimately intertwined with vascular tone and endothelial dysfunction (Montezano and Touyz, 2012).

Hydrogen Sulfide
Hydrogen sulfide (H 2 S) is an important biological mediator produced in VSMCs and potentially endothelial cells via the catalysis of L-cysteine by the enzyme cystathionine γ-lyase (CSE; Calvert et al., 2010;Pan et al., 2012). It has been reported that deficiency in H 2 S production is positively correlated with pathophysiology of hypertension in several animal models (Benavides et al., 2007;Liu et al., 2012). Indeed, CSE activity and H 2 S levels were notably decreased in the aorta and plasma of SHR, respectively (Yan et al., 2004). In addition, there was a significant increase in BP levels of Wistar Kyoto (WKY) rats treated with DL-propargylglycine (PPG), a CSE inhibitor (Yan et al., 2004). Furthermore, administration of H 2 S is sufficient to abolish the N ω -nitro-L-arginine methyl ester hydrochloride (L-NAME, an inhibitor of nitric oxide synthase)induced hypertension in WKY rats (Zhong et al., 2003).
At the molecular and cellular levels, H 2 S exhibits a vasorelaxant effect on VSMCs by increasing intracellular levels of cGMP (Bucci et al., 2012) and opening ATP-dependent potassium channels (K ATP ; Banerjee et al., 2002;Calvert et al., 2010;Bucci et al., 2012;Pan et al., 2012). Interestingly, H 2 S has also been reported to prevent vascular inflammation (Calvert et al., 2010;Pan et al., 2012), reduce ROS production, depress Ang II and ACE levels, potentiate antioxidant mechanisms, diminish VSMC proliferation, and induce NO synthesis (Benavides et al., 2007).

Angiotensin II
The Renin-Angiotensin-Aldosterone (RAA) system plays a pivotal role in regulating blood pressure (Nguyen Dinh Cat and Touyz, 2011). Activation of the RAA system in response to a decrease in cardiac output leads to the secretion of renin, which in turn catalyzes the conversion of angiotensinogen to angiotensin I (Ang I). Ang I is then cleaved by Angiotensin Converting Enzyme (ACE)-1 (ACE-1) to form Angiotensin II (Ang II). Ang IImediated hypertension occurs by promotion of sodium and water retention as well as enhancement of vasoconstriction by binding to the angiotensin type 1 (AT 1 ) receptor (Morgan, 2003;Nguyen Dinh Cat and Touyz, 2011;Savoia et al., 2011). Activation of AT 1 receptors is known to trigger the proliferation of VSMCs (Castro et al., 2010;discussed earlier). The fact that ACE is present in several tissues, including arteries, indicates that Ang II can be formed locally within the arteries themselves. Indeed, there is a higher concentration of Ang II in the vasculature of hypertensive compared to normotensive rats (Ma et al., 2010). Taken together, these observations may explain why inhibiting ACE is an attractive approach for antihypertensive therapies (Morgan, 2003;Bernstein et al., 2013). Ang II induces aldosterone production (Oparil et al., 2003;Manrique et al., 2009;Ma et al., 2010) and cardiac muscle cell growth (Manrique et al., 2009;Ma et al., 2010;Song and Zou, 2012). Blockade of AT 1 receptors improves endothelial dysfunction  and has been reported to decrease BP (Kang et al., 2009). Accumulating evidence demonstrates that Ang II also stimulates NADPH oxidase to generate ROS (Ma et al., 2010;. In addition, Ang II may increase the sympathetic nervous system (SNS) activity (Manrique et al., 2009), which participates in pathogenesis of hypertension by elevating cardiac output and increasing peripheral vascular resistance (Oparil et al., 2003).

Nuclear Factor Kappa B
Inflammation is well-documented to contribute to vascular remodeling and consequent hypertension (Vazquez-Prieto et al., 2011). Nuclear Factor kappa B (NF-κB), a transcription factor, is known to partake in the pathology of hypertension. It induces endothelial cell dysfunction, oxidative stress, and inflammation (Li and Zhuo, 2008;Kang et al., 2009) through the release of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6; Kang et al., 2009).
It has been shown that increased expression and activation of NF-κB contributes to renal injury and hypertension . Indeed, suppressing NF-κB with pyrrolidine dithiocarbamate (PDTC) decreased SBP in spontaneous hypertensive rats (SHRs; Elks et al., 2009). Interestingly, PDTC also suppressed the higher concentration of cytosolic and mitochondrial ROS in kidneys of these SHRs .

HERBS AND SPICES MOST COMMONLY USED FOR TREATMENT OF HYPERTENSION
Secondary metabolites of herbs and spices exhibit antihypertensive effects. Here, we present a comprehensive alphabetical list of herbs for which sound evidence suggests they could be beneficial in hypertension therapy (Tables 1-6; Figure 1).

Allium sativum (Garlic)
Garlic's multi-fold therapeutic effects have been recognized for thousands of years amongst different cultures around the world, and continues to attract interest from pharmacologists and health practitioners (Frishman et al., 2009;Qidwai and Ashfaq, 2013; Table 2). This herb is not only known for its hypotensive capacity, but is also characterized by antiinflammatory, antioxidant, antibacterial, hypocholesteremic, and anti-cancer properties (Banerjee et al., 2002;Mousa and Mousa, 2007;Frishman et al., 2009;Qidwai and Ashfaq, 2013). For health benefits, garlic can be consumed in different forms, such as raw, aged, an aqueous extract, oil, and in powder form (Banerjee et al., 2002;Frishman et al., 2009;Ried et al., 2013).
Several mechanisms have been alluded to in the explanation of garlic's hypotensive effects (Shouk et al., 2014). These are based on garlic's organo-sulfur constituents such as Allicin, Sallylcysteine (SAC), diallyl disulfides (DADS), diallyl trisulfides  (DATS), and methyl thiosulfonate (Banerjee et al., 2002;Qidwai and Ashfaq, 2013). Many hypertensive patients use garlic to lower their blood pressure (Qidwai and Ashfaq, 2013). The reported effects vary from significant reduction in mean arterial pressure, drop in either SBP or DBP only, to no alteration in blood pressure at all (Banerjee et al., 2002;Mousa and Mousa, 2007;Frishman et al., 2009;Yang et al., 2011;Augusti et al., 2012). However, most studies confirm the induction of hypotensive effects by garlic and its constituents. Banerjee and Maulik reviewed pertinent literature and concluded that different forms of garlic can reduce SBP, DBP, or both (Banerjee et al., 2002). Also, an investigation by Qidwai and Ashfaq indicated that an almost 80% efficacy in anti-hypertensive effects of garlic was reported (Qidwai and Ashfaq, 2013). Interestingly, evidence from meta-analysis studies indicates that aged garlic extract (AGE) produces consistent lowering of blood pressure compared to other forms of garlic. A recent meta-analysis of randomized, controlled trials concluded that garlic supplements induce a significant reduction in both SBP and DBP by 3.75 and 3.39 mmHg, respectively . Similarly, another meta-analysis on randomized, controlled trials also reported a significant decrease in SBP by 4.6 ± 2.8 mmHg compared to placebo (Ried et al., 2008). Moreover, in a double-blind, parallel randomized placebocontrolled study, individuals with uncontrolled hypertension (≥140 mmHg) who were treated with 960 mg/day of AGEs for 12 weeks exhibited an average decrease of 10.2 ± 4.3 mmHg in SBP (Ried et al., 2010). This effect appears to be due to the principle constituent S-allylcysteine, which is relatively more stable in relation to allicin (Ried et al., 2010). Furthermore, in another randomized, parallel, placebo-controlled trial, patients with stage 1 hypertension ingested garlic tablets (300-1500 mg/day) for 24 weeks (Ashraf et al., 2013). This study reported a significant decrease in SBP and DBP by a maximum of 9.2 and 6.27 mmHg, respectively (Ashraf et al., 2013).
Analysis of assays on antioxidant ability of different forms of garlic demonstrate far greater potency in aged extracts than other types of garlic clove derivatives (Mathew and Biju, 2008). Indeed, AGE potently scavenges ROS (Drobiova et al., 2011;Morihara et al., 2011) leading to an increase in cellular antioxidants (Banerjee et al., 2002;Drobiova et al., 2011). In comparable studies, Drobiova et al. (2011) treated two-kidney, one-clip (2K-1C) hypertensive rats for 3 weeks with an aqueous extract of garlic (500 mg/ml), which raised the antioxidant levels by over 60% and resulted in reduction of SBP by 50%. The superoxide scavenging abilities of AGE have also been demonstrated in human neutrophils (Morihara et al., 2011). In addition, a daily 150 or 400 mg/kg dose of garlic extracts has also been reported to decrease NADPH oxidase in fructose-fed rats' aorta (Vazquez-Prieto et al., 2011).
The endogenous signaling gases, NO and H 2 S, are recognized as mediators of garlic's antihypertensive properties (Banerjee et al., 2002;Mousa and Mousa, 2007;Ried et al., 2013). In a clinical trial performed by Mousa and Mousa (2007) on stage 1 hypertensive subjects (≥140 mmHg), who consumed a daily dose of 2600 mg of garlic (one tablet comprising of 650 mg of garlic bulb-Allium sativum-powder) for a period of 10 days, the authors reported a significant reduction of 17 mmHg in SBP, but the DBP remained unchanged (Mousa and Mousa, 2007; Table 6). In mechanistic support of the blood pressure measurements, the group exposed human umbilical vein endothelial cells (HUVECs) to a garlic extract, which caused an increase in the bioavailability of NO, a potent vasodilator, by 200% (Mousa and Mousa, 2007). This is thought to occur through the reaction between NO and the sulfide components of garlic (Ku et al., 2002). An ethanolic extract of garlic (0.8 mg/ml) caused relaxation in rat pulmonary arteries pre-contracted with phenylephrine (Ku et al., 2002). Another study has demonstrated that extracts (150 and 400 mg/kg daily) of garlic not only upregulate eNOS, but also induce an increase in eNOS activity in fructose-fed rats (Vazquez-Prieto et al., 2011). In addition, garlic does not merely increase H 2 S production, but induces its synthesis for vasorelaxant activity (Benavides et al., 2007). In their study, Benavides et al. (2007) demonstrated that red Inhibits VCAM-1 100 µg/ml Human umbilical vein endothelial cells Cho et al., 2013 blood cells synthesize H 2 S from polysulfides that were extracted from garlic. They also reported that garlic (500 µg/ml) and garlic compounds-mediated increase in H 2 S is correlated with an increase in vasorelaxant activities in rat aortic rings (Benavides et al., 2007). Moreover, treatment with 50 µM garlic-derived DADS induce an increase in expression of Connexin-43 (Cx43), a gap junction protein whose expression is correlated with a reduced VSMC proliferation and DNA synthesis (Joshi et al., 2012; Table 4).
Garlic's ability to inhibit ACE activity has also been recognized (Sendl et al., 1992), and in this regard gamma-glutamyl-cysteines have been identified as the antagonists (Sendl et al., 1992). In addition, a daily dose of 150 and 400 mg/kg of aqueous garlic extracts caused a reduction of VCAM-1 in fructose-fed rats (Vazquez-Prieto et al., 2011). Constituents of Garlic dampen Ang II-induced vasoconstrictor responses, antagonize endothelin-1 induced vasoconstriction, inhibit VSMCs proliferation in smooth muscles isolated from SHR and abrogate the activation of NF-κB (Banerjee et al., 2002;Castro et al., 2010;Pan et al., 2012). These effects are modulated by Allicin after the reaction of Alliin with the enzyme Alliinase (Frishman et al., 2009;Qidwai and Ashfaq, 2013).
Despite having these multifarious therapeutic effects, garlic also produces a few minor side effects. Several articles report garlic's ability to cause abdominal swelling, heartburn, flatulence, and acid reflux (Yang et al., 2011;Ried et al., 2013). Individuals under anticoagulant management are advised to avoid garlic consumption throughout the duration of treatment as the antihemostatic effect may be far more potent and detrimental (Qidwai and Ashfaq, 2013).
In addition to its antioxidant (Lobo et al., 2010) and antiinflammatory (Kunwar et al., 2010) characteristics, this herb can potently inhibit the activation of NFκB (Das et al., 2012; Table 3). Other reports also indicate that A. paniculata exhibits antiinflammatory activities in natriuretic peptide receptor-A (Npr1)gene knockout mice (Das et al., 2012). Indeed, a daily 4 mg/kg dose of andrographolide caused a significant reduction in the production of NF-κB (Das et al., 2012).

Apium graveolens (Celery)
The hypotensive effect of celery has been reported in in vivo animal studies. Seed extracts [300 mg/kg body weight, aqueousethanolic (20/80, v/v), hexanic and methanolic] of Apium graveolens reduce blood pressure in deoxycorticosterone acetateinduced hypertensive rats (Moghadam et al., 2013). Hexanic extract was by far the more potent in lowering BP in comparison to other solvent extracts. This was explained by greater retention of n-butylphthalide, which has been identified as the source of celery's flavor and aromatic odor (Moghadam et al., 2013). Similarly, this phthalide was reported to decrease BP in another animal model of hypertension (SHRs; Tsi and Tan, 1997). Apigenin, a flavone isolate of A. graveolens, blocked aortic ring contractions caused by cumulative calcium increases in high potassium (60 mM) Krebs' solution; this was suggested to result from blocking of Ca 2+ influx via calcium channels (voltage and receptor gated; Ko et al., 1991). The inhibition of calcium entry from extracellular sources was also responsible for apigenin-dependent relaxation of noradrenaline-preconstricted rat isolated aorta. This action was not influenced by either methylene blue, endothelial denudation, indomethacin, nifedipine, or caffeine, and the concentration of intracellular signaling molecules (cAMP, cGMP, and inositol monophosphate) were unaltered (Ko et al., 1991). Importantly, extracts and constituents of celery have been reported to lower arterial pressure in humans, possibly by lowering levels of circulating catecholamines and decreasing vascular resistance (Houston, 2005). Interestingly, this herb can reduce oxidative stress by virtue of its flavonoid content that potentiates antioxidant mechanisms (Popovic et al., 2006).

Bidens pilosa L. (Beggar's Tick, Black-Jack, etc.)
This plant belongs to the family Asteraceae and has several common names: beggar's tick, black-jack, and broom stick. In addition to exhibiting antihypertensive effects, B. pilosa also possesses anti-cancer, anti-bacterial, anti-malarial, and antiobesity properties (Bartolome et al., 2013). As of yet, no clinical trials have determined the potential effect of this plant on hypertension. However, extracts of its leaves were able to prevent and attenuate high blood pressure in different hypertensive rat models (SHRs and fructose-fed hypertensive rats) as well as normotensive Wistar rats (Dimo et al., 2002;Bartolome et al., 2013; Tables 2, 3). In fructose-fed rats, after 6 h of treatment with 75 and 150 mg/kg of methanolic leaf extract of B. pilosa, SBP was reduced by 17 and 21%, respectively (Dimo et al., 2002). Interestingly, the extract also showed preventive effect on SBP by 9 and 11% at 75 and 150 mg/kg, respectively. Using the same animal model, it was also shown that a 3-week treatment with aqueous and methylene chloride extracts of B. pilosa can prevent fructose-induced hypertension (Dimo et al., 2001).
There are conflicting reports regarding B. piloas's effect on insulin sensitivity, with some studies showing improvement in insulin sensitivity (Dimo et al., 2002;Bartolome et al., 2013), while others reporting no effect on plasma insulin concentration (Dimo et al., 2001). However, there is a definite agreement on its vasorelaxant responses (Dimo et al., 2002;Bartolome et al., 2013). Cumulative doses of a neutral extract of B. pilosa (with an optimum concentration of 0.32 mg/ml) relaxed potassium chloride and noradrenaline pre-constricted rat aortas (Nguelefack et al., 2005). The mechanism of vasodilation has not been completely deciphered. It appears to be independent of ATP-sensitive potassium channels, but possibly involves a calcium channel antagonism and cyclooxygenase metabolite (Nguelefack et al., 2005). Importantly, the crude extract, its fractions or the isolated phytochemicals of B. pilosa have been reported to display radical scavenging ability (Bartolome et al., 2013). Two of these compounds, luteolin (a flavonoid) and ethyl caffeate (ester of hydroxycinnamic acid), exhibit potent antiinflammatory activities. For example, luteolin blocked the effects of inflammatory cytokines, TNF-α, and IL-6 (Xagorari et al., 2001). Moreover, both luteolin (Xagorari et al., 2001) and ethyl caffeate (Chiang et al., 2005) can inhibit the pro-inflammatory transcription factor, NF-κB.

Camellia sinensis (Tea)
Collectively, the teas prepared from Camellia sinensis are the most frequently consumed beverages and are second only to water, worldwide (Faria et al., 2012). Tea has pleiotropic effects including antibacterial, anti-inflammatory (Deka and Vita, 2011), anti-cancer, anti-diabetic, as well as antihypertensive actions (Deka and Vita, 2011; Table 1). The data on the hypotensive effect of tea are not concrete. Hodgson et al. reported increases in BP after 30 min of consuming tea, with the BP returning to its baseline value after 60 min (Hodgson et al., 1999). Another study suggested that green tea causes a decrease in SBP for participants with BP of 140 mmHg or higher (Nagao et al., 2007). A meta-analysis of five trials came to conclusion of no change in blood pressure subsequent to drinking tea (Taubert et al., 2007). However, a more recent meta-analysis study of randomized controlled trials demonstrated that green tea reduces both SBP and DBP by 1.98 and 1.92, respectively (Peng et al., 2014). Likewise, other meta-analysis of randomized controlled trials came to the same conclusion that green tea reduces SBP and DBP by 1.8 and 1.4 mmHg, respectively. Interestingly, it was reported that green tea evoked a more powerful hypotensive effect compared to black tea, and that long-term tea consumption produced a more significant SBP and DBP reduction. Moreover, in a double-blind, placebo-controlled trial, obese hypertensive patients who received 379 mg green tea extract for 12 weeks exhibited a significant decrease in SBP and DBP by 4 mmHg each (Bogdanski et al., 2012). Another randomized double-blind, placebo-controlled trial concluded that hypertensive subjects who consumed 4479 mg (3 cups/day, 1493 mg each) of black tea for 24 weeks exhibited a significant reduction in both SBP and DBP by 2 and 2.1 mmHg, respectively (Hodgson et al., 2012). It is important to note here that ingestion of green or black tea (7.6 g in 400 ml water) by mild hypertensive subjects did not decrease blood pressure. On the contrary, green or black tea ingestion caused a non-significant increase in SBP/DBP by 1.7/0.9 and 0.7/0.7 mmHg, respectively (Hodgson et al., 1999).
Flavonoids are noted for their vasorelaxant responses, including flow-mediated (Ras et al., 2011), and endothelialdependent dilation (Oyama et al., 2010; Table 2). Black tea catechins are converted by an enzymatic (polyphenol oxidase and peroxidase) oxidative polymerization reaction to tannins: theaflavins (benztropolone ring) and thearubigins, both of which are orange-red colored polyphenolic pigments that are also potent vasodilators (Yang et al., 2011). A couple of clinical studies have reported black tea's positive effect on flow-mediated dilation (FMD), an index of endothelial function (Duffy et al., 2001;Hodgson et al., 2002). In subjects with moderately elevated cholesterol and/or triglyceride levels, consumption of black tea increased FMD in brachial arteries (Hodgson et al., 2002) as well as in patients with coronary arterial disease (450 mL of tea or water-short-term, after 2 h; and 900 mL of tea or water/day for 4 weeks long-term, n = 50 subjects; Duffy et al., 2001). In a clinical trial, Oyama et al. (2010) used venous occlusion strain-gauge plethysmography to demonstrate the beneficial effects of green tea catechins (580 mg/day for 4 weeks) on blood flow in forearms of smokers. The data revealed a significant increase in blood flow due to an augmented release of NO with a concomitant decrease in levels of both asymmetrical dimethylarginine (an endogenous inhibitor of eNOS) and oxidative stress (Oyama et al., 2010; Table 6).
The bioactive components of tea are reported to express anti-inflammatory properties (Table 3), reflected by mitigated expression and release of different cytokines. In a clinical doubleblind, placebo-controlled study on 56 obese, hypertensive males and females, green tea extract (379 mg/day for 3 months) caused a decrease in BP as well as TNF-α levels (Bogdanski et al., 2012). In other studies, EGCG (Ludwig et al., 2004) and theaflavin (Lü et al., 2005) derived from tea have been reported to reduce VCAM-1 levels. In addition, EGCG was able to inhibit NF-κB activation in human endothelial cells (Hong et al., 2007). Interestingly, EGCG derived from green tea also elicited a concentration-dependent inhibition of proliferation in human aortic VSMCs by increasing HO-1 enzyme expression .

Coptis chinensis (Goldthread)
Coptis chinensis, commonly known as Chinese goldthread, is widely used in Chinese folk medicine (Affuso et al., 2010). Evidence indicates that goldthread, and its main component Berberine (BBR), have the ability to lower blood pressure (Affuso et al., 2010;Xiong et al., 2013). Indeed, a recent meta-analysis of twenty-seven randomized controlled trials involving 2569 patients reported that BBR can cause a significant hypotensive effect (Lan et al., 2015). In addition, this meta-analysis concluded that combined with an oral hypotensor, BBR can significantly reduce BP more than the hypotensor alone can do. The magnitude of the decrease was determined to be an average of 4.91 and 2 mmHg for SBP and DBP, respectively (Lan et al., 2015). Several mechanisms have been proposed for Chinese goldthread's antihypertensive effect. One mechanism appears to be via amelioration of oxidative stress (Zhang et al., 2011;Wan et al., 2013; Table 1). Indeed, BBR (150 mg/kg) is reported to scavenge ROS, inhibit NADPH oxidase (Wan et al., 2013), and increase the antioxidant enzyme, SOD, in rats with atherosclerotic renovascular disease.
Constituents of goldthread also act by relaxing arterial tissues through endothelial-dependent and independent routes (Affuso et al., 2010). In chronic intermittent hypobaric hypoxic and normoxic animal models, goldthread has been shown to relax NE-induced contractions in rat isolated thoracic aortic rings (Zhang et al., 2011). The same authors also reported BBR's vasorelaxant activity on KCl-induced contractions using the same models (Zhang et al., 2011). Apparently, BBR elevates the expression of eNOS with a concomitant rise in NO release that leads to enhanced flow-mediated vasodilation (Affuso et al., 2010;Zhang et al., 2011). This dilation is likely mediated by the vasodilator PGI 2 as well as the opening of K ATP channels and blockage of Ca 2+ influx (Zhang et al., 2011). In a clinical study, BBR (1.2 g/day for 1 month) decreased the formation of endothelial microparticles (EMPs) which are known to induce endothelial dysfunction and pro-coagulant activity in healthy humans Affuso et al., 2010).

Coriandrum sativum (Cilantro or Coriander)
In several countries, coriander (also known as cilantro or dhania) is not only used as a culinary ingredient (Anilakumar et al., 2010;Wu et al., 2010) but also as a traditional medicine for the treatment of cardiovascular and gastrointestinal diseases (Jabeen et al., 2009).
Vasodilatory effects of coriander are well-established. Indeed, intravenous application of aqueous methanolic extract of dried, ground coriander seeds (1-30 mg/ml) produced a dosedependent fall in SBP, DBP, and mean arterial blood pressure (MABP) in normotensive Sprague-Dawley rats by 40.84 ± 6.34% (Jabeen et al., 2009). The same report also showed that coriander fruit extracts produced dose-dependent relaxation of pre-constricted (phenylephrine and potassium chloride) rabbit aortas, and this response was atropine and calcium-channel dependent (Jabeen et al., 2009). Further, the same extracts showed diuretic affects as well. The active component of which should act synergistically with the vasoactive constituent to complement the treatment and management of hypertension (Jabeen et al., 2009). Moreover, coriander acts as an inhibitory agent to reduce the activities of NF-κB and iNOS (Wu et al., 2010).

Crataegus spp. (Hawthorns)
Hawthorns (hawberry or thorn apple) plants are shrubs that belong to a genus comprising almost 300 species (Tassell et al., 2010) that have been used in traditional medicine for thousands of years (Tassell et al., 2010;Asher et al., 2012). Hawthorns have been used for treatment of CVDs since the seventeenth century (Asher et al., 2012).
Modest decreases in blood pressure have been observed in a few human-based studies with a demographic of hypertensive patients (Walker et al., 2002;Tassell et al., 2010). In a randomized, double-blind, placebo-controlled study where mildly hypertensive subjects were treated with 500 mg of hawthorn extract for 10 weeks, a promising tendency for a reduction in DBP (by 13.1 mmHg) was reported (Walker et al., 2002). It is argued that the dose and duration were not sufficient for a more effective result to be noted. Indeed, in phytotherapy practice, a significant decrease in BP is only noted after a longer duration and higher doses (Bone and Mills, 2013), In another randomized, double-blind, placebo-controlled clinical study, administration of hydro-alcoholic extracts of Crataegus curvisepala Lind flowers to hypertensive patients (age range 40-60 years) for 3 months induced a decrease in both SBP and DBP by around 13 and 8 mmHg, respectively (Asgary et al., 2004).
The aforemnetioned antihypertensive actions are credited to the plant's multiple components: flavonoids (hyperoside, quercetin, rutin, and vitexin) and oligomeric proanthocyanidins (OPCs, epicatechin, procyanidin, and procyanidin B-2; Valli and Giardina, 2002;Houston, 2005;Asher et al., 2012;Yang and Liu, 2012). Quercetin, a major polyphenolic flavonoid in hawthorn shrubs, expresses numerous bioactive functions including antioxidant, anti-inflammatory, and vasorelaxant effects. Quercetin supplement intervention studies have demonstrated a reduction in blood pressure of hypertensive subjects (Larson et al., 2012). Interestingly, hawthorn extracts have an effect on both VSMCs and endothelial cells (Tassell et al., 2010). The latter interaction is attributable to increased NOS activity and hence NO release (Brixius et al., 2006;Anselm et al., 2009), possibly due to an enhanced phosphorylation of eNOS at serine 1177 (Brixius et al., 2006;Anselm et al., 2009; Table 2). In porcine isolated coronary arterial rings, WS 1442 (an extract of Crataegus leaves with flowers) induced endothelium-dependent relaxation through the activation of multiple signaling pathways, including ROS, Src, PI 3 -kinase, Akt, and eNOS (Anselm et al., 2009). Moreover, WS 1442 caused endothelium-dependent and NO-mediated vasorelaxation of phenylephrine-preconstricted rings of rat aorta as well as human internal mammaria (Brixius et al., 2006). In the L-NAME-induced hypertension model, the blood pressure decreased after the administration of Crataegus tanacetifolia leaf extract or its isolate, hyperoside. Both C. tanacetifolia extract and hyperoside display protective effects at multiple levels. These include improving hyperlipidemia, decreasing body weight, resolving hyperplasia, reducing thickness of the vascular medial layer as well as improving kidney function. Such effects appear to be mediated by an increase in diuretic activity, efflux of water and sodium, as well as expression of NOS enzyme. Together, all of these mechanistic actions contribute to the amelioration of hypertensive outcome (Koçyildiz et al., 2006).
Several reports support the use of saffron for anti-hypertensive benefits. A clinical study reported that 400 mg of saffron tablets administered for 7 days were able to significantly reduce the SBP and mean arterial pressure in healthy humans by 11 and 5 mmHg, respectively (Modaghegh et al., 2008). Saffron demonstrates vasorelaxant activities in different animal models. Extracts of C. sativus petals (rich in flavonoids and anthocyanins) dose-dependently reduced the BP of male Sprague-Dawley rats, possibly by modulating peripheral vascular resistance (Fatehi et al., 2003). Moreover, extract of C. sativus stigma (10 mg/kg), and two of its primary components [Crocin (200 mg/kg) and Safranal (1 mg/kg)], attenuated MABP in normotensive and desoxycorticosterone acetate (DOCA)-salt induced hypertensive male Wistar rats (Imenshahidi et al., 2010). More recently, it was shown that chronic administration of safranal (1, 2, and 4 mg/Kg/day) reduced SBP in DOCA-salt hypertensive but not normotensive rats (Imenshahidi et al., 2015).

Cymbopogon citratus (Lemongrass)
Lemongrass (common name) has been widely used in traditional medicine of Brazil, China, and Southern Asia (Devi et al., 2012). It has been reported to possess antihypertensive properties, which have been attributed to its active phytochemicals, the principle of which being Citral (Devi et al., 2011(Devi et al., , 2012. However, no clinical trials have yet investigated the effect of Lemongrass on BP. The relaxant effect of lemongrass has been demonstrated in several different tissues, including the rabbit ileum (Devi et al., 2011), rat aortic rings (Devi et al., 2012), and the rat mesentery (Bastos et al., 2010; Table 2). For instance, Citral or crude extracts of C. citratus (leaves, stems, or roots) generated a dose-dependent vasorelaxation in phenylephrine pre-constricted aortic rings from male WKRs or SHRs (Devi et al., 2012). Further, the underlying mechanism for this relaxation appeared to be mediated by activation of NO and/or the inhibition of calcium channels (Devi et al., 2012). Likewise, administration of an intravenous bolus of Citronellol, an acyclic monoterpenoid isolated from lemongrass, to male Wistar rats produced a hypotensive response. This hypotensive effect was not affected by L-NAME, indomethacin, atropine, or hexamethonium (Bastos et al., 2010). Citronellol also induced relaxation of rat superior mesenteric artery via an endothelium-independent mechanism. Moreover, arteries denuded of endothelium were not reliant on tetraethylammonium-dependent potassium channels. Rather, citronellol acted by inhibiting Ca 2+ -influx through voltage operated calcium channels (VOCCs) as well as regulating IP 3 -and caffeine-gated intracellular Ca 2+ stores (Bastos et al., 2010).
Lemongrass is known to display moderate antioxidant activity. In male rats treated with H 2 O 2 , 100 mg/kg of lemongrass was able to reduce oxidative stress and increase GSH expression in testes (Rahim et al., 2013). Results from another study showed an increase in antioxidant enzymes and molecules such as SOD and GSH in murine lungs after administering 5 and 10 µg of lemongrass' extracts (Tiwari et al., 2010). Lemongrass was reported to suppress ROS molecular activity (Tiwari et al., 2010;Koh et al., 2012). In addition, lemongrass' Citral contributes to the anti-inflammatory pathways by inhibiting NF-κB (Lee et al., 2008;Francisco et al., 2013) and iNOS activity (Lee et al., 2008;Figueirinha et al., 2010).

Hibiscus sabdariffa (Roselle)
Hibiscus, widely known as roselle, is used for hypertension, fever, and other diseases in folk medicine. Different parts of this plant (buds, calyx, flowers, leaves, and petals-fresh or dried) are used for health purposes and as refreshing beverages, food items (jams, preserves), or lotions.
A strong body of evidence is reported to support roselle's ability as a diuretic agent (Onyenekwe et al., 1999;Ali et al., 2005;Herrera-Arellano et al., 2007;Alarcon-Alonso et al., 2012). One clinical study detected a lower concentration of uric acid in urine of healthy humans consuming roselle (Ali et al., 2005). Another clinical study reflected the decrease in blood sodium content of stage 1 and 2 hypertensive humans after 4 weeks administration of 250 mg of roselle's extracts (Herrera-Arellano et al., 2007), thus verifying its multiple diuretic properties. This diuretic activity is related to the vasorelaxant effect, as NO elevation is positively correlated with increases in renal filtration rates (Alarcon-Alonso et al., 2012).
Roselle exhibits potent antioxidant function (Ali et al., 2005;McKay et al., 2010). Its anthocyanin extracts (2 mg/ml) were reported to reduce oxidative stress, potentially by scavenging free radicals in livers of CCl 4 -treated rats (Ajiboye et al., 2011). In a clinical study, roselle's aqueous extracts enhanced the concentration of cellular antioxidants in healthy humans (Frank et al., 2012; Table 1). Moreover, it blocks the oxidation of LDL, indicating its role as an anti-atherogenic . Roselle also shows anti-inflammatory capacity by inhibiting not only ACE activity (Herrera-Arellano et al., 2007;Ojeda et al., 2010) but also the proliferation of VSMCs . The effect of roselle on ACE activity was confirmed in a Lisinopril-controlled clinical trial, where 250 mg of its extract was administered to patients with stage 1 or 2 hypertension (Herrera-Arellano et al., 2007).

Nigella sativa (Black Cumin; Seed of Blessing)
Black cumin, also known as Habbatul barakah (seed of blessing), has been used in the kitchens of Europe, the Middle East, Africa, and South and Southwest Asia for centuries (Ahmad et al., 2013;Leong et al., 2013;Tables 2, 5). In addition to its antihypertensive role, black cumin is also effective against diabetes and gastrointestinal diseases (Leong et al., 2013). Thymoquinone (TQ), one of the most abundant and bioactive components in Nigella sativa's seeds, has been identified as the major element in its healing effects (Ahmad et al., 2013).
N. sativa, and its constituents, have been reported to lower blood pressure in humans and in different animal models of hypertension (Zaoui et al., 2000;Khattab and Nagi, 2007;Dehkordi and Kamkhah, 2008;Fallah Huseini et al., 2013) and also decrease heart rate (Leong et al., 2013). For example, L-NAME-induced hypertension in rats was ameliorated by concomitant treatment with thymoquinone (0.5 and 1 mg/kg/day for 4 weeks; Khattab and Nagi, 2007). Improvement in renal function and antioxidant activity were also noted, evident by the reduced serum creatinine or increased glutathione in control vs. L-NAME treated rats, respectively (Khattab and Nagi, 2007). Likewise, in SHRs, an oral dose of dichloromethane extract of black cumin seeds (0.6 ml/kg/day for 15 days) reduced mean arterial pressure by 22% and increased diuretic activity (Khattab and Nagi, 2007), mirrored by urinary excretion of urea, Cl − , Na + , and K + (Zaoui et al., 2000; Table 5).
A randomized, double-blind placebo-controlled clinical trial of the effects of N. sativa's seed extract administrated orally (either 100 or 200 mg, two times per 24 h for 8 weeks) to mild hypertensive male patients recorded a dose-dependent fall in both SBP and DBP, in the two treated groups compared to placebo (Dehkordi and Kamkhah, 2008; Table 6). For the 200 mg dose, there was a decrease of around 2.2 and 2 mmHg in SBP and DBP, respectively. Moreover, the NS's extract reduced total cholesterol as well as low density lipoprotein (LDL)cholesterol relative to pretreatment concentrations (Dehkordi and Kamkhah, 2008). Again, in a randomized, placebocontrolled, double-blind study with 70 healthy subjects, N. sativa oil caused a significant decrease of 10.6 and 9.6 mmHg, respectively in both SBP and DBP (Fallah Huseini et al., 2013).
Another route by which black cumin attenuates hypertension is by vasorelaxant means. This is illustrated by its ability to inhibit Ca 2+ channels (voltage-gated and ligand-gated) leading to concomitant relaxation of rat aorta (Leong et al., 2013). Moreover, TQ is reported to inhibit the release of vasoconstrictor metabolites of COX-1 (Ahmad et al., 2013) and COX-2 (Ahmad et al., 2013;Kundu et al., 2013). TQ's antihypertensive effects are partly due to its antioxidant activities as it lowers oxidative stress (Khattab and Nagi, 2007;Ahmad et al., 2013). Another mechanism that may explain the hypotensive effect of black cumin pertains to its diuretic action (Zaoui et al., 2000;Ahmad et al., 2013;Leong et al., 2013). This has been highlighted by the ability of black cumin seeds to increase urea, calcium, sodium, and potassium in urine of rats (Zaoui et al., 2000;Leong et al., 2013), where it also increases renal filtration and urinary output (Leong et al., 2013). Yet another mechanism that underlies black cumin's actions is its anti-inflammatory property since it inhibits the generation of TNF-α and NF-κB (Kundu et al., 2013).

Panax (Ginseng)
For centuries, the species Panax, especially the Asian variety, has been used in folk medicine (Jang et al., 2011;Kim, 2012). Ginseng is prepared and administered in various forms, either as a solid: tablets, capsules, dried roots; or as a liquid: oil, extracts or tea (Valli and Giardina, 2002). P. ginseng (Asian or Korean ginseng), P. quinquefolius (American ginseng), P. japonicas (Japanese ginseng) and P. notoginseng (Chinese ginseng) are the four most common species of ginseng (Valli and Giardina, 2002;Kim, 2012). Interestingly, these-as a group-have the most reported hypotensive effects. Heterogeneous triterpenoid saponins and steroid glycosides or ginsenosides (or panaxosides) are the active principle components of ginseng (Valli and Giardina, 2002;Kim, 2012). In addition to anti-hypertensive effects, ginseng also plays anti-carcinogenic and antidiabetic roles .
Although ginseng's blood pressure lowering effect is widely reported (Jeon et al., 2000;Valli and Giardina, 2002;Jang et al., 2011;Kim, 2012;Mucalo et al., 2013; Tables 1, 2), conflicting reports of elevated blood pressure also exist (Valli and Giardina, 2002;Jang et al., 2011;Kim, 2012). Contextually, low doses of ginseng raise BP, while higher concentrations are hypotensive (Jang et al., 2011). A probable explanation for this phenomenon is the varied action of different ginsenosides (Valli and Giardina, 2002). Interestingly, Kim (2012) has used the term "normalize" to describe hypotensive and hypertensive actions of ginseng. Therefore, these studies suggest that ginseng rheostatically adjusts the BP level in hypotensive patients (Kim, 2012), possibly by tuning vascular function, modulating the autonomic nervous system, or regulating the arterial baroreflex.
Several clinical trials have been conducted to assess the efficacy of ginseng in modulating BP ( Table 6). In one trial, P. ginseng extract rich in ginsenoside protopanaxatriol (300 mg/day) was administered to mild hypertensive patients and caused a significant decrease of 3.1 and 2.3 mmHg in SBP and DBP, respectively (Rhee et al., 2014). Furthermore, a randomized, double-blind, placebo-controlled trial where hypertensive patients ingested American ginseng (3 g/day) for 12 weeks showed that SBP was significantly lowered by 11.7% (17.4 mmHg; Mucalo et al., 2013). Along the same line, another randomized, double-blind, crossover trial reported that central SBP and DBP of healthy subjects was significantly reduced by 4.8 ± 6.8 and 3.6 ± 6.4 mmHg, respectively, after hours of ingesting Ginsenoside Rg3-enriched P. ginseng (400 mg; Jovanovski et al., 2014).
The primary mechanism associated with ginseng-induced hypotensive effect is attributed to an improvement in arterial function. Indeed, ginseng causes a dramatic increase in eNOS expression and NO production (Valli and Giardina, 2002;Jang et al., 2011Jang et al., , 2012Hong et al., 2012;Pan et al., 2012; Table 2). Ginsenoside Rg3 (red ginseng) is known to activate eNOS (Valli and Giardina, 2002;Jang et al., 2011), increase NO and cGMP levels, as well as activate Ca 2+ -gated potassium channels (Kim et al., 1999b). Ginsenosides mediate vasorelaxation of different vessels in different animals: rat aortas (Kim et al., 1999a), murine coronary arteries , and monkey cerebral arteries (Toda et al., 2001). In the same context, this relaxation may be aided by ginseng's ability to diminish secretion of adrenal catecholamines in hypertensive rats (Jang et al., 2011).
Ginseng also elicits an anti-proliferative effect on VSMCs, and hence, it can be expected to possess antihypertensive and anti-atherosclerotic capacities (Table 4). Importantly, results of a clinical trial indicate that administering 3 g/day of P. quinquefolius for 12 weeks improves arterial stiffness in hypertensive patients (Mucalo et al., 2013; Table 6). Further support for this beneficial effect of ginseng comes from another clinical trial, where taking 400 mg of P. ginseng caused a significant reduction in aortic Alx, a marker of arterial stiffness (Jovanovski et al., 2014; Table 6). It has been reported that Chinese ginseng blocks the activation of extracellular signal-regulated protein kinases (ERK) pathway, and therefore inhibits PDGF-induced VSMCs proliferation (Zhang et al., 2012). Moreover, Chinese and other ginsengs reduced vascular aging of SHRs compared to WKY rats; this was reflected by inhibition of proliferation of VSMCs isolated from both WKY and SHRs. The mechanistic pathway for the effect of ginseng on SHR VSMCs entailed the decrease in the number of senescence-associated β-galactosidase (SA-β-gal) positive cells. In the SHR, expression of p16, and retinoblastoma protein (Rb) was elevated whereas that of cyclin D1 and cyclin-dependent kinase 4 (CDK4) was decreased (Tao and Lei, 2012). Further, red ginseng also attenuated Ang II-induced VSMC growth (Kim, 2012).
Amongst ginseng's other hypotensive mechanisms is its antioxidant ability (Table 1). In this regard, it has been reported that ginsenoside Rg1 (60-120 µM) inhibits oxidative stress (Doh et al., 2013), possibly by increasing antioxidant enzymes (Zhu et al., 2009) and scavenging free radicals (Zhu et al., 2009). In addition to its antioxidant effect, ginseng exhibits antiinflammatory properties. Indeed, Asian ginseng (red) inhibits the release of TNF-α (Kim, 2012) as well as attenuates NF-κB and p38 mitogen activated protein kinase (MAPK) pathways (Bak et al., 2012). It has been suggested that the consequence of this effect is a reduction in the vasoconstrictor activity of COX-2 enzyme (Bak et al., 2012; Table 3).
Danshen relaxes the vasculature via endothelium-dependent and endothelium-independent mechanisms. A combination treatment of danshen and gegen (Pueraria lobata) was shown to lower blood pressure in SHRs (Ng et al., 2011) and to induce relaxation of porcine coronary arteries , rat aorta (Ng et al., 2011), and basilar arteries ; Table 2). Similarly, dihydrotanshinone (lipophilic constituent of danshen) is a vasorelaxant of rat coronary arteries (Lam et al., 2008). Danshen's endothelium-dependent relaxations occur via an NOdependent mechanism Ng et al., 2011;Shou et al., 2012). SalB-derived vasodilation in rabbit aorta is mediated by the NO-sGC-cGMP pathway (Shou et al., 2012). Other studies have also demonstrated that L-NAME inhibits eNOS and blocks the activity of danshen Shou et al., 2012), further verifying the NO-dependent mechanism of vasodilation. In VSMCs, danshen exhibits its vasodilating effect by opening of K ATP , K ir , and K v channels (Ng et al., 2011;Jiang et al., 2013a) as well as blocking the Ca 2+ influx (Lam et al., 2008;Hu et al., 2012).
Apart from its vasodilatory capacity, danshen expresses additional anti-hypertensive parameters such as antioxidative, anti-proliferative, and anti-inflammatory activities. Its extracts have been shown to decrease ROS production in rat thoracic aorta (Cho et al., 2013). In a randomized, placebo-controlled clinical study involving chronic heart disease patients, danshen's hydrophilic extract (5 g/twice a day/60 days) increased antioxidative enzymes like CAT, SOD, and the tripeptide glutathione (Qian et al., 2012; Table 1). Danshen was also reported to inhibit PDGF-induced proliferation of VSMCs (Cho et al., 2013; Table 4). The anti-inflammatory capacity of danshen was demonstrated by virtue of its ability to inhibit TNF-α, NF-κB production, and VCAM-1 expression (Cho et al., 2013) in HUVECs (Table 3). Taken together, these results illustrate the underlying molecular mechanism for danshen's antihypertensive effect.
The aqueous extract of ginger (0.05 mg/ml) has also been reported to inhibit lipid peroxidation as well as ACE in rat hearts (Akinyemi et al., 2013). In addition, zingerone, another active compound in ginger, can potently scavenge oxidant molecules like peroxynitrite (Shin et al., 2005). Recently, it was found that ginger not only reduces levels of total cholesterol, triglyceride, LDL, and vLDL, but it can also inhibit ACE-1 activity (Akinyemi et al., 2014).

CONCLUSION
With CVD remaining as a leading cause of worldwide mortality, the search for more effective treatments ought to be of prime importance. An approach that appears promising is CAM (Frishman et al., 2009;Su and Li, 2011;Orekhov et al., 2013). Not surprisingly, of all small-molecule new chemical entities introduced as drugs during the last three decades, a significant fraction were either obtained from or inspired by nature (Newman and Cragg, 2012). Perhaps this could explain, at least partly, the "phenomenon" that more American patients visit CAM providers than primary care physicians (Eisenberg et al., 1998;Tachjian et al., 2010). Of relevant interest, it is important to note that herbal consumption appear to be the most common type of CAM among CVD patients (Yeh et al., 2006).
In this first part of our review, we discussed the mechanisms of action of several plants that are most commonly used in the treatment or management of hypertension.
The evidence presented is strongly indicative of the notion that herbs and plants are becoming part of evidence-based medicine in the prevention and/or treatment of CVD. The pharmacological actions of herbs or herbal isolates appear to favorably modulate several parameters implicated in the pathogenesis of blood pressure, including but not limited to ROS production, VSMC phenotype, endothelial function, platelet activation, pro-inflammatory signaling, and gene expression. With such a broad spectrum of actions, one may predict that herbal remedies will receive even more attention in the coming years, perhaps accentuating the need for further experimentations and clinical trials. Indeed, the lack of sufficient clinical trials constitutes a significant limitation on their use at the present time. Of equal importance, it may be advisable that patients be appropriately educated, particularly in relation to herbs whose consumption has been considered safe for thousands of years (black cumin, Chinese sage, coriander, garlic, ginger, ginseng, and tea), and has been supported by sound scientific evidence such as one based on clinical trials with large population groups. It is important to note that there are herbs and plants that could actually raise blood pressure and thus should be avoided by hypertensive patients. There are also other limitations for herbal therapy of hypertension. These limitations would be discussed in the second part of this review.

AUTHOR CONTRIBUTIONS
All authors contributed to the writing. AE conceived, designed and revised the manuscript.

FUNDING
This publication was made possible by grant # NPRP 4-571-3-171 from the Qatar National Research Fund (a member of Qatar Foundation). The Statements made herein are solely the responsibility of the authors. This grant was awarded to AE.