Exploring the Anti-Hypertensive Properties of Medicinal Plants and Their Bioactive Metabolites: An Extensive Review

Medicinal plants are extensively used in traditional folk medicine. High blood pressure is associated with the risk of cardiovascular diseases (CVDs) and many other serious health complications resulting from it as a major concern of morbidity and mortality in health sector. Use of diuretics, angiotensin converting enzyme (ACE) inhibitors, beta adrenergic receptor antagonists (beta blockers), alpha adrenergic receptor antagonists (alpha blockers), calcium channel blockers (CCBs) etc. are not efficient enough to cure hypertension. Side effects regarding these medications lead to intolerance, impaired control of the disease, and also mismanagement of therapy. So, approach regarding quenching new potent therapeutic compounds from medicinal plants draws attention nowadays. For example, as a first-line therapeutic agent, an alkaloid is highly effective in lowering systolic blood pressure which is isolated from root extract of the plant of Rauwolfia serpentina species, namely reserpine. This article comes up with a list of 63 plant species from 37 families, compiling information related to plant parts used for making extracts, types of extract and animals used in these studies, antihypertensive effect of the extracts etc. It also refers to 74 chemically defined molecules, with in vitro and in vivo anti-hypertensive potential, isolated from these extracts along with their dosage and mechanism of action by using electronic searches of published articles from various databases and reference books. Our present


Introduction
The definition of hypertension (HTN) is when office systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) is equal or greater than 140 mmHg, and 90 mmHg respectively [1]. HTN is often called "the silent killer". If HTN is left untreated, end organ damage may occur [2]. People with elevated blood pressure (BP) may face some major risk of being affected by coronary artery disease with the following complications e.g., blindness in diabetic patients, heart failure, renal diseases, and stroke [3]. 972 million people had HTN in 2000 and this number was predicted to be about 1.56 billion in 2025 [4]. Obesity, unhealthy diet, tobacco use, physical inactivity, and HTN are some factors that increase the risk of CVDs [5]. Reducing SBP by 5 mmHg is shown to lower mortality rate by 9%, 14%, and 7% respectively for coronary heart disease, stroke, and in total [6].
Until now, there are different antihypertensive therapies available, such as: ACE (classified as EC3.4.15.1) inhibitors, angiotensin receptor blocker (ARB), beta blockers, diuretics, and also CCBs [7] [8]. They show their antihypertensive effect by controlling cardiac output (CO) (affecting stroke volume and heart rate), and peripheral or systemic vascular resistance. Impairment in production of nitric oxide (NO) is a very common reason behind endothelial dysfunction, which leads to HTN [9] [10]. Figure 1 shows that, endothelial NO synthase (eNOS) produces NO from L-arginine in the blood vessels to control cardiovascular function [11]. High BP was induced due to chronic blocking of NO after administrating Nω-Nitro-l-arginine methyl ester (l-NAME) depending upon dose and time [12]. l-NAME contributes to endothelial dysfunction in resistant vessels by decreasing metabolites of NO present in plasma and downregulating expression of eNOS protein [13].
Oxidative stress also promotes HTN pathogenesis [15]. In a rat model of NO depletion-induced hypertension, excess reactive oxygen species (ROS) and declined amount of endogenous antioxidant enzymes have been found [16]. High amount of vascular superoxide ( 2 O − ), malondialdehyde (MDA), and plasma protein carbonyl were found in NO deficient hypertensive rats [17] [18]. 2 O − quenches NO to produce peroxynitrite (ONOO − ) directly and decreases NO bioavailability [19].
Again, l-NAME causes overproduction of ROS and activates the renin-angiotensin system (RAS) [20] [21]. Angiotensin II (Ang-II) is a potential vasoconstrictor and for that as shown in Figure 2, RAS is a compulsory factor in pathogenesis of HTN [22]. Renin is released by renal artery constriction and Ang-II Figure 1. The mechanism of action of Nitrates, and nitrites that increase NO in vascular smooth muscle cells (VSMC). Steps producing vascular contraction are presented with red arrows, and those causing vascular relaxation are displayed with blue arrows [14]. MLCK* = activated myosin light-chain kinase; GC* = activated guanylyl cyclase or guanylate cyclase; PDE = phosphodiesterase. production is increased by activating RAS in NO deficient hypertensive rats [23] [24]. In l-NAME treated rats, Ang-II stimulates the Ang-II type 1 receptor (AT 1 R) which produces 2 O − activated by nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase [13]. Elevated ACE, cardiac and plasma Ang-II, and AT 1 R expression also confirmed RAS stimulation in those above-mentioned rats [25]. RAS is also a vital factor because chronic NO inhibition results in arterial remodeling and AT 1 R blockers prevent that [26]. Vascular remodeling occurs by Ang-II binding to AT 1 R and activating serine/threonine kinase (Akt), one of its own intracellular downstream signaling protein responsible for Ang-II driven proliferation in VSMC [27]. Signal transducers and activators of transcription protein get phosphorylated by Janus kinases induced by AT 1 R activation that causes vascular proliferation and remodeling [28]. often found in extracts. Our review includes 63 species of plants from 37 family, plant parts used for making extracts, types of extract and animals used for these experiment, antihypertensive effect of the extracts as well as 74 confirmed antihypertensive compounds isolated from these extracts with their dosage and mechanism of action.

Discussion about Promising Anti-Hypertensive Plants
Herbal medicine is a tremendous source for seeking out novel therapeutic compounds for numerous diseases. The idea of generating medicine from scratch had originally come out from the traditional uses of herbs and plants by our fellow ancestor to cure many of their ailments. Herbal medicines are quite preferable among people for its significantly low side effects and also the belief regarding nature made. Among the described compounds, we think four of the compounds were therapeutically efficient. The first one, tilianin which is derived from Agastache mexicana, demonstrated dose-dependent anti-hypertensive effects, with an ED 50 of 53.51 mg/kg which was lower than the LD 50 of 6624 mg/kg, offers a wide spectrum of pharmacology responses. In addition, this study provides evidence about safety and efficacy of tilianin as antihypertensive agent, as well as, claims of no damage at physiologic, functional and cellular levels in rodent models [41].
Curcumin nanoemulsion is our favorite choice, prepared from Curcuma domestica and having a 71.166% inhibition (after corrections) on HMGCR (a liver enzyme that contributes to cholesterol synthesis) to assess antihypercholesterolemic activity when compared to pravastatin. Curcumin: 1) Inhibits hepatic HMG-CoA activity and lowers HMGR gene expression (that produces the HMG-CoA enzyme).
2) Suppresses triglyceride and cholesterol accumulation in the liver due to its antihyperlipidemic properties.
3) Enhances PPARα gene expression that regulates fatty acid oxidation.  The NO-cGMP pathway has been identified as the most important signaling mechanism of plant extracts and Naringenin's vasorelaxant activities.
1) synergistic effect of the compounds 2) CGA inhibit ROS generating enzymes (NADPH, xanthine oxidase), reduce the formation of ONOO − and increase bioavailability of NO. It also has protective role in eNOS [94]. [95] Psidium guineense  [109] by Ca 2+ inflow inhibition through VDCC. [110] 4) Elevates the transcription of the LXRα gene, which controls the CYP7A1 enzyme (encoding cholesterol-7a-hydroxlylase, an enzyme that participates in converting cholesterol to bile acids before excretion). 5) Prevents atherosclerotic lesion formation in the atherogenic diet-fed mice, as evidenced by a decrease in the atherogenic indicator and an increase in the % ratio of HDL and total cholesterol [60].

Conclusion
The goal of our research is to let everyone know that there are an ample number of natural compounds that can be made into antihypertensive therapies. We noticed that the majority of the researches focused on the effect of the extracts on antihypertensive therapy along with the mechanism of action and more than half of them elucidated structures of compounds responsible for the activity. As a result, expanding studies into mechanisms and structure elucidation can contribute to the development of new drugs. 63 plant species from 37 families and 74 isolated compounds are reviewed here. Among them, tilianin, naringenin, curcumin nanoemulsion, 2,7-dihydroxy-3,4,9-trimethoxyphenanthrene are the topmost candidate for producing antihypertensive therapy from natural products in a safe, efficient, and patient adhering way. On the other hand, relaxation of blood vessels, formation of NO, blockage of calcium channels, increase in potassium, suppression of the renin-angiotensin pathway, activation of intracellular cGMP, and inactivation of the sympathetic system are mostly the mechanisms discovered in these medicinal plants for antihypertensive activity. Depending upon the side effects of the ongoing therapies, we think it is high time that the pharmaceuticals took the appropriate steps to synthesize effective drug candidate from these phytochemicals that can reach every human being's doorway.
Further studies of the rest of the compounds could also lead to promising antihypertensive therapies.