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REVIEW ARTICLE
Year : 2022 | Volume
: 8
| Issue : 3 | Page : 135-143
Role of Indian fruits in the prevention and management of hypertension
Pankaj Prabhakar
Department of Pharmacology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
Correspondence Address:
Pankaj Prabhakar
Department of Pharmacology, Indira Gandhi Institute of Medical Sciences, Sheikhpura, Patna - 800 014, Bihar
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/jpcs.jpcs_63_22
Hypertension (HTN) is a serious health problem worldwide and worse than other cardiovascular diseases. HTN is a chief risk factor for stroke, myocardial infarction, heart failure, aortic aneurysm, peripheral arterial disease, and renal vascular disease. Herbal medicines are used by about 75% to 80% of the world population, in primary health care because of their enhanced tolerability and minor side effects. The consumption of fruits is advised for good health as a result of their high fiber, antioxidant, mineral, vitamin, and phytochemical contents. Of the many fruiting trees, indigenous to India such as mango (Mangifera indica), black plum (Eugenia jambolana), pomegranate (Punica granatum), and amla (Emblica officinalis) are useful in preventing HTN and in the treatment of HTN in validated preclinical and clinical studies. In this review, efforts are made to collate the fruits' antihypertensive effects and their important phytochemicals. Efforts are also made to address the underlying mechanism/s responsible for the beneficial effects of these fruits in HTN prevention and treatment.
Keywords: Emblica officinalis, Eugenia jambolana, fruits, hypertension, Mangifera indica, Punica granatum
Hypertension (HTN) is a global disease in which the blood pressure (BP) in the arteries increases. HTN is considered the leading risk factor for cardiovascular diseases (CVDs).[1] BP is a silent killer which is triggered by an array of factors, including the interaction of genetic and environmental factors.[2] HTN increases the risk of stroke, heart failure, and myocardial infarction. The worldwide prevalence of HTN is estimated at about 1.28 billion adults aged between 30 and 79 years.[3] Further, the prevalence of HTN is 26.4% of the world population and is predicted to increase by 60% in 2025.[4] According to the WHO, the global target is to decrease the prevalence of HTN by 33% between 2010 and 2030.[3] It has been found that HTN is the most universal risk factor in acute myocardial infarction and is responsible for about 16.5% of deaths annually worldwide. In addition, HTN is accountable for 8·5 million deaths from ischemic heart disease, stroke, other vascular diseases, and renal disease worldwide.[5] Moreover, HTN is a central cause of untimely death worldwide.[3] HTN is typically classified based on systolic BP (SBP) and diastolic BP (DBP). SBP is the BP in vessels during a heartbeat. DBP is the pressure between heartbeats. According to the New American College of Cardiology and American Heart Association, normal BP ranges below SBP 120 mm Hg/DBP 80 mm Hg, and elevated BP ranges from SBP 120-129 mm Hg/DBP <80 mm Hg. HTN is defined as SBP ≥140 mm Hg and DBP ≥90 mm Hg when measured on two different days.[3],[6] There are several antihypertensive drugs are available for the management of HTN, such as renin inhibitors, calcium channel blockers, diuretics, sympatholytic agents, angiotensin-converting enzyme (ACE) inhibitors, vasodilators, β-adrenergic, and α1/β-adrenergic antagonists.[7] However, these drugs are not effective in all hypertensive patients and have side effects too. It has been demonstrated that clinically available drugs have a range of side effects such as abnormal heart rate, muscle cramps, excessive micturition, diarrhea, blurred vision, headaches, skin rash, dryness of legs, vomiting, kidney failure, dizziness, extreme tiredness, and edema.[1],[2] Epidemiological studies have established that fruit consumption significantly decreased the risk of CVDs.[8],[9],[10],[11],[12] It has been demonstrated that diets low in fruits are a key risk factor for CVDs following elevated BP.[13] Moreover, experimental studies also support the beneficial effect of fruits against HTN. In addition, the WHO also suggested the consumption of fruits and vegetables (400 g per day) for the prevention of other chronic diseases such as diabetes, heart disease, obesity, and cancer.[14],[15] It has been suggested by International Scientific Societies/committees that dietary approaches should be considered to manage HTN. They suggested consuming a diet rich in whole grains, fruits, and vegetables, and reduced saturated total fat with low-fat dairy products to decrease BP and regulate lipid metabolism.[14],[16] Furthermore, several fruits such as mango (Mangifera indica), black plum (Eugenia jambolana), pomegranate (Punica granatum), and amla (Emblica officinalis) are effective against HTN. The molecular mechanism of action of fruit is not completely known against CVD, although their excellent free radical scavenging and antioxidant activities are considered for this.[17] It has been observed that fruits are a rich source of polyphenols which we obtained from the fruit consumption. Moreover, it has been established that polyphenols have a major role in the prevention of heart disease.[18] Thus, fruit consumption can prevent heart disease. This review summarizes the effect of fruits such as mango, black plum, pomegranate, and amla in HTN.
MethodologyA comprehensive literature search was performed on different scientific literature databases such as PubMed/Medline, ScienceDirect, Google Scholar, and Web of Science using a number of keywords: Hypertension, hypertension, and medicinal plants, hypertension and fruits name, and hypertension and polyphenols. All studies and publications were scrutinized for their relevance to our review theme.
Types of HypertensionHTN is mainly of two types: primary or essential HTN and secondary HTN. Primary or essential HTN is in about 90% to 95% of cases, which refers to elevated BP with an uncertain identifiable medical cause. The rest 5% to 10% of cases are of secondary HTN, which are caused mainly by renal or adrenal, arteries, endocrine system, and heart diseases.[19]
Pathophysiology of HypertensionSeveral parameters of the cardiovascular system such as blood volume, cardiac output, and balance of arterial tone determine the elevation in BP. The genetic predisposition (allelic variants of several genes), in company with a host's environmental factors also responsible for developing primary HTN.[20] Various factors are accountable for the pathophysiology of HTN such as enhancement in the sympathetic nervous system, abnormal G protein-coupled receptor signalling, activated renin-angiotensin-aldosterone system, and vasopressin.[21] Vasoconstriction leads to HTN which occurs due to an increase in arterial reactivity due to the loss of balance between pro-oxidant and endothelial nitric oxide synthase (eNOS) enzyme and activation of L-type calcium channels in the vascular smooth muscle cell.[22] Increased sodium transport in the renal proximal tubule due to impaired endothelin type B receptor plays an important role in the pathogenesis of genetic HTN.[23]
Fruits and HypertensionIt has been established that fruit and vegetable intake lower the incidence of CVD and obesity. The Dietary Guidelines for Americans 2010 recommend that everyone should take one-half the plate of fruits and vegetables during the meal.[24] Several epidemiological and experimental studies have demonstrated that fruit intake reduced the incidence of HTN and CVD risk.[9],[10],[11],[12] It has been established that fruit and vegetables are the rich sources of several bioactive phytocompounds, such as carotenoids, phenolic compounds, anthocyanins, Vitamin C, and Vitamin E, which display good antioxidant and anti-inflammatory activities.[25] Further, Lauricella et al. have also demonstrated that the utilization of fruits and vegetables decreases the prevalence of chronic diseases, such as diabetes, CVD, and cancer.[26] Thus, the present review emphasizes the usefulness of M. indica, E. jambolana, P. granatum, and E. officinalis in the prevention and treatment of HTN and also on the underlying mechanism of action mediated by the phytochemicals present in these fruits.
Mangifera indica L.M. indica L., commonly called mango (Aam in Hindi; family Anacardiaceae), has been used in the Indian traditional medicine system (Ayurveda) for 4000 years.[27] Mango is one of the most popular fruits and is often known as the “King of fruits.” Mango is used for various ailments such as liver disorders, HTN, piles, dysentery, asthma, and anemia.[27] The mango tree is originally native to India but is also cultivated in the South-east Asian region, Sri Lanka, Pakistan, Philippines, Bangladesh, Australia, Central America, Africa, and some parts of Europe.[26] Mango is a good source of mangiferin, polyphenols, quercetin, rhamnentin, flavonoids, dietary fiber, ellagic acid, carotenoids, kaempferol, and Vitamin E. Mangiferin, one of the bioactive components of mango, being a polyphenolic, possesses antioxidant, cardiotonic, antidiabetic, hypotensive, immunomodulatory, and antidegenerative activities. The bark of mango possesses catechin, mangiferin alanine, glycine, shikimic acid protocatechic acid, γ-aminobutyric acid, and kinic acid, etc.[27],[28] Furthermore, several studies have also demonstrated that mango exhibited an array of pharmacological activities such as hypotensive, antioxidant, cardiotonic, antidiabetic, anti-viral, wound healing, and anti-inflammatory properties, etc.[26],[27],[29]
The use of mango with regard to HTN, Ronchi and colleagues established that dichloromethanic fraction, aqueous fraction, ethanol extract, ethanol extract, and n-butyl alcohol fraction of leaves extract of mango at the dose of 100 μg/ml possessed antihypertensive activity 99.5% ± 7.2%, 93.6% ± 6.0%, 72.9% ± 3.7%, 72.9% ± 3.7% and 24% ± 2.1%, respectively, by the inhibition of the ACE in vitro study which was comparable to captopril (83.0% ± 20%). In addition, they evaluated the in vivo ACE inhibitory activity of the dichloromethanic fraction of leaves of mango as compared to captopril in Wistar–Kyoto (WKY) rats. They administered angiotensin (Ang) I intravenous (IV) at the dose of (0.03, 3, and 300 μg/kg) before and after the administration of captopril (30 mg/kg, intravenously; n = 5) and dichloromethanic fraction (100 mg/kg, IV; n = 5) in WKY rats. The mean arterial pressure (MAP) was significantly reduced by captopril (6 ± 2 mmHg, 21 ± 5 mmHg, and 30 ± 4 mmHg) and dichloromethanic fraction of leaves of mango extract (5 ± 2 mmHg, 22 ± 4 mmHg, and 54 ± 3 mmHg). Ronchi et al., also evaluated the acute and chronic antihypertensive effect of dichloromethanic fraction of mango leaves extract. There was a dose-dependent acute hypotensive effect of dichloromethanic fraction of mango leaves in WKY rats (n = 5). They found that dichloromethanic fraction decreased MAP in the dose-dependent manner [1 mg/kg (−13.7 ± 3 mmHg), 50 mg/kg (−27 ± 3 mmHg), 100 mg/kg (−38 ± 4 mmHg), 200 mg/kg (−54 ± 3 mmHg), and 300 mg/kg (−58 ± 4 mmHg)] which were compared to acetylcholine (−60.7 ± 3 mmHg). In a chronic study, they divided WKY rats and SHRs into six groups (n = 5): Negative normotensive (WKYC) and hypertensive (SHRC) control that received normal saline; positive normotensive (WKYE) and hypertensive (SHRE) controls which received enalapril (10 mg/kg, i. p.); and normotensive (WKYM) and hypertensive (SHRM) rats received dichloromethanic fraction of mango leaves extract (200 mg/kg, i. p.). Rats were treated for 30 days twice a day. It was observed that chronic administration of mango leaf extracts significantly reduced MAP in SHRs (145 ± 9 mm Hg) as compared to SHRC (209 ± 3 mmHg). The effect of SHRM was comparable to SHRE (150 ± 3 mmHg). Further, they observed that the extract of leaves of mango significantly prevented cardiac hypertrophy in spontaneously hypertensive rats (SHRs) (SHRM; 3.103 ± 0.21 mg/g; P < 0.01) as compared to SHRC (4.342 ± 0.10 mg/g) which were comparable to enalapril (SHRE; 3.192 ± 0.17 mg/g).[30] They also reported the safety profile of leaves extract of mango in vitro (22.31 ± 3.25% of cell death at 160 μg/ml) and in vivo acute toxicity studies. There was no mortality after the administration of 2000 mg/kg of leaves extract of mango.[30] Further, scientists have demonstrated the cardioprotective effects of mangiferin (10 mg/100 g body weight) against isoproterenol-induced myocardial infarction in rats at the end of 28 days by virtue of its antioxidant activity.[31],[32] Yang and groups reported that mangiferin (120 mg/kg) administration significantly prevented hyperuricemia (using potassium ozonate; 750 mg/kg)-induced HTN in Sprague − Dawley (SD) rats by increasing nitric oxide releases and improving endothelial function like intercellular adhesion molecule-1. They observed that mangiferin (120 mg/kg) administration significantly reduced SBP as compared to the hyperuricemia model at the end of 8 weeks (105.5 ± 11.8 mmHg vs. 129.2 ± 11.6 mmHg, P < 0.05; n = 8) and 12 weeks (106.9 ± 10.2 mmHg vs. 128.0 ± 4.7 mmHg, P < 0.05; n = 8).[33] Further, Lin et al. demonstrated that the seed of Irwin mango (1000 mg/kg) has the potential to regulate BP in SHR (141. 11 ± 6.51 mmHg vs. 169.75 ± 9.84 mmHg, P < 0.01; n = 8) at the end of 6 weeks.[34] In addition, Hassan and groups established that an aqueous leaf extract of mango (1 gm/kg once daily) administration significantly reduced BP and blood glucose levels in streptozotocin-induced diabetic rats at the end of 8 weeks. They took 10 rats in each group and found that leaves extract of mango significantly reduced SBP by 14.7% (132.1 ± 1.0 vs. 155 ± 1.8 mmHg, P < 0.01).[35] Scientists have also demonstrated that mango leaf administration caused a significant reduction in SBP and improvement in metabolic abnormalities caused by a high fructose diet in SD rats. Gabal et al. tested the anti-hypertensive effect of leaf extract of mango in high fructose diet-induced HTN (n = 15 in each group). They found that mango leaves extract treatment significantly reduced SBP by 21.8% as compared to high fructose diet-fed rats (110.12 ± 0.42 mmHg vs. 140.86 ± 4.15 mmHg, P < 0.05).[36] Recently, Keathley and groups reported that daily consumption of mango (280 g/day) for 8 weeks caused a significant 3.5% reduction in SBP (−4 ± 6 mm Hg, P = 0.011)) in individuals with overweight and obesity (8 males and 19 females). Furthermore, mango intake significantly reduced oral glucose tolerance at the end of 8 weeks (−0.58 ± 1.03 mmol/L, P = 0.008). Mango utilization also enhanced gut microbial diversity and abundance of specific bacterial species at the end of 12 weeks.[37] It has been established that gut microbiota persuaded the state of immunity and inflammation, proliferation, and metabolism which eventually influence BP.[38] Similarly, Horne et al. also reported that mango utilization (280 g/day) for 8 weeks caused a significant 3.5% reduction in SBP (−4.2 ± 5.8 mmHg; P = 0.011) in overweight/obese individuals (8 men and 19 women). Though, there was significant reduction in systolic (−4. 6 ± 5.6 mm Hg, P = 0.0001) and diastolic (−2. 6 ± 4.9 mm Hg, P = 0.0322) BP in women participants at the end of 8 weeks. Mango consumption also caused a significant improvement in postprandial glucose (10.5%) and oral glucose tolerance test (−0.58 ± 1.03 mmol/L, P = 0.008) in overweight or obese individuals.[39] Nevertheless, Rosas et al. conducted a clinical study of 27 participants and observed that fresh mango consumption (166 g/day) did not significantly decrease BP in overweight and obese adults at the end of 12 weeks. Furthermore, they observed that mango utilization significantly improved liver function tests and decreased fasting glucose but did not improve insulin or HbA1c levels at the end of 12 weeks.[40] Besides, Evans and groups also conducted a pilot study with obese adults (11 males and 9 females) and observed that freeze-dried mango pulp (10 g/day) consumption did not cause any significant change in BP, anthropometrics and biochemical parameters at the end of 12 weeks.[41] It has been also established that mango consumption (400 g/day) for 42 days caused a significant reduction in SBP (119.83 ± 13.16 vs. 115.42 ± 12.33; P < 0.05) in lean individuals and maintained long-term glucose homeostasis in obese individuals.[42] The difference in the findings may be due to variations in the dose and duration of mango consumption. Furthermore, scientists have observed that Ataulfo mangos (250 g four times per week) consumption caused a significant decrease in systolic and DBP at the end of 8 weeks (108.5 ± 2.28 mmHg vs. 113 ± 2.28 mmHg; P = 0.02) and 16 weeks (108.2 ± 2.28 mmHg vs. 113 ± 2.28 mmHg; P = 0.01) in postmenopausal women in a randomized two-group parallel-arm. They also reported that Ataulfo mangos consumption improved lipid profile and wrinkles in fair-skinned postmenopausal women at the end of 16 weeks.[43] Furthermore, McLendon and groups demonstrated that African mango has the potential to decrease BP (−3.75 mmHg), body weight, fasting blood glucose, and improve lipid profile in obese participants (214 subjects).[44]
Eugenia jambolana Lam.E. jambolana Lam.(syn. Syzigium cumini (L.) Skeels; S. jambolana DC; belongs to Family: Myrtaceae), popularly known as Indian blackberry, jamun, black plum, and Malabar plum, etc., is a large evergreen tree native to India.[45] Nevertheless, E. jambolana is also cultivated all over Eastern Africa, South America, the Asian subcontinent, Madagascar, and warmer regions of the United States of America (in Florida and Hawaii).[45] Black plum trees yearly produce ellipsoid fruits (berries). Colors of fruits are green while raw and purplish black after fully ripe. Many scientists have shown that the pulp of Jamun is extremely nutritive and contains vital minerals such as potassium, phosphorous, sodium, calcium, zinc, and iron; vitamins such as niacin, thiamine, and ascorbic acid; carbohydrates like sucrose, fructose, glucose, galactose, mannose, maltose, and mannose; amino acids like tyrosine, glutamine, asparagine, cysteine, and alanine, etc.[46] The jamun trees are reported to contain a variety of secondary metabolites such as terpenes, phenolic acids, flavonoids, and tannins.[47] Furthermore, fruits also contain anthocyanins, such as delphinidin, petunidin, and cyaniding[48] which provide bright violet color to fruits. It has been demonstrated that the jamun tree is widely used for the management of different ailments such as obesity, HTN, urinary disorders, diabetes, inflammation, and constipation.[49],[50],[51] Jamun possesses a range of pharmacological properties such as antioxidant, anti-diabetic, anti-atherosclerotic, anti-inflammatory, and cardioprotective activities.[52],[53],[54]
With regard to HTN, Ribeiro et al. have demonstrated that Syzygium cumini reduced BP and heart rate of SHR due to the reduction of arterial tone by the blockade of extracellular Ca2+ influx.[49] It has been demonstrated that jamun leaf extract administration (0.5 g/kg per day) for 8 weeks decreased BP by 62% and heart rate by 32% in male SHRs (n = 57) which might be due to the presence of flavonoids in jamun leaf extract.[49] Ribeiro also reported that chronic administration of the hydroalcoholic leaf extract of S. cumini significantly decreased MAP by 11.258.3 mmHg in normotensive rats, due to decreased reactivity of vascular smooth muscle.[55],[56] It has been demonstrated that seed extracts of jamun reduced BP by 34.6% and this effect is accredited to the ellagic acid content of the seed.[57] Furthermore, the seed extract fractions have inhibitory action against low-density lipoprotein (LDL) oxidation and other enzymes such as HMG-CoA reductase and ACE due to the high content of gallic acid in seed extract.[58] Moreover, Sidana and Singh also observed that jamun seed powder (10 gms/day) administration to type 2 diabetes patients with HTN (n = 50) significantly improved HTN of patients with type 2 diabetes by 6.29% and 8.57% at the end of 60 days and 90 days, respectively, as compared to the placebo group (n = 49).[59] They observed that jamun seed powder also significantly decreased triglyceride levels, total cholesterol, LDL-C, and very LDL-C and increased high-density lipoprotein-C in type 2 diabetic patients. Further, it has been established that dyslipidemia, a strong interpreter of CVD, is allied with an increased risk of HTN due to the loss of physiological vasomotor activity caused by endothelial damage.[60] Thus, treating dyslipidemia might have some consequences on BP. Furthermore, Herculano et al. reported that the hydroalcoholic extract of jamun fruits exhibited anti-hypertensive properties in SHR. In addition, they observed that jamun fruit extract possessed hypotensive activity in vivo and in vitro studies due to a decrease in peripheral resistance mediated by endothelium. They also demonstrated that jamun fruits extract at the doses of 0.5, 1, 5, 10, 20, and 30 mg/kg intravenously caused hypotension (-15% ± 1%, −14% ± 1%, −15% ± 1%, −13% ± 1%, −11% ± 1%, and − 13 ± 2%, respectively) associated with bradycardia (−6% ± 1%, −5% ± 1%, −6% ± 1%, −14% ± 1%, −8% ± 1%, and −10% ± 2%, respectively) in normotensive rats which might be acted through the direct activation of cardiac muscarinic receptors and indirectly through vagal enhancement.[61] Furthermore, Sehwag and Das established that whole jamun-based functional confection (containing 26.585% jamun pulp with adhering skin, 2% jamun seed powder, hydrocolloid mixture, and 40% water) could be beneficial against HTN.[62]
Punica granatum L.P. granatum L.(Pomegranate), belongs to the family-Punicaceae and genus-Punica L., which is a very old fruit native to India and Central Asia. Pomegranate is extensively consumed and used in the Indian traditional medicine system since ancient times.[63] Currently, it is cultivated in Iran, Africa, Afghanistan, South Caucasus, the Mediterranean region, and North and South America.[64] The fruit of pomegranate is a round berry with a solid reddish rind. The inner part of the rind is a white, thin mesocarp that forms chambers with edible arils. The colour of arils is deep red or purple, owing to a high amount of polyphenols, mainly anthocyanins.[65] Pomegranate is a very good and strong antioxidant than vitamins A, E, or C due to its high content of polyphenols.[64],[66] Several studies have demonstrated that pomegranate fruit juice possessed the utmost antioxidant capacity than other frequently consumed fruit juices such as orange, grape, cranberry, etc., and polyphenol-rich beverages like red wine and green tea.[67],[68],[69] Rind of pomegranate is the non-edible part of the fruit which comprises approximately 40% of the total fruit weight.[70] Singh and colleagues reported that pomegranate peel and seed possessed high content of antioxidants than other parts of fruits.[71] Further, pomegranate peel is a good source of many bioactive compounds, including phenolic acids, ellagitannins, flavonoids and proanthocyanidins, and hydrolysable tannins.[71],[72] It has been observed that commercially available pomegranate juice is prepared from whole pomegranate fruit which contains high amounts of several phytochemicals.[64] Aviram and groups established that pomegranate juice administration exhibited antiatherogenic activity in human volunteers and atherosclerotic mice due to its antioxidant properties.[73] Furthermore, Aviram et al. demonstrated that pomegranate juice consumption (50 ml/day) by ten patients with carotid artery stenosis for 1 year caused significant decrease in carotid intima-media thickness by 9%, SBP by 12% and serum lipid peroxidation. Five out of ten patients continued to take pomegranate juice for 3 years which resulted in a reduction in carotid intima-media thickness by 30% and serum lipid peroxidation by 16% while no significant change was observed in SBP. Furthermore, patients were also treated with anti-hypertensive and hypercholesterolemic drugs during the study, demonstrating an additive and synergistic effect of pomegranate juice.[74] Asgary and groups reported that pomegranate juice consumption significantly reduced BP in short-term as well as long-term periods.[75] Sahebkar et al. performed a meta-analysis of eight randomized controlled trials and observed that pomegranate juice significantly decreased both systolic and DBP. The efficacy of pomegranate juice depends on the duration of consumption and the treatment dose.[76] In an earlier clinical trial, scientists have also demonstrated that pomegranate juice (50 ml contained 1.5 mmol of total polyphenols per day, for 2 weeks) consumption as an add-on therapy along with anti-hypertensive drug by ten uncontrolled hypertensive patients caused a significant reduction in SBP by 5% and serum angiotensin converting enzyme activity by 36% as compared to baseline.[77],[78] Sun and groups reported that the chronic treatment of SHRs with extract of pomegranate (150 mg/kg/day containing 40% punicalagin for 8 weeks) significantly decreased mean arterial pressure and cardiac hypertrophy (heart weight/body weight ratio) as compared to saline-treated SHR at the end of 8 weeks. Interestingly, they observed that mean arterial pressure was stable even after 8 weeks in pomegranate extract-treated SHRs at the end of 16 weeks. Moreover, they observed that the extract of pomegranate significantly decreased oxidative stress in terms of decreased malondialdehyde levels, reduction in oxidized glutathione, increased in antioxidant enzymes like superoxide dismutase, reduced glutathione, and the ratio of reduced glutathione to oxidized glutathione. Further, the extract of pomegranate attenuated mitochondrial impairment by activating AMPK-Nrf2 in SHRs.[79] Furthermore, Stockton and groups conducted a randomized double-blinded placebo-controlled clinical trial in 55 participants and observed that a pomegranate extract capsule (containing 210 mg of punicalagins, 328 mg of other pomegranate polyphenols [such as flavonoids and ellagic acid] and 0·37 mg of anthocyanins) significantly decreased DBP by 2·79 mmHg (P < 0.05) as compared to placebo at the end of eight weeks. There was no significant change in SBP as compared to placebo[80] It has been also found that punicalagin (100 mg/kg), a polyphenol present in pomegranate juice, significantly prevented NG-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg daily for 6 days on days 1419 of pregnancy)-induced HTN in pregnant rats. In addition, punicalagin exhibited antioxidant effects and also restored angiogenic balance by elevating the vascular endothelial growth factor expression and decreasing the vascular endothelial growth factor receptor-1/fms-like tyrosine kinase-1 expression. Punicalagin also significantly amplified the nitric oxide levels in the placenta as compared to the preeclampsia (PE) group.[81] Furthermore, de Nigris et al. also reported that fruit extract of pomegranate significantly increased eNOS[82] which has a vasodilatory effect and causes a reduction in systemic vascular resistance.[83] The increased levels of oxidative stress in rats with PE were markedly decreased by treatment with punicalagin. De Nigris et al. demonstrated that pomegranate juice downregulated the expression of redox-sensitive genes i.e., ELK-1 and p-JUN and increased the expression of eNOS which is essential for the proper performance of blood endothelial cells.[84] Mohan and groups also established that fruit juice of pomegranate significantly prevented Angiotensin II (Ang II)-induced HTN in diabetic Wistar rats by inhibiting ACE activity.[85] Clinical studies have also reported the efficacy of the fruit juice of pomegranate against HTN. Asgary et al. evaluated the effect of pomegranate juice (150 ml/day on a single occasion between lunch and dinner) in 21 hypertensive patients. They observed that pomegranate juice treatment significantly decreased systolic (−6.36 ± 5.05 mmHg) and diastolic (−3.64 ± 5.05 mm Hg) BP at the end of 2 weeks. Moreover, pomegranate juice also improved endothelial function by decreasing the serum concentrations of VCAM-1 in hypertensive patients.[86] Asgary and groups also evaluated the acute effect of natural pomegranate juice (150 ml/day) on BP and endothelial function in 13 hypertensive individuals. They found that pomegranate juice consumption led to a reduction in systolic and DBP by 7% and 6%, respectively, after 46 h.[87]
Emblica officinalis Gaertn or Phyllanthus emblica L.E. officinalis Gaertn, commonly known as amla or Indian gooseberry, is one of the most essential medicinal plants in Indian traditional medicine systems and Southeast Asia.[88] Amla is native to India, however, is also cultivated in other countries such as China (southern part), Uzbekistan, the Mascarene Islands, Bangladesh, Malaysia, Sri Lanka, Myanmar, and Pakistan.[89] Different parts of E. officinalis are used to manage a variety of ailments; however, the most vital is the fruit. Almost every part of the amla plant possessed medicinal properties; however, amla fruit holds the most significance in the treatment of various diseases. The fruits have been used either alone or in combination with therapy in Ayurveda to treat numerous disorders such as dyspepsia, fever, common cold, and peptic ulcer and also used as a liver tonic, antipyretic, diuretic, laxative, hair tonic, anti-inflammatory, refrigerant, and stomachic.[88] The phytochemical study has demonstrated that amla fruit possesses a large amount of emblicanin-A and emblicanin-B, and is a rich source of Vitamin C, as compared to other fruits such as lime, apple, pomegranate, Pusa Navrang grape, Perlette grape and also bears an enormous quantity of polyphenols such as ellagic acid, gallic acid, vitamins, different tannins, minerals, various amino acids, fixed oils, and flavonoids such as quercetin and rutin.[88],[90] Various preclinical studies established that amla has beneficial effects against a large number of ailments such as cancer, inflammation, HTN, osteoporosis, neurological disorders, infectious disorders, and lifestyle diseases such as diabetes and metabolic syndrome (MetS).[90],[91],[92],[93],[94],[95],[96],[97] Amla possesses anti-hypertensive properties[95] and various pharmacological properties like antidiabetic,[97] antioxidant,[90] anti-inflammatory,[91] anti-hyperlipidemic,[90],[96] anticoagulant, antiplatelet,[98] and cardioprotective[99],[100] activities etc. Hashem-Dabaghian and groups demonstrated the cardioprotective effects of amla in vitro, animal, and clinical studies. They assessed clinical trials and animal studies using the Jadad scale and ARRIVE checklist respectively. They observed that amla caused prevention against isoproterenol and doxorubicin cardiotoxicity and myocardial ischemia/reperfusion injury, and ameliorates vascular endothelial function in animal studies. In addition, amla showed myocardial antioxidant and vasodilatory activities as well as anti-platelet aggregation properties in clinical studies.[98]
Concerning HTN, Bhatia et al. have observed that hydroalcoholic lyophilized extract of amla (75, 150, and 300 mg/kg/day) administration for 5 weeks significantly prevented DOCA and salt-induced HTN in a dose-dependent manner in Wistar albino rats. They also observed that amla extract significantly reduced oxidative stress and cardiac and renal hypertrophy in hypertensive rats.[95] They reported that the preventive potential of amla in hypertensive rats was due to the activation of serum NO, eNOS, endogenous antioxidants, and electrolyte levels.[95] Further, Kim et al. demonstrated that extract of amla (10 mg/kg and 20 mg/kg) significantly prevented HTN in a high fructose diet (65% w/w)-induced MetS in male Wistar rats (n = 8). They found that amla extract significantly prevented the systolic (by 6% with 10 mg/kg and 11% with 20 mg/kg) and diastolic (by 7% with 10 mg/kg and 9% with 20 mg/kg) BP as compared to high fructose-fed rats at the end of 2 weeks.[96] In addition, Yokozawa and groups observed that Sun Amla (40 mg/kg) and ethyl acetate extract of amla (10 mg/kg) caused a significant reduction in SBP (P < 0.05) in aged control rats as compared with young rats at the end of 100 days due to reduction in inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 expression levels by inhibiting NF-κB activation.[101] Other scientists have also observed that both amla fruit juice (2 ml/kg, once daily) and gallic acid (100 mg/kg, once daily), a principal bioactive molecule of amla, treatment in 3T3-L1 preadipocytes and db/db mice significantly prevented the elevation of mean arterial BP caused by fructose in rats due to increase in insulin sensitivity through Akt as well AMPK activation.[102] However, Shanmugarajan et al. conducted a randomized double-blind placebo-controlled trial on 150 patients with essential HTN and found that capsule of amla (500 mg, twice daily) did not exhibit anti-hypertensive effects as an add-on therapy in patients at the end of 12 weeks. However, they observed a good safety profile of amla in patients with essential HTN.[103] Further, amla extract (250 mg) was found to be effective against cold pressor stress test-induced changes in cardiovascular parameters in healthy human subjects. It has been observed that amla administration caused a significant reduction in augmentation index, and radial and aortic BP at the end of 14 days.[104] Moreover, Gopa and colleagues observed that a capsule of amla (500 mg once daily) consumption significantly showed a hypolipidemic effect along with a reduction in BP among sixty type II hyperlipidemic patients at the end of 42 days.[105] Recently, Ghaffari et al. conducted a randomized, triple-blind, placebo-controlled, add-on clinical trial on 92 patients with uncontrolled HTN and observed that amla (500 mg/TDS after meal) caused a significant reduction in systolic (15.6% ± 8.23%; P < 0.001) and diastolic (12.3 ± 7.87%; P < 0.001) BP in patients with uncontrolled HTN as compared to the placebo group at the end of 8 weeks.[106] Furthermore, its beneficial effects against HTN were found to be due to its antioxidant, ACE inhibitor, and diuretic activities.[106],[107],[108] Endothelial functions and oxidative stress were found to be improved by amla administration in a clinical study among healthy subjects as compared to the placebo group. Scientists have also demonstrated that ellagitannins (hydrolysable to ellagic acid and gallic acid) rich amla (500 mg/day) might be beneficial against HTN, dyslipidemia, and atherosclerosis due to their action against endothelial dysfunction.[109]
ConclusionThere are many pharmacological agents available in the clinics. However, their efficacy, side effects, drug resistance, and poor adherence is a burning issue with the treatment of HTN. HTN is very much related to poor diet habit. A number of fruits can alter metabolic risk factors such as insulin resistance, diabetes, dyslipidemia, and central obesity. Further patients with HTN frequently have other concomitant metabolic cardiovascular risk factors. In addition, many studies have also demonstrated the relationship between fruit consumption and metabolic risks that provided similar protective effects of fruits on HTN. The mechanisms of action of fruits against HTN mainly incorporated the modulation of molecular events associated with correcting endothelial dysfunction, eNOS activity, reducing oxidative stress, improving lipid levels, and inhibiting inflammation. In the future, the protective effects of a large number of fruits on HTN and CVDs should be evaluated with their mechanism of action, and their bioactive components should be isolated and identified. It has been observed that the interest of the scientists in the hunt for new drugs/molecules from natural sources has gained global attention during the last two decades. Thus, fruits can be our source of drugs, with fewer side effects and better bioavailability for the treatment of HTN in future. In addition, more basic and clinical studies should be conducted with these fruits against HTN to provide its scientific and translational value.
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