An Ethnopharmacological Review: On Commonly used Anti-Oxidant Plants with Anti-Hypertensive

 

Jhakeshwar Prasad¹*, S. Prakash Rao², Ashish Kumar Netam², Trilochan Satapathy²

¹Associate  Professor, Department of  Pharmacology, Columbia Institute of  Pharmacy, Tekari, Raipur (CG)

Pin 493111.

²Department of Pharmacology, Columbia Institute of Pharmacy, Tekari, Raipur (CG) pin 493111.

 

ABSTRACT:

Hypertension is a chronic disorder characterized by a persistently elevated blood pressure exceeding 140/90 mmHg or greater. Many antihypertensive agents are used for treatment of hypertension like Thiazide, loop, and potassium - sparing diuretics,  calcium channel blockers,  Angiotensin - converting enzyme inhibitors, Central α 2 - adrenergic agonists, β - adrenergic and α 1/β - adrenergic antagonists, Peripheral α 1- adrenergic antagonists, and Direct - acting vasodilators etc. But these drugs have some side effect s like diuretics may cause muscle cramps, dizziness, extreme tiredness, dehydration, blurred vision, abnormal heart rate, skin rash, and others. The ACE inhibitors are caused by cough, skin rash, vomiting, kidney failure, fever, sore throat, diarrhea, and others. And use of calcium channel blockers are caused by fatigue, headache, diarrhea, constipation, edema, and others side effects. The use of medicinal plants for treatment of hypertension is very common because these remedies are easily available and low cost than novel pharmaceuticals. Herbs do not cause side effects like weakness, tiredness, drowsiness, impotence, cold hands and feet, depression, insomnia, abnormal heartbeats, skin rash, dry mouth, dry cough, stuffy nose, headache, dizziness, swelling around eyes, constipation or diarrhea, fever etc. Hence the present article focuses on different medicinal plants worldwide used for hypertension rather than on medications. The present article emphasizes on causes for hypertension, its signs, symptoms, preventive measures as well as its safer options of treatments.

 

 

 

INTRODUCTION:

Cardiovascular disease (CVD) remains the leading cause of debility and premature death 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. [1]

 

Hypertension is responsible for around 16.5% of annual deaths worldwide and is indeed the main cause of morbidity and mortality associated with CVDs. [2] By 2030, the annual death toll is estimated to reach 23.5 million people 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. [3,4]  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). [5] 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 [6] 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. 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. [7] 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. [8] 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. [9] 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. [10] 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. [11,12] 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. [13] The major concerns that often delay treatment allude to higher costs of antihypertensive drugs, [14] their availability and accessibility, the undesired side effects of antihypertensive drugs, [15] and the reduced patient compliance to consume more than a pill per day. 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.

 

 

Figure: 1 A schematic diagram indicating the favorable effects of plants/herbs on the molecular pathogenesis of hypertension. Different molecular, biochemical, and cellular pathways are favorably modulated by herbs/plants or their extracts.

 

Table 1: Commonly used antihypertensive plants with antioxidant activity.

Herb	Effect	Concentration/Dose	Experimental setting/Model	References
Allium sativum	Scavenges ROS	3 mg/ml	Human neutrophils
	Increases antioxidants	500 mg/ml	2K-1C rats
		125–2000 mg/kg	Wistar albino rats’ hearts
	Reduces NADPH activity	150 and 400 mg/kg	Fructose-fed rats	[16]
Andrographis	Scavenges ROS	0.7–2.8 g/kg	SHR
paniculata
Apium graveolens	Increases antioxidants	1 ml/kg (of different extracts)	CCl4-treated mice
Camellia sinensis	Scavenges ROS	1–5 µg/ml	Superoxide-generating system
	Decreases NADPH oxidase	13.3 g/L	STZ fed SHR
	Increases antioxidants	0.1%	Streptozotocin (STZ)-fed Sprague-Dawley rats
		1% Green Tea Extract	C57BL/6 mice
	Inhibits eNOS uncoupling	5 g/kg	STZ fed SHR	[17]
Coptis chinensis	Increases antioxidants	150 mg/kg	Atherosclerotic renovascular disease (ARD)
			Wistar rats
	Decreases NADPH oxidase	150 mg/kg	ARD Wistar rats
Coriandrum	Inactivates ROS produced	200 and 300 mg/kg	Isoproterenol-induced cardiotoxicity in male	[18]
sativum	by β-adrenoceptor		Wistar rats.
	stimulation
	Increases antioxidants	200 mg/kg	CCl4-induced hepatotoxicity in Wistar albino
			rats
Crataegus spp.	Scavenges ROS	100–400 µg/ml	enzymatic assay
Crocus sativus	Reduces oxidative stress	200 mg/kg	BeCl2-treated Wistar rats
	Increases antioxidants	200 mg/kg	BeCl2-treated Wistar rats
		20–80 mg/kg	Genotoxins-treated Swiss albino mice	[19]
Hibiscus sabdariffa	Scavenges ROS	2 mg/ml	CCl4-induced hepatotoxicity in rat liver
	Increases antioxidants	10 g extract (powder),	Healthy humans
		dissolved in 200 mL water
Panax	Increases antioxidants	60–120 µM	Hypoxia/Reoxygenation-induced oxidative	[20]
			injury in rat cardiomyocytes
Salviae miltiorrhizae	Reduces ROS	100 µg/ml	Sprague-Dawley rat thoracic aortic VSMCs
	Increases antioxidants	5 g extract/time, twice per	Chronic heart disease (CHD) patients
		day; 60 days
Zingiber officinale	Scavenges ROS	0–60 µM	Enzymatic assay
	Inhibits lipid peroxidation	0.05 mg/ml	Rat heart	[21]
Agelanthus dodoneifolius	Scavenges ROS	0.125 mg/ml	DPPH enzymatic assay	[22]
Alpinia zerumbet	Reduces oxLDL	0.1 mg/L	Human umbilical vein endothelial cells
Apocynum venetum	Scavenges ROS	10 µg/ml	Rat isolated aortic rings
Arctium lappa	Scavenges ROS	4.79 µg/ml	DPPH enzymatic assay
Cnidium monnieri	Increases antioxidants	20 mg/kg	Renovascular hypertensive rats
Cnidium officinale	Scavenges ROS	0.32–200 µg/ml	DPPH enzymatic assay
Desmodium gangeticum	Reduces ROS	50–200 µg/ml	Isoproterenol-treated cardiomyocytes
Elettaria cardamomum	Increases antioxidants	3 g/day	Stage 1 hypertensive patients	[23]
Embelia ribes	Increases antioxidants	100 mg/kg	Isoproterenol-treated rats
		50 mg/kg	High fat-fed rats
Ferula gummosa	Increases antioxidants	90 mg/kg	SHR
Gastrodia elata Blume	Decreases LDL cholesterol	6 mg/kg/day	High fat-fed SHR
Kalanchoe pinnata	Increases antioxidants	25–100 mg/kg/day	High salt-loaded rats
Lepidium sativum	Scavenges ROS	500 µg (of the lyophilized extract in a tube)	DPPH enzymatic assay	[24]
Melothria maderaspatana	Increases antioxidants	50, 100, and 200 mg/kg	DOCA-salt hypertensive rats
Ocimum basilicum	Scavenges ROS	IC50 range: 8.17–24.91 µg/ml (for different solvent-extractions)	DPPH enzymatic assay
Phyllanthus amarus	Increases antioxidants	200 mg/kg	Male Albino Wistar rats
	Scavenges oxidants	0–1 mg/ml (varies for each assay)	DPPH enzymatic assay (and other
			oxidant scavenging assays)
Picrasma quassiodes	Regulates SOD and  NO	100 and 200 mg/kg	SHR	[25]

 

Table 2: Commonly used antihypertensive plants with vasorelaxant activity.

Herb	Effect	Concentration/Dose	Experimental setting/Model	References
Allium sativum	Increases NO	Reported only as garlic extract	Human umbilical vein endothelial cells	26]
		0.8 mg/ml	Rat isolated pulmonary arteries
	Increases eNOS	150 and 400 mg/kg/day	Fructose-fed Wistar rats
	Increases H2S	500 µg/ml	Sprague-Dawley rat aortic rings
	Inhibits ACE		Fructose-fed rats
Andrographis paniculata	Increases NO	1 mg/ml	Isolated hearts from Sprague-Dawley rats	27]
	Blocks Ca2+ channels	1 mg/ml	Isolated hearts from Sprague-Dawley rats
	Reduces ACE	0.7–2.8 g/kg	SHR
Apium graveolens	Blocks Ca2+ influx	48 mM	Rat isolated aortic rings
Bidens pilosa L.	Ca2+ antagonists	0.32 mg/ml	KCl-treated rat aorta
	Mechanism not determined	40 mg/ml	High-fructose fed Wistar rats	28]
Camellia sinensis	Increases flow-mediated	2 g in 250 ml boiled water/day	Brachial arteries of subjects with elevated
	dilation (FMD)		cholesterol level
		450 and 900 mL	Brachial arteries of coronary heart disease
			patients
	Increases NO	580 mg	Healthy male smokers (preclinical pilot)
	Inhibits eNOS uncoupling	5 g/kg daily	Diabetic SHR
	Blocks AT1 receptor	0.1%	STZ-fed Sprague-Dawley rats	[29]
Coptis chinensis	Upregulates eNOS	2.99, 3.45, 5.81, and 6.14 g/L	Rat isolated cardiomyocytes (insulin-induced
	expression		hypertrophy)
		2.99, 3.45, 5.81, and 6.14 g/L	Isolated thoracic aorta rings from CIHH rats
	Decreases EMP	1.2 g/L	Healthy humans
	Blocks Ca2+ channels	5.18 and 6.14 g/L	Isolated thoracic aorta rings from CIHH rats
Crataegus spp.	Activates eNOS	100 mg/kg/day	L-NAME-induced hypertensive rats
		100 µg	Male Wistar Rat isolated aortic rings
		100 µg	Human isolated mammarian arterial rings
Crocus sativus	Activates eNOS	0.1–0.5 ml/kg	ischemia-reperfusion (IR) in rats	[30]
	Blocks Ca2+ channels	1 and 5 mg%	Guinea pig Isolated heart
Cymbopogon citratus	Increases NO bioavailability	30 mg/ml	Isolated aorta from SHR	[31]
		30 mg/ml	Isolated aorta from WKR
		1–20 mg/kg	Rat isolated thoracic aorta
	Inhibits Ca2+-influx	1–20 mg/kg	Rat isolated thoracic aorta
Hibiscus sabdariffa	Increases NO	0.3 mg/ml	SHR isolated aorta	[32]
		1500–2500 mg/kg	Not clear
	Blocks Ca2+ channels	10 ng−1 mg/ml	SHR isolated aorta
Nigella sativa	Blocks Ca2+ channels	2–14 mg/ml	Rat isolated aorta	[33]
Panax	Increases eNOS	150 µg/ml	SHR adrenal medulla
Salviae miltiorrhizae	Increases NO	0–10 mg/ml (of SalB, a major	Rabbit thoracic aortic rings
		ingredient of this plant)
	Opens KATP channels	0.25–2 mg/ml	SHR aorta
	Blocks Ca2+ channels	300–1000 µg/ml	Porcine coronary rings
		10.39 ± 1.69 µM	Rat coronary arterial rings	[34]
	Reduces ACE activity	0.05 mg/ml	Rat heart

 

 

Table 3: Commonly used antihypertensive plants with anti-inflammatory activity.

Herb	Effect	Concentration/Dose	Experimental setting/Model	References
Allium sativum	Inhibits NF-κB	250 mg/kg	High fructose-fed rats	[35]
	Reduces VCAM-1	150 mg/kg	Fructose-fed Wistar rats
Andrographis paniculata	Inhibits NF-κB	4 mg/kg	Npr1 gene-knockout mice
Bidens pilosa L.	Inhibits NF-κB and TNF-alpha activation	10–20 µg/ml	LPS-stimulated RAW 264.7
		1 µM
Camellia sinensis	Inhibits NF-κB	5–30 µM (of EGCG)	Human endothelial cells	[36]
	Reduces VCAM-1	10–100 µM (of EGCG)	In vitro endothelial cells
	Decreases TNF-α	379 mg	Obese, hypertensive humans
Coptis chinensis	Decreases NF-κB	150 mg/kg	Atherosclerotic renovascular rats	[37]
		25 µM (of Berberine)	Rat aortic endothelial cells
	Inhibits VCAM-1	25 µM (of Berberine)	Rat aortic endothelial cells
Coriandrum sativum	Decreases NF-κB	150 µg/ml	LPS-stimulated RAW 264.7
Crataegus spp.	Decreases TNF-α	100 mg/kg	STZ-induced diabetic rats
	Decreases IL-6	100 mg/kg	STZ-induced diabetic rats
Crocus sativus	Inhibits NF-κB	0.1–0.5 mL/kg/day	Ischemia-reperfusion injury (IRI) in rats
Panax	Inhibits NF-κB	2–5 µM (one of its components)	Mouse cardiomyocytes	[38]
		10 µM (one of its components)	Mouse macrophages
	Decreases TNF-α	10 µM (one of its components)	Mouse macrophages
	Decreases IL-6	10 µM (one of its components)	Mouse macrophages
Salviae miltiorrhizae	Decreases TNF-α	100 µg/ml	Human umbilical vein endothelial cells
	Inhibits NF-κB	100 µg/ml	Human umbilical vein endothelial cells
	Inhibits VCAM-1	100 µg/ml	Human umbilical vein endothelial cells	[39]
Arctium lappa	Suppresses VCAM-1 (aortic endothelia)	100 and 200 mg/kg/day	High fat-fed Sprague-Dawley rat
			thoracic aorta
Carthamus tinctorius	Decreases soluble (plasma) VCAM-1	2.1 g/day	Healthy humans
Cirsium japonicum	Decreases NF-κB expression (mast	0.05–0.4 mg/ml	HMC-1 human mast cells	[40]
	cells)
Cuminum cyminum	Decreases TNF- α and IL-6 (renal tissue)	200 mg/kg	renovascular hypertensive rats
Cynanchum wilfordii	Inhibits VCAM-1 and ET-1 activity	100 and 200 mg/kg/day	High fat/cholesterol-fed
	(aortic endothelia)		ApoE-deficient mice
Gastrodia elata Blume	Decreases iNOS expression (gastric	0.02 mL/g	Stress-induced gastric lesions in mice
Phyllanthus amarus	Decreases NF-κB, TNF-α, and COX-2	0–250 µg/ml (aqueous ethanol)	LPS-treated RAW 264.7	[41]
	(RAW 264.7 cells)	or 0–200 µg/ml (hexane)	macrophages
		fractions

 

Table 4: Commonly used antihypertensive plants with anti-proliferative activity.

Herb	Effect	Concentration/Dose	Experimental setting/Model	References
Allium sativum	Induces Cx43 expression	50 µM	Sprague-Dawley rat thoracic aortic	[42]
			VSMCs
	Inhibits Ang-II-induced cell cycle	100 µM (two of its components)	VSMCs isolated from SHR
	progression
Camellia sinensis	Increases HO-1 enzyme	0–50 µM	Human aortic smooth muscle cells
Coptis chinensis	Inhibits cardiac hypertrophy	300 mg/kg	Rat isolated cardiomyocytes
			(insulin-induced hypertrophy)
Panax	Inhibits ERK pathway activation	10% of plasma isolated from rats	PDGF-treated rat VSMCs
		injected with 200 mg/kg of the extract
	Decreases CDK4, pRb, and	20–40 mg/ml	SHR thoracic aortic VSMCs
	cyclin D1
	Decreases β-galactosidase	20–40 mg/ml	SHR and WKY rat thoracic aortic VSMCs	[43]
Salviae miltiorrhizae	Inhibits PDGF proliferation	100 µg/ml	Sprague-Dawley rat thoracic aortic
			VSMCs

 

Table 5: Commonly used antihypertensive plants with diuretic activity.

Herb	Effect	Concentration/Dose	Experimental setting/Model	References
Hibiscus sabdariffa	Lowers uric acid concentration	16 g/day	Healthy men
		1500–2500 mg/kg	SHR
	Reduces plasma Na+ levels	250 mg	Stage 1 and 2 hypertensive humans	[44]
Nigella sativa	Increases Na+, K+, and Cl− in urine	5 ml/kg/day	SHR	[45]

 

Herb	Effect/Mechanism	Concentration/Dose		Model	References
Elettaria cardamomum	Increases urine output and enhances	1, 3, and 10 mg/kg		Anesthetized rats	[46]
	Na+ and K+ excretion
Lepidium latfolium	Increases urine output and electrolyte	50–100 mg/kg		Rats
	excretion
Lepidium sativum	Increases electrolyte excretion	20 mg/kg		SHR
Phyllanthus amarus	Increases urine volume and Na+	80 mg/kg (in rabbits)		Mild hypertensive patients
	levels in serum (humans) and			and rabbits
	decreases SBP and DBP (in man)				[47]
Tropaeolum majus L	Reduces aldosterone	300 mg/kg ethanolic extract, 200 mg/kg		SHR
			purified fraction, 10 mg/kg isoquercitrin
	Downregulates renal Na+/K+ pump
	Increases urine volume
Viscum articulatum Burm	Increases urine volume	200 mg/kg/day		L-NAME-treated rats
	Increases urine volume, electrolyte	100, 200, and 400 mg/kg		Male Wistar rats	[48]
	excretion and glomerular filtration rate

 

Table 6: Commonly used plants that were studied in clinical trials, and details of these trials.

Herb	Design	Population	Condition	Dose	Duration	Effect	Magnitude of	References
		size					change
Allium	Double-blind, parallel,	50	Uncontrolled	960 mg/day aged garlic	12 weeks	SBP decrease	10.2 ± 4.3 mmHg	[49]
sativum	randomized,		hypertension	extract
	placebo-controlled
	Placebo-controlled,	6	Mild hypertension	2600 mg/day (4 tablets,	10 days	SBP decrease	17 mmHg
	crossover			650 mg each) garlic powder
	Double-blind, parallel,	79	Uncontrolled	480 mg/day aged garlic	12 weeks	SBP decrease	11.8 ± 5.4
	randomized,		hypertension	extract
	placebo-controlled
	Randomized, parallel,	210	Stage 1	300–1500 mg/day garlic	24 weeks	SBP and DBP	9.2 and	[50]
	placebo-controlled		hypertension	powder		decrease	6.26 mmHg
Camellia	Double-blind,	20	Mild hypertension	7.6 g tea leaves in 400 ml	1 h	SBP and DBP	1.7 and 0.9 mmHg
sinensis	placebo-controlled			water		increase	(green tea)
							0.7 mmHg each
							(black tea)
	Randomized, parallel,	56	Obese,	379 mg green tea extract	12 weeks	SBP and DBP	4 each mmHg
	placebo-controlled		hypertension			decrease
	Randomized, parallel,	95	Mild hypertension	4479 mg (3 cups/day,	24 weeks	SBP and DBP	2 and 2.1 mmHg	[51]
	placebo-controlled			1493 mg each) black tea		decrease
Crocus	Randomized,	30	Healthy	400 mg/day	7 days	SBP and MAP	11 and 5 mmHg
sativus	double-blind,					decrease
	placebo-controlled
Hibiscus	Randomized,	75	Mild to moderate	10 g/day dried calyx	4 weeks	SBP and DBP	15.32 and
sabdariffa	captopril-controlled		hypertension			decrease	11.29 mmHg
	Randomized,	193	Stage 1 and 2	250 mg dried calyx extract	4 weeks	SBP and DBP	16.59 and
	double-blind,		hypertension			decrease	11.8 mmHg
	Lisinopril-controlled
	Randomized,	65	Pre- and mild	720 mL/day (3 servings,	6 weeks	SBP, DBP, and	7.2, 3.1, and	[52]
	double-blind,		hypertension	240 mL each) hibiscus tea		MAP decrease	4.5 mmHg
	placebo-controlled			(3.75 g hibiscus)

 

Panax	Randomized,	90	Mild hypertension	300 mg/day P. ginseng	8 weeks	SBP and DBP	3.1 and 2.3 mmHg
	placebo-controlled			extract		decrease
	Randomized,	64	Essential	3 g/day P. quinquefolius	12 weeks	SBP decrease	17.4 mmHg
	double-blind,		hypertension
	placebo-controlled
	Randomized,	23	Healthy	400 mg	3 h	SBP and DBP	4.8 and 3.6 mmHg	[53]
	double-blind,					decrease
	crossover

 

CONCLUSION:

This review focuses on recent literature evaluating naturally occurring antioxidants with respect to their impact on hypertension.

 

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Received on 28.03.2018        Modified on 29.05.2018

Accepted on 12.07.2018       ©A&V Publications All right reserved