Special article
Nutraceuticals, Vitamins, Antioxidants, and Minerals in the Prevention and Treatment of Hypertension

https://doi.org/10.1016/j.pcad.2005.01.004Get rights and content

Vascular biology assumes a pivotal role in the initiation and perpetuation of hypertension and target organ damage sequelae. Endothelial activation, oxidative stress, and vascular smooth muscle dysfunction (hypertrophy, hyperplasia, remodeling) are initial events that start hypertension. Nutrient-gene interactions determine a broad array of phenotypic consequences such as vascular problems and hypertension. Optimal nutrition, nutraceuticals, vitamins, antioxidants, minerals, weight loss, exercise, smoking cessation, and moderate restriction of alcohol and caffeine in addition to other lifestyle modifications can prevent, delay the onset, reduce the severity, treat, and control hypertension in many patients. An integrative approach combining these lifestyle suggestions with the correct pharmacological treatment will best achieve new goal blood pressure levels, reduce cardiovascular risk factors, improve vascular biology and vascular health, and reduce target organ damage including coronary heart disease, stroke, congestive heart failure, and renal disease. The expanded scientific roles for nutraceutical supplements will be discussed in relation to the prevention and treatment of essential hypertension with emphasis on mechanisms of action and clinical integration with drug therapy as indicated based, in part, on the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the European Society of Hypertension, the European Society of Cardiology, the International Society of Hypertension, the Canadian Society of Hypertension, and other hypertension guidelines.

Section snippets

Nutrition and Disease Prevention

An integrative approach that uses nutrition, vitamins, antioxidants, minerals, functional food, nutraceuticals, weight loss, exercise, and judicious use of alcohol and caffeine with tobacco cessation combined with optimal pharmacological therapy is the best means to reduce BP and TOD in most hypertensive patients. Lower BP goals will require a combination of lifestyle modifications and drug therapy, especially for those patients5 with multiple risk factors, TOD, or clinical cardiovascular

Hypertension and Oxidative Stress in Animal Models

Excess production of oxidants (reactive oxygen species [ROS]) and a deficiency of antioxidant systems contribute to hypertension and ED with endothelial-dependent impairment of vascular relaxation in spontaneously hypertensive rats (SHRs).18 In SHRs, an increase in ROS precedes the development of hypertension.19 Increased ROS production in vitro and in vivo has been demonstrated in several animal models of hypertension.19 These studies suggest that ROS participate in the development and

Hypertension and Oxidative Stress in Human Beings

Oxidative stress with an imbalance between ROS and the antioxidant defense mechanisms may contribute to the etiology of human hypertension as well as its initiation, maintenance, pathogenesis, pathophysiology, and cardiovascular complications.44 Oxidative stress has been implicated in many hypertensive disorders including lead-induced,[34], [45], [46], [47] uremic, cyclosporin-induced,[48], [49], [50], [51] salt-sensitive,[52], [53] preeclampsia, essential hypertension,[54], [55], [56], [57],

Evolutionary Nutrition

Human beings have evolved from a preagricultural, hunter-gatherer society to a commercial agriculture society with highly processed, refrigerated, and fast food that has imposed an unnatural and unhealthy nutrition. The human genetic makeup is 99.9% that of our Paleolithic ancestors, yet our nutritional, vitamin, and mineral intakes are vastly different.2 The macronutrient and micronutrient variations of protein, fats, carbohydrates, fiber, Na, K, Mg, and various vitamins and minerals

Nutrient-Gene Interactions

The human genetic pool has remained essentially unchanged for the past 35 000 years.2 Human beings are genetically geared to a preagricultural, hunter-gatherer nutritional and exercise lifestyle. This includes, at a minimum, a low Na+ intake (<2 g/d), high K+ intake (>500 mEq/d), a K+/Na+ ratio higher than 5:1, low saturated fat (<10% total calories), high ω-3 PUFAs, more monounsaturated fats (MUFAs) with a total fat intake of 20% to 25% of total calories, high fiber (>50 g/d), moderate protein

Sodium (Na+)

The average Na intake in the United States is 5000 mg/d with some areas of the country consuming 15 000 to 20 000 mg/d.14 However, the minimal requirement for Na is probably about 500 mg/d.14 Epidemiological, observational, and controlled clinical trials demonstrate that an increased Na intake is associated with higher BP. 111 A reduction in Na intake in hypertensive patients, especially the salt-sensitive patients, will significantly lower BP by 4 to 6/2 to 3 mm Hg.[98], [112], [113], [114] The

Potassium (K+)

The average American dietary intake of K (K+) is 45 mEq/d with a K/Na ratio (K+/Na+) of less than 1:2.14 The recommended intake of K+ is 650 mEq/d with a K+/Na+ ratio of more than 5:1.14 Numerous epidemiological, observational, and clinical trials have demonstrated a significant reduction in BP with increased dietary K+ intake.[14], [152], [153] The magnitude of BP reduction with a K+ supplementation of 60 to 120 mEq/d is 4.4/2.5 mm Hg in hypertensive patients and 1.8/1.0 mm Hg in normotensive

Magnesium (Mg2+)

A high dietary intake of Mg of at least 500 to 1000 mg/d reduces BP in most of the reported epidemiological, observational, and clinical trials, but the results are less consistent than those seen with Na+ and K+.[14], [111], [155], [160], [161], [162], [163], [164], [165], [166] In most epidemiological studies, there is an inverse relationship between dietary Mg intake and BP.[147], [155], [162], [163], [166], [167], [168], [169], [170], [171] A study of 60 essential hypertensive subjects

Calcium (Ca2+)

Population studies show a link between hypertension and Ca,[14], [155], [178] but clinical trials that administer Ca supplements to patients have shown inconsistent effects on BP.[179], [180] Higher dietary Ca is not only associated with a lower BP, but also with a decreased risk of developing hypertension.[155], [181] A 23% reduction in the risk of developing hypertension was noted in those individuals taking a dose higher than 800 mg/d compared with those taking one lower than 400 mg/d.[155],

Zinc (Zn2+)

Low serum Zn levels in observational studies correlate with hypertension as well as CHD, type II DM, hyperlipidemia (especially hypertriglyceridemia and low high-density lipoprotein cholesterol [HDL-C]), elevated lipoprotein a, 2-hour postprandial plasma insulin levels, and insulin resistance.205 Elderly hypertensives with very low plasma renin activity (PRA) have high urinary excretion of Zn2+ and low serum levels that are partially corrected by the administration of oral Ca in a dose greater

Protein

Observational and epidemiological studies demonstrate a consistent association between a high protein intake and a reduction in BP in Japanese rural farmers, Japanese-American men in Hawaii, American men in 2 cohort studies, British men and women, Chinese men and women, and American children as well as children in other countries.[209], [210], [211], [212] The protein source is an important factor in the BP effect, animal protein being less effective than nonanimal protein.213 However, lean or

Fats

Observational, epidemiological, biochemical, cross-sectional studies and clinical trials on the effect of fats on BP have been disappointing and inconsistent.[231], [232], [233], [234], [235] However, many of these studies have probably missed small associations, were prone to inaccurate measurement of diet through recall or recording, had inadequate or incorrect BP measurement, and did not correct for numerous dietary or nondietary confounding factors.231 An exhaustive meta-analysis and review

Palmitoleic acid

Palmitoleic acid reduces the incidence of stroke in stroke-prone SHRs without any change in BP.282 This may be caused by a direct metabolic effect in vascular smooth muscle. An extremely low saturated fat intake in the Asian population is associated with an increased risk of intracranial hemorrhage in women.283 This is also independent of BP. Perhaps some saturated fat and ω-6 FAs from dairy products and red meat are essential for membrane integrity and reduction in intracranial hemorrhage.

Fiber

The clinical trials with various types of fiber to reduce BP have been inconsistent.211 Soluble fiber, guar gum, guava, psyllium, and oat bran reduce BP and the need for antihypertensive medications in hypertensive subjects, diabetic subjects, and hypertensive-diabetic subjects.[284], [285], [286], [287] Vuksan et al285 reduced SBP 9.4 mm Hg in hypertensive subjects with the fiber Glucomannan. Keenan gave oat bran (β-glucan) to hypertensive patients and reduced BP 7.5/5.5 mm Hg. The doses

Garlic

Good clinical trials using the correct type and dose of garlic have shown consistent reductions in BP in hypertensive patients. [14], [238], [290], [291], [292], [293], [294], [295], [296], [297], [298], [299] Not all garlic preparations are processed similarly and are not comparable in antihypertensive potency.[300], [301] In addition, cultivated garlic (Allium sativum),[300], [301] wild uncultivated garlic or bear garlic (Allium urisinum),[300], [301], [302], [303], [304], [305], [306], [307]

Tea: Green and black

The effects of chronic green or black tea ingestion on BP in human beings have not been studied extensively and results are inconsistent.[313], [314], [315], [316], [317], [318] However, green tea, black tea, and extracts of active components in both teas have demonstrated reduction in BP in the SHR model.[319], [320], [321]

Norwegians consuming black tea had a significant decrease in BP in an observational study.316 Normotensive subjects consuming 6 mugs of black tea per day for 4 weeks had no

Mushrooms

The effects of mushrooms on BP in human beings have not been studied. However, in SHRs, shiitake and maitake mushrooms reduce BP and serum lipids.[14], [325], [326], [327] Mushrooms are low in carbohydrates, have no sugar, but also have high amounts of Zn and other vitamins and minerals that may reduce BP. In addition, the cellulose provides a small amount of fiber.

Seaweed

Wakame (Undaria pinnatifida) is the most popular edible seaweed in Japan.328 In SHRs, Wakame has similar ACEI activity to captopril with similar reductions in BP.328 In human beings, 3.3 g of dried Wakame for 4 weeks significantly reduced both the SBP 14 ± 3 mm Hg and the DBP 5 ± 2 mm Hg (P < .01).329 In a study of 62 middle-aged male subjects with mild hypertension given a K-loaded, ion-exchanging, Na-adsorbing, K-releasing seaweed preparation showed significant BP reductions at 4 weeks on 12

Natural ACEIs

Many other food have demonstrated ACEI activity in vitro, but whether they are active after oral ingestion in vivo remains to be proven in human studies (Table 13).[302], [305], [309], [310], [328], [331], [332], [333], [334], [335], [336], [337], [338], [339], [340], [341], [342], [343], [344], [345], [346], [347]

Vitamin C

Vitamin C is a potent water-soluble antioxidant that recycles vitamin E, improves ED, and produces a diuresis.[238], [348], [349], [350], [351], [352] Numerous epidemiological, observational, and clinical studies have demonstrated that the dietary intake of vitamin C or plasma ascorbate concentration in human beings is inversely correlated with SBP, DBP, and HR.[81], [84], [86], [353], [354], [355], [356], [357], [358], [359], [360], [361], [362], [363], [364], [365], [366], [367], [368], [369]

Mechanism of Vitamin C on BP

Vitamin C improves ED in hypertensive[238], [350] and hyperlipidemic349 patients and reduces BP in a dose-related manner with higher pharmacological doses.[238], [348] The improvement of ED in hypertensive patients occurs in conduit arteries, epicardial coronary arteries, and forearm resistance arteries.[85], [349], [379], [380] Vitamin C restores NO-mediated flow-dependent vasodilation in patients with CHF.380 Hypertensive patients exhale less NO than healthy patients.357 After vitamin C

Vitamin C—A Perspective

Combined nutrients, vitamins, minerals, and antioxidants have clearly been shown to lower BP in the DASH-I,104 DASH-II,98 NHANES-III,381 and other studies.[86], [366], [376], [377] Although these varied diets confer more antihypertensive and cardiovascular benefits than any single nutrient, it is also quite probable that vitamin C, as a single nutrient, plays a significant role in the regulation of BP in both normotensive and hypertensive patients. Almost all studies and reviews reported have

Vitamin C and BP

The present conclusions based on these available studies correlating vitamin C and BP are shown in Table 15. The observational, epidemiological, and prospective clinical trials point strongly to a role of vitamin C in reducing BP in hypertensive and normotensive subjects as well as in those in other disease categories. A dose relationship is suggested, but the efficacy of “supraphysiological” doses of vitamin C and BP effects are yet to be confirmed.

Vitamin E

The relationship of vitamin E and BP has been

Vitamin D

Epidemiological, clinical, and experimental investigations all demonstrate a relationship between the plasma levels of 1125 (OH)2 D3 (1,25-dihydroxycholecalciferol), the active form of vitamin D and BP,[408], [409], [410], [411], [412], [413], [414] including vitamin D–mediated reduction in BP in hypertensive patients. Although the mechanism of action of vitamin D on vascular tone and BP is not completely understood, both a direct effect on cell membranes and an indirect effect on Ca transport,

Vitamin B6 (Pyridoxine)

Low serum vitamin B6 levels are associated with hypertension in rats[188], [423], [424], [425], [426], [427] and human beings.[423], [428], [429], [430], [431], [432], [433], [434] Vitamin B6 is a readily metabolized and excreted water-soluble vitamin.435 Six different B6 vitamins exist, but pyridoxal 5′ phosphate (PLP) is the primary and most potent active form that is produced by rapid hepatic oxidation by pyridoxine phosphate oxidase and pyridoxine kinase in the presence of Zn and Mg.[435],

Flavonoids

More than 4000 naturally occurring flavonoids have been identified in such diverse substances as fruits, vegetables, red wine, tea, soy, and licorice.[379], [441], [442], [443], [444], [445], [446] Flavonoids (flavonols, flavones, and isoflavones) are potent free radical scavengers that inhibit lipid peroxidation, prevent atherosclerosis, promote vascular relaxation, and have antihypertensive properties.[379], [441] In addition, they reduce stroke446 and provide cardioprotective effects that

Lycopene (Carotenoid)

Lycopene is a non–provitamin A carotenoid potent antioxidant found in tomatoes and tomato products, guava, pink grapefruit, watermelon, apricots, and papaya in high concentrations.454 Lycopene has recently been shown to produce a significant reduction in BP, serum lipids, and oxidative stress markers.[455], [456] Paran and Engelhard456 evaluated 30 subjects with grade I hypertension, aged 40 to 65 years, taking no antihypertensive or antilipid medication treated with a tomato lycopene extract

Coenzyme Q-10 (Ubiquinone)

Coenzyme Q-10 is a potent lipid-phase antioxidant, free radical scavenger, cofactor, and coenzyme in mitochondrial energy production and oxidative phosphorylation that regenerates vitamins E, C and A, inhibits oxidation of LDL, membrane phospholipids, DNA, mitochondrial proteins, and lipids, reduces TC and TG, raises HDL-C, improves insulin sensitivity, reduces fasting and random and postprandial glucose, lowers SVR, lowers BP, and protects the myocardium from ischemic reperfusion injury.[14],

α-Lipoic acid

α-Lipoic acid is a potent and unique thiol compound-antioxidant that is both water and lipid soluble.238 α-Lipoic acid helps to recirculate tissue and blood levels of vitamins and antioxidants in both lipid and water compartments such as vitamins C and E, glutathione, and cysteine.[238], [476], [477] To date, only animal studies in SHRs have been performed to determine the effects of α-lipoic acid on the vasculature and BP.[238], [476], [478] Vasdev et al476 administered 500 mg/(kg·d) in their

N-acetyl Cysteine

N-Acetyl cysteine, a source of sulfhydryl groups, is a potent thiol compound and antioxidant that scavenges radical oxygen species and supports intracellular glutathione synthesis by binding to endogenous aldehydes, reducing their production and increasing excretion to nontoxic compounds.[490], [491], [492], [493], [494] N-Acetyl cysteine also increases interleukin 1-B–induced nitrite production by increasing NOS-messenger RNA transcription and protein expression, elevating NO levels, and

l-Arginine

l-Arginine is the primary precursor for the production of NO,[503], [504] which has numerous cardiovascular effects[393], [504] mediated through conversion of l-arginine to NO by eNOS to increase cyclic GMP levels in vascular smooth muscle, improve ED, and reduce vascular tone and BP.505 Patients with hypertension, hyperlipidemia, and atherosclerosis have elevated serum levels of asymmetric dimethyl arginine, which activates NO.[393], [506] Administration of l-arginine in human beings at doses

Hawthorne

Hawthorne may reduce SVR and BP,[14], [161], [238], [520], [521] decrease the pressure-rate product in the myocardium, improve ejection fraction and CHF,[161], [520], [521] improve arrhythmias,[520], [521] lower cholesterol,520 dilate coronary arteries, and improve myocardial perfusion and angina.[161], [521] The mechanism of some of these effects is the ACEI effect of Hawthorne.[14], [238], [522] No controlled clinical trials in hypertensive individuals have been reported to date. Doses of

l-Carnitine

l-Carnitine is a nitrogenous constituent of muscle primarily involved in the oxidation of FAs in mammals.523 Clinical and experimental studies demonstrate significant therapeutic benefits in l-carnitine and its derivative, propionyl-l-carnitine, in the treatment of DM,[393], [524] hypertension,525 ischemic heart disease,[393], [524], [526] acute MI,[393], [524]CHF,[393], [524], [527], [528], [529] arrhythmias and peripheral vascular disease with claudication,[393], [523], [524], [530], [531],

Taurine

Taurine is a sulfonic β-amino acid that is considered a conditionally essential amino acid, which is not used in protein synthesis, but is found free or in simple peptides with its highest concentration in the brain, retina, and myocardium.[541], [542] In cardiomyocytes, it represents about 50% of the free amino acids and has a role of an osmoregulator and inotropic factor and has been used to treat hypertension,543 hypercholesterolemia, arrhythmias, atherosclerosis, CHF, and other

Celery

Animal studies have demonstrated a significant reduction in BP using a component of celery oil, 3-N-butyl phthalide.[566], [567], [568] There was a dose-response relationship in SBP with a 24 mm Hg fall (14%; P < .05) in the Sprague-Dawley hypertensive rat model.568 Significant decreases in plasma NE, epinephrine, and dopamine were also highly dose dependent. Celery, celery extract, and celery oil contain apigenin (which relaxes vascular smooth muscle), CCB-like substances, and components that

Pycnogenol

Pycnogenol, a bark extract from the French maritime pine, at doses of 200 mg/d resulted in a significant reduction in SBP from 139.9 to 132.7 mm Hg (P < .05) in 11 patients with mild hypertension over 8 weeks. Diastolic BP fell from 93.8 to 92.0 mm Hg (NS). Serum thromboxane concentrations were significantly reduced (P < .05).571

Natural Antihypertensive Compounds Categorized by Antihypertensive Class

As has been discussed previously, many of the natural compounds in food, certain nutraceutical supplements, vitamins, antioxidants, and minerals function in a similar fashion to a specific class of antihypertensive drugs. Although the potency of these natural compounds may be less than the antihypertensive drug, when used in combination with other nutrients and nutraceuticals, the antihypertensive effect is magnified. In addition, many of these nutrients and nutraceuticals have varied,

Summary and Conclusions

  • 1.

    Vascular biology (ED and vascular smooth muscle dysfunction) plays a primary role in the initiation and perpetuation of hypertension, CVD, and TOD.

  • 2.

    Nutrient-gene interactions are a predominant factor in promoting beneficial or detrimental effects in cardiovascular health and hypertension.

  • 3.

    Nutrition (natural whole food, nutraceuticals) can prevent, control, and treat hypertension through numerous vascular biology mechanisms.

  • 4.

    Oxidative stress seems to initiate and propagate hypertension and

Recommendations

NutritionDaily Intake
1. DASH I, DASH II-Na+, and PREMIER diets
2. Na restriction50-100 mmol
3. K100 mEq
4. K/Na ratio >5:1
5. Mg1000 mg
6. Ca1000 mg
7. Zn25-30 mg
8. Protein: total intake (30% total calories)1.0-1.8 g/kg
a. Nonanimal sources preferred but lean or wild animal protein in moderation is acceptable
b. Hydrolyzed whey protein30 g
c. Soy protein (fermented is best)30 g
d. Hydrolyzed wheat germ isolate2-4 g
e. Sardine muscle concentrate extract3 mg
f. Cold-water fish, fowl poultry
9. Fats: 30%

Vitamins, antioxidants, and nutraceutical supplements

Daily Intake
1. Vitamin C250-500 mg BID
2. Vitamin E (mixed tocopherol/tocotrienols)400-800 IU QD
3. Vitamin B6100 mg QD to BID
4. Co-Q-1060 mg QD to BID
5. Lipoic Acid (with biotin)100-200 mg BID
6. NAC1000 mg BID
7. Hawthorne standardized extract160-900 mg QD
8. l-Carnitine1000 mg BID
9. Taurine1.0-1.5 g BID
10. l-arginine (food and supplements)5 g BID

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