Nutrition and Nutraceutical Supplements for the Treatment of Hypertension: Part II

Abstract

Vascular biology, endothelial and vascular smooth muscle, and cardiac dysfunction play a primary role in the initiation and perpetuation of hypertension, cardiovascular disease, and target organ damage. Nutrient‐gene interactions and epigenetics are predominant factors in promoting beneficial or detrimental effects in cardiovascular health and hypertension. Macronutrients and micronutrients can prevent, control, and treat hypertension through numerous mechanisms related to vascular biology. Oxidative stress, inflammation, and autoimmune dysfunction initiate and propagate hypertension and cardiovascular disease. There is a role for the select use of single and component nutraceutical supplements, vitamins, antioxidants, and minerals in the treatment of hypertension based on scientifically controlled studies, which complement optimal nutrition, coupled with other lifestyle modifications.

In part I of this 3‐part series, the pathophysiology of hypertension based on 3 finite responses of inflammation, oxidative stress, and immune vascular dysfunction were reviewed. The Dietary Approaches to Reduce Hypertension (DASH) diet was briefly discussed related to these concepts. In part II, the role of specific nutrition recommendations, minerals, food groups, and nutraceutical supplements in the treatment of hypertension was discussed in more detail.

Sodium Reduction

The average sodium intake in the United States is 5000 mg/d, with some areas of the country consuming 15,000 to 20,000 mg/d.1 Epidemiologic, observational, and controlled clinical trials demonstrate that increased sodium intake is associated with higher blood pressure (BP) as well as increased risk for cardiovascular (CV) disease (CVD), cerebrovascular accident (CVA), left ventricular hypertrophy (LVH), coronary heart disease (CHD), myocardial infarction (MI), renal insufficiency, proteinuria, and increased sympathetic nervous system activity.1 A reduction in sodium intake in hypertensive patients, especially in salt‐sensitive patients, significantly lowers BP by 4 to 6 mm Hg/2 to 3 mm Hg that is proportional to the degree of sodium restriction and may prevent or delay hypertension in high‐risk patients and reduce future CV events.2

Salt sensitivity (≥10% increase in mean arterial pressure with salt loading) occurs in about 51% of hypertensive patients.3 CV events are more common in salt‐sensitive patients than in salt‐resistant patients, independent of BP.3 Increased sodium intake has a direct positive correlation with BP and the risk of CVA and CHD.3 The risk is independent of BP for CVA, with a relative risk of 1.04 to 1.25 from the lowest to the highest quartile.1, 3 In addition, patients will convert to a nondipping BP pattern with increases in nocturnal BP as sodium intake increases.1, 3

Increased sodium intake has a direct adverse effect on endothelial cells.4 Sodium promotes cutaneous lymphangiogenesis; increases endothelial cell stiffness; reduces size, surface area, volume, cytoskeleton, deformability and pliability, endothelial nitric oxide (NO) synthase (eNOS) and NO production; and increases asymmetric dimethylarginine (ADMA), oxidative stress, and transforming growth factor β (TGF‐β). All of these abnormal vascular responses are increased in the presence of aldosterone.4, 5 These changes occur independent of BP and may be partially counteracted by dietary potassium (K⁺). The endothelial cells act as vascular salt sensors.4, 5 Endothelial cells are targets for aldosterone, which activate epithelial sodium channels and have negative effects on release of NO and endothelial function. The mechanical stiffness of the cell plasma membrane and the submembranous actin network (endothelial glcyocalyx) (“shell”) serve as a “firewall” to protect the endothelial cells and are regulated by serum sodium, K⁺, and aldosterone within the physiologic range.4, 5 Changes in shear–stress‐dependent activity of the endothelial NO synthase located in the caveolae regulate the viscosity in this “shell.”4, 5 High plasma sodium gelates the shell of the endothelial cell, whereas the shell is fluidized by high K⁺. Blockade of the epithelial sodium channel (ENaC) with spironolactone (100%) or amiloride (84%) minimizes or stops many of these vascular endothelial responses and increases NO.4, 5 NO release follows endothelial nano‐mechanics, not vice versa, and membrane depolarization decreases vascular endothelial cell stiffness, which improves flow‐mediated NO‐dependent vasodilation.6 In the presence of vascular inflammation and increased high‐sensitivity C‐reactive protein (hs‐CRP), the effects of aldosterone on the ENaC is enhanced further, increasing vascular stiffness and BP.7 High sodium intake also immediately abolishes the angiotensin II (AT2) receptor–mediated vasodilation with complete abolition of endothelial vasodilation within 30 days.8 Thus, it has become clear that increased dietary sodium has adverse effects on the vascular system, BP, and CVD by altering the endothelial glycocalyx, which is a negatively charged biopolymer that lines the blood vessels and serves as a protective barrier against sodium overload, increased sodium permeability, and sodium‐induced target organ damage.6, 7, 8 Certain single nucleotide polymorphisms (SNPs) of salt‐inducible kinase I, which alter Na⁺/K⁺ ATPase, determine sodium‐induced hypertension and LVH.9

The sodium intake per day in hypertensive patients should be between 1500 mg to 2000 mg. Sodium restriction improves BP reduction in patients who are taking pharmacologic treatment, and the decrease in BP is additive with restriction of refined carbohydrates.10 Reducing dietary sodium intake may reduce damage to the brain, heart, kidney, and vasculature through mechanisms dependent on the small BP reduction as well as those independent of decreased BP.10

A balance of sodium with other nutrients, especially K⁺, magnesium, and calcium is important, not only in reducing and controlling BP, but also in decreasing CV and cerebrovascular events.10 An increase in the sodium to K⁺ ratio is associated with significantly increased risk of CVD and all‐cause mortality.10

Potassium

The average US dietary intake of K⁺ is 45 mmol/d with a K⁺ to sodium (K⁺/Na⁺) ratio of <1:2.10, 11, 12, 13 The recommended intake of K⁺ is 4700 mg/d (120 mmol) with a K⁺/Na⁺ ratio of about 4:5:1.10, 11, 12, 13 Numerous epidemiologic, observational, and clinical trials have demonstrated a significant reduction in BP with increased dietary K⁺ intake in both normotensive and hypertensive patients.10, 11, 12, 13 The average BP reduction with a K⁺ supplementation of 60 to120 mmol/d is 4.4/2.5 mm Hg in hypertensive patients but may be as much as 8/4.1 mm Hg with 120 mmol/d (4700 mg).10, 11, 12, 13 In hypertensive patients, the linear dose‐response relationship is 1.0 mm Hg reduction in systolic BP and 0.52 mm Hg reduction in diastolic BP per 0.6 g/d increase in dietary K⁺ intake that is independent of baseline dietary K⁺ ingestion.11 The response depends on race (black > white) and sodium, magnesium, and calcium intake.10, 11, 12, 13 Alteration of the K⁺/Na⁺ ratio to a higher level is important for both antihypertensive as well as CV and cerebrovascular effects.11, 12 High K⁺ intake reduces the incidence of CV (CHD and MI) and cerebrovascular accidents independent of the BP reduction.11, 12 If the serum K⁺ is <4.0 meq/dL, there is an increased risk of CVD mortality, ventricular tachycardia, ventricular fibrillation, and CHF [REF 10 PART 1]. Red blood cell K⁺ is a better indication of total body stores and CVD risk than is serum K⁺.10, 11, 12, 13

K⁺ increases natriuresis, modulates baroreflex sensitivity, vasodilates, decreases the sensitivity to catecholamines and AT2, increases sodium K⁺ ATPase and DNA synthesis in the vascular smooth muscle cells, and decreases sympathetic nervous system activity in cells with improved vascular function.11 In addition, K⁺ increases bradykinin and urinary kallikrein; decreases NADPH oxidase, which lowers oxidative stress and inflammation; improves insulin sensitivity; decreases ADMA; reduces intracellular sodium; and lowers production of TGF‐β.11

Each 1000 mg increase in K⁺ intake per day reduces all‐cause mortality by approximately 20%. Potassium intake of 4.7 g/d is estimated to decrease CVA by 8% to 15% and MI by 6% to 11%.11 Numerous SNPs such as nuclear receptor subfamily 3 group C (NR3C2), AT type I receptor (AGTR1), and hydroxysteroid 11 beta dehydrogenase (HSD11B1 and B2) determine an individual's response to dietary K⁺ intake.13 Each 1000 mg decrease in sodium intake per day will decrease all‐cause mortality by 20%.11 A recent analysis suggested a dose‐related response to CVA with urinary K⁺ excretion.14 There was an RRR of CVA of 23% at 1.5 g to 1.99 g, 27% at 2.0 g to 2.49 g, 29% at 2.5 g to 3 g, and 32% over 3 g per day of K⁺ urinary excretion.14 The recommended daily dietary intake for patients with hypertension is 4.7 g to 5.0 g of K⁺ and <1500 mg of sodium.10, 11, 12, 13 Potassium in food or from supplementation should be reduced or used with caution in patients with renal impairment or those taking medications that increase renal K⁺ retention such as angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers, direct renin inhibitors, and serum aldosterone receptor antagonists.15

Magnesium

High dietary intake of magnesium (Mg⁺⁺) of at least 500 mg/d to 1000 mg/d reduces BP but the results are less consistent than those seen with Na⁺ and K⁺.16 In most epidemiologic studies, there is an inverse relationship between dietary Mg⁺⁺ intake and BP.16, 17 The maximum reduction in clinical trials has been 5.6/2.8 mm Hg but some studies have shown no change in BP.17 The combination of high K⁺ and low sodium intake with increased Mg⁺⁺ intake has additive antihypertensive effects.17 Mg⁺⁺ also increases the effectiveness of all antihypertensive drug classes.17

Mg⁺⁺ competes with Na⁺ for binding sites on vascular smooth muscle and acts as a direct vasodilator, like a calcium channel blocker. Mg⁺⁺ increases prostaglandin E and NO; regulates intracellular calcium, sodium, K⁺, and pH; improves endothelial function; and reduces hs‐CRP, AT2, and norepinephrine. Mg⁺⁺ binds in a necessary cooperative manner with K⁺, inducing endothelial vasodilation and BP reduction, inhibiting nuclear factor Kb, and reducing oxidative stress.17, 18, 19

A meta‐analysis of 241,378 patients with 6477 strokes showed an inverse relationship between dietary Mg⁺⁺ and the incidence of ischemic stroke.20 For each 100 mg of dietary Mg⁺⁺ intake, ischemic stroke was decreased by 8%. A meta‐analysis showed reductions in BP of 3 to 4 mm Hg/2 to 3 mm Hg in 22 trials of 1173 patients (45). Mg⁺⁺ may be supplemented in doses of 500 mg/d to 1000 mg/d chelated to an amino acid to improve absorption and decrease the incidence of diarrhea.17 Adding taurine at 1000 mg/d to 2000 mg/d enhances the antihypertensive effects of Mg⁺⁺.17 Mg⁺⁺ supplements should be avoided or used with caution in patients with known renal insufficiency or in those taking medications that induce Mg⁺⁺ retention.17

Zinc

Low serum zinc (Zn⁺⁺) levels in observational studies correlate with hypertension as well as CHD.21 Zn⁺⁺ is transported into cardiac and vascular muscle and other tissues by metallothionein.21 Genetic deficiencies of metallothionein with intramuscular Zn⁺⁺ deficiencies may lead to hypertension.21 There is an inverse correlation of BP and serum Zn⁺⁺‐ and Zn⁺⁺‐dependent enzyme‐lysyl oxidase activity. Zn⁺⁺ inhibits gene expression and transcription through nuclear factor κ‐β and activated protein‐1 and is an important cofactor for superoxide dismutase.21 These effects as well as those on the renin‐angiotensin‐aldosterone system and sympathetic nervous system effects may account for Zn⁺⁺ antihypertensive effects.21 Zn⁺⁺ intake should be 50 mg/d.

Protein

Observational and epidemiologic studies demonstrate a consistent association between high protein intake and reduction in BP, incident BP, and stroke.22, 23 Animal protein is less effective than non‐animal or plant protein.22, 23 In the INTERSALT study of more than 10,000 patients, those with a dietary protein intake 30% above the mean had a lower BP by 3.0/2.5 mm Hg compared with those that were 30% below the mean (81 g/d vs 44 g/d).22 However, lean or wild animal protein with less saturated fat and more essential omega‐3 fatty acids may reduce BP, lipids, and CHD risk.24, 25 Soy protein and milk protein also reduce BP.22, 23 Office BP was decreased by 4.9/2.7 mm Hg in patients given a combination of 25% protein intake vs the control group given 15% protein in an isocaloric manner.26 The daily recommended intake of protein from all sources is 1.0 g/kg to 1.5 g/kg of body weight, varying with exercise level, age, renal function, and other factors.10

Fermented milk supplemented with whey protein concentrate significantly reduces BP in human studies.27, 28Administration of 20 g/d to 30 g/d of hydrolyzed whey protein supplement rich in bioactive peptides significantly reduced BP over 6 to 8 weeks by 8 to 11/6 to 7 mm Hg.27, 28, 29 Milk peptides that contain both caseins and whey proteins are a rich source of ACE inhibitor peptides. Val‐Pro‐Pro and Ile‐Pro–Pro given at 5 mg/d to 60 mg/d have variable reductions in BP with an average decrease in pooled studies of about 1.28 to 4.8/0.59 to 2.2 mm Hg.27, 28, 29 Milk peptides are beneficial in treating the metabolic syndrome.29 The clinical response is attributed to fermented milk's active peptides, which inhibit ACE. Bovine casein–derived peptides and whey protein–derived peptides exhibit ACE inhibitor activity.27, 28, 29 These components include B‐caseins, B‐lg fractions, β₂‐microglobulin, and serum albumin. The enzymatic hydrolysis of whey protein isolates releases ACE inhibitor peptides.

Marine collagen peptides (MCPs) from deep sea fish have antihypertensive activity.15, 29, 30 Bonito protein (Sarda orientalis), from the tuna and mackerel family, has natural ACE inhibitory peptides and reduces BP 10.2/7 mm Hg at 1.5 g/d.15, 29, 30

Sardine muscle protein, which contains valyl‐tyrosine, significantly lowers BP in hypertensive patients.31 Kawasaki and colleagues treated 29 hypertensive patients with 3 mg of valyl‐tyrosine sardine muscle concentrated extract for 4 weeks and lowered BP 9.7 mm Hg/5.3 mm Hg (P<.05).31 Valyl‐tyrosine is a natural ACE inhibitor. A similar study with a vegetable drink with sardine protein hydrolysates significantly lowered BP by 8/5 mm Hg in 13 weeks.32

Soy protein lowers BP in hypertensive patients in most studies.33, 34, 35 Soy protein intake was significantly and inversely associated with both systolic BP and diastolic BP in 45,694 Chinese women consuming ≥25 g/d of soy protein over 3 years and the association increased with age.33 The systolic BP reduction was 1.9 mm Hg to 4.9 mm Hg lower and the diastolic BP 0.9 mm Hg to 2.2 mm Hg lower.33 However, randomized clinical trials and meta‐analyses have shown mixed results on BP with no change in BP to reductions of 7% to 10% for systolic BP and diastolic BP.33, 34, 35 A recent meta‐analysis of 27 trials found a significant reduction in BP of 2.21/1.44 mm Hg.34 Fermented soy at about 25 g/d is recommended. The optimal protein intake, depending on level of activity, renal function, stress, and other factors, is about 1.0 g/kg/d to 1.5 g/kg/d.

Amino Acids and Related Compounds

l‐Arginine

l‐arginine and endogenous methylarginines are the primary precursors for the production of NO, which has numerous beneficial CV effects, mediated through conversion of l‐arginine to NO by eNOS. Patients with hypertension have increased levels of hs‐CRP and inflammation, increased microalbumin, low levels of apelin (stimulates NO in the endothelium), increased levels of arginase (breaks down arginine), and elevated serum levels of ADMA, which inactivates NO.36, 37, 38, 39, 40

Human studies in hypertensive and normotensive patients of parenteral and oral administrations of l‐arginine demonstrate an antihypertensive effect given alone or with N‐acetyl cysteine.36, 37 The BP decreased by 6.2/6.8 mm Hg on 10 g/d of l‐arginine when provided as a supplement or through natural foods to a group of hypertensive patients.36, 37 Arginine produces a statistically and biologically significant decrease in BP and improved metabolic effect in normotensive and hypertensive humans that is similar in magnitude to that seen with the DASH I diet.36, 37 A meta‐analysis of 11 trials with 383 patients administered arginine 4 g/d to 24 g/d found average reduction in BP of 5.39/2.66 mm Hg (P<.001) in 4 weeks.38 Although these doses of l‐arginine appear to be safe, no long‐term studies in humans have been published at this time and there are concerns of a pro‐oxidative effect or even an increase in mortality in patients who may have severely dysfunctional endothelium, advanced atherosclerosis, CHD, ACS, or MI.39 In addition to the arginine‐NO path, there exists a nitrate/nitrite pathway that is related to dietary nitrates from vegetables, beetroot juice, and the DASH diet that are converted to nitrites by symbiotic, salivary, gastrointestinal, and oral bacteria.40 Administration of beetroot juice or extract at 500 mg/d will increase nitrites and lower BP, improve endothelial function and increase cerebral, coronary, and peripheral blood flow.40

l‐Carnitine and Acetyl–l‐Carnitine

l‐carnitine is a nitrogenous constituent of muscle primarily involved in the oxidation of fatty acids in mammals that improves endothelial function, NO, and oxidative defense, while oxidative stress and BP are reduced.41, 42

Human studies on the effects of l‐carnitine and acetyl–l‐carnitine are limited, with minimal to no change in BP.43, 44, 45 In patients with the metabolic syndrome, acetyl–l‐carnitine at 1 g twice daily over 8 weeks reduced systolic BP by 7 mm Hg to 9 mm Hg, but diastolic BP was significantly decreased only in patients with higher glucose.45 Low carnitine levels are associated with a nondipping BP pattern in type 2 diabetes mellitus (DM).46 Doses of 2 g to 3 g twice per day are recommended.

Taurine

Taurine is a sulfonic beta‐amino acid that is considered a conditionally essential amino acid, with its highest concentration in the brain, retina, and myocardium.47 In cardiomyocytes, it represents about 50% of the free amino acids and has a role of an osmoregulator, inotropic factor, and antihypertensive agent.24

Human studies have noted that essential hypertensive patients have reduced urinary taurine as well as other sulfur amino acids.24, 47 Taurine lowers BP, systemic vascular resistance, heart rate, and sympathetic nervous system activity; increases urinary sodium and water excretion; increases NO improves endothelial function; decreases AT2, plasma renin activity, aldosterone, intracellular calcium and sodium; and has antioxidant, anti‐atherosclerotic, and anti‐inflammatory activities.47 Fujita and colleagues24 demonstrated a reduction in BP of 9/4.1 mm Hg (P<.05) in 19 hypertension patients given 6 g of taurine for 7 days. The BP reductions ranged from 9 to 14.8/4.1 to 6.6 mm Hg.24, 47 The recommended dose of taurine is 2 g/d to 3 g/d, at which no adverse effects were noted, but higher doses up to 6 g/d may be needed to reduce BP significantly.24, 47

Omega‐3 Fats

The omega‐3 fatty acids found in cold water fish, fish oils, flax, flax seed, flax oil, and nuts lower BP in observational, epidemiologic, and prospective clinical trials.25, 48, 49, 50, 51, 52, 53, 54

Docosahexaenoic acid (DHA) at 2 g/d reduces BP by 8/5 mm Hg and heart rate by 6 beats per minute in 6 weeks.48 Fish oil at 4 to 9 g/d or combination of DHA and eicosapentaenoic acid (EPA) at 3 to 5 g/d reduces BP.25, 48, 49, 50, 51, 52, 53, 54 Eating cold water fish 3 times per week may be as effective as high‐dose fish oil in reducing BP in hypertensive patients, and the protein in the fish may also have antihypertensive effects.48

Omega‐3 fatty acids increase eNOS and NO, improve endothelial dysfunction, reduce calcium influx, reduce plasma norepinephrine, increase parasympathetic nervous system tone, and suppress ACE activity.25, 48, 49, 50, 51, 52, 53, 54 The recommended daily dose is 3000 mg/d to 5000 mg/d of combined DHA and EPA in a ratio of 3 parts EPA to 2 parts DHA and about 50% of this dose as GLA combined with gamma/delta tocopherol at 100 mg/g of DHA and EPA to get the omega 3 index to 8% to reduce BP and provide optimal cardioprotection.54 DHA is more effective than EPA in reducing BP and should be given at 2 g/d if administered alone.48, 49

Omega‐9 Fats

Olive oil is rich in omega‐9 monounsaturated fat oleic acid (MUFA), which has been associated with BP reduction in Mediterranean and other diets.55, 56, 57, 58, 59, 60 Olive oil and monounsaturated fats have shown consistent reductions in BP in most clinical studies in humans.55, 56, 57, 58, 59, 60 Systolic BP was been reduced by 8 mm Hg (P≤.05) and diastolic BP was decreased by 6 mm Hg (P≤.01) in both clinic and 24‐hour ambulatory BP monitoring (ABPM) in the MUFA‐treated patients compared with the polyunsaturated fatty acid–treated patients.55, 56, 57, 58, 59, 60 In stage I hypertensive patients, oleuropein‐olive leaf (Olea eurpoaea) extract 500 mg twice a day for 8 weeks reduced BP 11.5/4.8 mm Hg, which was similar to captopril 25 mg twice a day.59 Olive oil intake in the European Prospective Investigation into Cancer and Nutrition (EPIC) study of 20,343 patients was inversely associated with both systolic and diastolic BP.56 Olive oil inhibits the AT1R receptor, exerts L‐type calcium channel antagonist effects, and improves wave reflections and augmentation index.60

Extra virgin olive oil (EVOO) also contains lipid‐soluble phytonutrients such as polyphenols. Approximately 5 mg of phenols are found in 10 g of EVOO. About 4 tablespoons of extra virgin olive oil is equal to 40 g of EVOO, which is the amount required to get significant reductions in BP.

Fiber

Clinical trials with various types of fiber to reduce BP have been inconsistent.61, 62 Soluble fiber, guar gum, guava, psyllium, and oat bran may reduce BP and reduce the need for antihypertensive medications in hypertensive patients, diabetic patients, and hypertensive‐diabetic patients.61, 62 The average reduction in BP is about 7.5/5.5 mm Hg on 40 to 50 g/d of a mixed fiber. There is improvement in insulin sensitivity and endothelial function, reduction in sympathetic nervous system activity, and increase in renal sodium loss.61, 62

Vitamin C

Vitamin C is a potent water‐soluble electron donor. At physiologic doses, vitamin C recycles vitamin E, improves endothelial dysfunction, and produces a diuresis.63, 64, 65, 66, 67, 68, 69 Dietary intake of vitamin C and plasma ascorbate concentration in humans is inversely correlated with systolic BP, diastolic BP, and heart rate.63, 64, 65, 66, 67, 68, 69

An evaluation of published clinical trials indicates that vitamin C dosing at 250 mg twice significantly lowers BP 5 to 7/2 to 4 mm Hg during 8 weeks.63, 64, 65, 66, 67, 68, 69 Vitamin C induces sodium water diuresis; improves arterial compliance, endothelial function, sympathovagal balance, aortic elasticity and compliance, and flow‐mediated vasodilation; increases NO and PGI2, superoxide dismutase, RBC Na/K ATPase, and cyclic GMP; activates K⁺ channels; and decreases adrenal steroid production, pulse wave velocity, augmentation index, cytosolic calcium, and serum aldehydes.63, 64, 65, 66, 67, 68, 69 Vitamin C enhances the efficacy of amlodipine, decreases the binding affinity of the ATR1 for ATR2 by disrupting the ATR1 disulfide bridges and enhances the antihypertensive effects of medications in the elderly with refractory hypertension.66, 67, 68 In elderly patients with refractory hypertension already taking maximum pharmacologic therapy, 600 mg of vitamin C daily lowered the BP by 20/16 mm Hg.68 The lower the initial ascorbate serum level, the better is the BP response. A serum level of 100 μmol/L is recommended.63, 64, 65, 66, 67, 68, 69 The systolic BP and 24‐hour ABPM show the most significant reductions with chronic oral administration of vitamin C.63, 64, 65, 66, 67, 68, 69 In a meta‐analysis of 13 clinical trials with 284 patients, vitamin C at 500 mg/d over 6 weeks reduced BP 3.9/2.1 mm Hg.69

Vitamin E

Most studies have not shown reductions in BP with most forms of tocopherols or tocotrienols.10 Patients with type 2 diabetes mellitus and controlled hypertension (130/76 mm Hg) taking prescription medications with an average BP of 136/76 mm Hg were administered mixed tocopherols containing 60% γ‐, 25% δ‐, and 15% α‐tocopherols.70 BP actually increased by 6.8/3.6 mm Hg in the study patients (P<.0001) but was lower compared with patients who received α‐tocopherol (7/5.3 mm Hg) (P<.0001). This may be a reflection of drug interactions with tocopherols via cytochrome P450 (3A4 and 4F2) and reduction in serum levels of the pharmacologic treatments that were given simultaneously.70 γ‐Tocopherol may have natriuretic effects by inhibition of the 70pS K⁺ channel in the thick ascending limb of the loop of Henle and lower BP.71 Both α‐ and γ‐tocopherol improve insulin sensitivity and enhance adiponectin expression via peroxisome proliferator‐activated receptor γ–dependent processes, which have the potential to lower BP and serum glucose.72 If vitamin E has an antihypertensive effect, it is likely small.

Vitamin D

Vitamin D3 may have an independent and direct role in the regulation of BP.73, 74, 75, 76, 77, 78 If the vitamin D level is below 30 ng/mL, the circulating plasma renin activity levels and AT2 are higher.73, 74, 75, 76, 77, 78 The lower the level of vitamin D, the greater the risk of hypertension, with the lowest quartile of serum vitamin D having a 52% incidence of hypertension and the highest quartile having a 20% incidence.73, 74, 75, 76, 77, 78 Vitamin D3 markedly suppresses renin transcription by a vitamin D receptor–mediated mechanism via the juxtaglomerular apparatus. Vitamin D lowers ADMA, suppresses pro‐inflammatory cytokines such as tumor necrosis factor α, increases NO, improves endothelial function and arterial elasticity, decreases vascular smooth muscle hypertrophy, regulates electrolytes and blood volume, and lowers hs‐CRP.73, 74, 75, 76, 77, 78

Although vitamin D deficiency is associated with hypertension in observational studies, randomized clinical trials and their meta‐analyses have yielded inconclusive results.77 In addition, vitamin D receptor gene polymorphisms may affect the risk of hypertension in men.78 A 25‐hydroxyvitamin D level of 60 ng/mL is recommended.

Conclusions

The published literature documents significant reductions in BP with alterations in dietary intake of sodium, potassium, magnesium, and protein. In addition, nutraceutical supplementation with zinc, arginine, carnitine, taurine omega 3 fatty acids, vitamin C and D will lower BP and improve vascular health. These treatments may be appropriate together or as single treatment for initial therapy in mild hypertension, in combination with drugs, or in combination with one another. Utilization of combined treatments with nutrition, supplements, and drugs may reduce the need for more pharmacologic anti‐hypertensive therapies and reduce side effects.

J Clin Hypertens (Greenwich). 2013;15:845–851. ©2013 Wiley Periodicals, Inc.