Integrative Management of Hypertension: Pathophysiology, Epidemiology, Clinical Aspects, Diagnosis, Prevention, and Treatment With Nutrition, Nutritional Supplements, Lifestyle, and Drugs
Mark C. Houston, MD, MS, MSc, FACP, FAHA, FASH, FACN, FAARM, ABAARM, DABC
Introduction
Cardiovascular disease (CVD) remains the leading cause of death in the United States, is the most common reason for visits to primary care physicians with over 20 billion USD expenditure annually in antihypertensive drug costs, and is one of the top five coronary heart disease (CHD) risk factors.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 There are over 100 million people in the United States with hypertension based on new hypertension guidelines.19 In numerous clinical trials, pharmacotherapy will control blood pressure (BP) and reduce stroke, CHD, myocardial infarction (MI), congestive heart failure (CHF), and renal disease.16,17 However, some hypertensive patients either refuse to take drugs or prefer to treat with nutrition or nutritional supplements, if appropriate, as recognized by national and international guidelines.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20
Hypertension is a consequence of micro- and macronutrient insufficiencies, abnormal vascular biology, reduced bioavailability of nitric oxide (NO), and the three finite vascular responses to injury that include inflammation, oxidative stress, and vascular immune dysfunction2,3,4,5,11,12,13,14 (Figure 21.1). These abnormalities coexist and interact with genetics, epigenetics, nutrient-gene expression, and other environmental and lifestyle factors.2,3,4,5,11,12,13,14 Hypertension is the “correct” but chronic dysregulated response of these infinite insults to the endothelium with gene expression patterns in which the vascular system becomes an innocent bystander.2,3,4,5,11,12,13,14 Hypertension is one of several responses of the blood vessel to endothelial dysfunction (ED), cardiac smooth muscle, vascular dysfunction, and abnormalities of both microvascular function and structure, which may precede the development of hypertension by decades. This consequently leads to vascular and cardiac hypertrophy, remodeling, functional and structural network rarefaction, decreased vasodilatory reserve, altered media to lumen ratio, stiffness, loss of arterial elasticity, fibrosis, increased pulse pressure, elevated pulse wave velocity (PWV), and increased augmentation index (AI) (Figure 21.2).2,3,4,5,11,12,13,14 Significant functional, then structural microvascular impairment begins before elevations in BP in normotensive offspring of hypertensive parents.2,3,4,5,11,12,13,14
As the BP increases, a bidirectional feedback occurs that exacerbates and perpetuates the cardiovascular functional and structural abnormalities. Macronutrients and micronutrients are crucial in the regulation of BP and subsequent cardiovascular target organ damage (TOD)2,3,4,5,11,12,13,14 and are more common in patients with hypertension than in the general population.2,3,4,5,11,12,13,14 The appropriate measurement, interpretation, and treatment of these nutrient deficiencies may effectively lower BP and improve ED, vascular and cardiac functional and structural abnormalities, and CV events.2,3,4,5,11,12,13,14
This chapter will primarily review the role of nutrition and selected nutraceutical supplements, minerals, vitamins, anti-inflammatory agents, natural immune modulators, and antioxidants in the treatment of hypertension.
 Figure 21.1 Infinite insults to the blood vessel result in only three finite responses of inflammation, oxidative stress, and vascular immune dysfunction. |
Epidemiology and Pathophysiology
The human genome is 99.9% identical to our Paleolithic ancestors, but the changes in modern nutrition and macronutrient and micronutrient intake impair our ability to reduce CVD21 (Table 21.1). Vascular biology assumes a pivotal role in the initiation
and perpetuation of hypertension.2,3,4,5,11,12,13,14 Radical oxygen species (ROS) coupled with impaired oxidative defense, inflammatory mediators, vascular immune dysfunction, and loss of nitric oxide bioavailability contribute to hypertension through complex nutrient-gene interactions.2,3,4,5,11,12,13,14,22,23,24,25,26,27,28,29,30,31,32 The high Na+/K+ ratio of modern diets, the reduced intake of magnesium, fiber, protein, and omega-3 fatty acids with increased consumption of omega-6 fatty acids, saturated fat (SFA), and trans fatty acids (TFA) have contributed to hypertension.2,3,4,5,11,12,13,14,21
and perpetuation of hypertension.2,3,4,5,11,12,13,14 Radical oxygen species (ROS) coupled with impaired oxidative defense, inflammatory mediators, vascular immune dysfunction, and loss of nitric oxide bioavailability contribute to hypertension through complex nutrient-gene interactions.2,3,4,5,11,12,13,14,22,23,24,25,26,27,28,29,30,31,32 The high Na+/K+ ratio of modern diets, the reduced intake of magnesium, fiber, protein, and omega-3 fatty acids with increased consumption of omega-6 fatty acids, saturated fat (SFA), and trans fatty acids (TFA) have contributed to hypertension.2,3,4,5,11,12,13,14,21
 Figure 21.2 Infinite insults and the three finite vascular responses of inflammation, oxidative stress, and vascular immune dysfunction lead to endothelial dysfunction and cardiac and vascular dysfunction. |
Table 21.1 CONTRASTING THE INTAKE OF NUTRIENTS INVOLVED IN VASCULAR BIOLOGY. EVOLUTIONARY NUTRITIONAL IMPOSITIONS | |||||||||||||||||||||||||||
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The Three Finite Vascular Responses and Cardiovascular Disease (Figures 21.1 and 21.2)
Oxidative Stress, Inflammation, and Vascular Immune Dysfunction
Oxidative stress is an imbalance of ROS with a decrease in antioxidant defenses that contributes to hypertension in humans based on genetics and environment.2,3,4,5,11,12,13,14,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37 The predominant ROS produced is superoxide anion, which is generated by numerous cellular sources, will uncouple endothelium-derived NO synthase (U-eNOS) and reduce nitric oxide bioavailability, induces ED, and increases BP.24,27 Antioxidant deficiency and excess free radical production have been implicated in human hypertension in epidemiologic, observational, and interventional studies.29,30,31 These degrade NO, influence eicosanoid metabolism, and increase catecholamine levels in serum and urine.2,3,4,5,11,12,13,14,24,26,27 The interrelations of neurohormonal systems, oxidative stress, and CVD are shown in Figure 21.3.
 Figure 21.3 The neurohormonal and oxidative stress systems with interactions on cardiac and vascular muscle. |
Acute and chronic inflammation with abnormal vascular immune responses and pattern recognition receptors (PRRs) and toll-like receptors (TLRs) are involved in hypertension.2,3,4,5,11,12,13,14,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50 Low levels of IL-10 (interleukin 10) and increased levels of high-sensitivity C-reactive protein (hs-CRP), numerous inflammatory cytokines such as interleukins (IL-6, IL-1b, IL-2, and IL-8), and tumor necrosis factor alpha (TNF-α) are excellent markers for hypertension and hypertensive-related TOD, such as CHD, CHF, and increased carotid intima-media thickness (IMT).2,3,4,5,11,12,13,14,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50 Elevated hs-CRP is both a risk marker and risk factor for hypertension and CVD.2,38,39 Increases in hs-CRP of over 3 µg/mL may increase BP rapidly that is proportional to the serum hs-CRP level.38,39 Nitric oxide and endothelial nitric oxide synthase (eNOS) are inhibited by hs-CRP.38,39 The angiotensin 2 receptor (AT2R), which increases NO when stimulated, normally counterbalances AT1R but it is downregulated or blocked by hs-CRP.2,38,39 Angiotensin II (A-II) is inflammatory, atherogenic, increases oxidative stress and vascular immune dysfunction, and upregulates many of the cytokines.2,44,49
Innate and adaptive immune responses induce hypertension by numerous mechanisms that include angiotensin II, antibodies to the AT1R, cytokine and chemokine production, PRR and TLR activation, central nervous system (CNS) stimulation, and renal damage.2,3,4,35,36,40,41,42,43,44,45,46,47,48,49,50 Monocytes cross the endothelial lining, invade the subintimal layer, transform into macrophages and various T-cell subtypes that regulate BP, cause vascular damage, and promote vascular immune dysfunction.41 Angiotensin II activates immune cells directly and in the CNS via T cells, macrophages, and dendritic cells and promotes cell infiltration into target organs.41,44,49 Activation of the AT1R and PPAR (peroxisome proliferator-activated
receptor) gamma receptors that are expressed on CD4+ T lymphocytes releases TNF-α, interferon, and interleukins within the vascular wall.41,50 Interleukin 17 (IL-17) produced by T-17 cells may play a pivotal role in the genesis and perpetuation of hypertension caused by angiotensin II.41
receptor) gamma receptors that are expressed on CD4+ T lymphocytes releases TNF-α, interferon, and interleukins within the vascular wall.41,50 Interleukin 17 (IL-17) produced by T-17 cells may play a pivotal role in the genesis and perpetuation of hypertension caused by angiotensin II.41
The Balance of Hypertension
Hypertension is a balance of vascular damage and repair that is mediated through the three finite responses: angiotensin II, endothelin, and aldosterone (Figures 21.4 and 21.5).2,3,4,5,11,12,13,14 The vascular protection and repair is mediated by nitric oxide and bone marrow-derived endothelial progenitor cells (EPCs).2,3,4,5,11,12,13,14 The endothelium maintains communication and homeostasis between the circulating blood cells and the vascular media by modulation of the permeability, contractile state, proliferation, migratory response, and the redox state in the vascular media and modulates platelet function, coagulation, monocyte and leukocyte adhesion, inflammation, oxidative stress and immune responses in the blood2,3,4,5,11,12,13,14 (Figures 21.6 and 21.7).
 Figure 21.4 Cardiovascular disease is a balance of vascular injury and vascular repair. (Adapted from Houston MC. Vascular Biology in Clinical Practice. Hanley & Belfus: Philadelphia, PA; 2000 and Houston MC. Handbook of Hypertension. Wiley- Blackwell: Oxford, UK; 2009.) |
 Figure 21.5 The three finite responses and vascular biology play a key role between CHD risk factors, endothelial and CV dysfunction, and CVD. (From Houston MC. Handbook of Hypertension. Wiley- Blackwell: Oxford, UK; 2009. Copyright © 2009 Mark Houston.) |
Treatment of Hypertension With Nutritional Supplements
A large number of nutraceutical supplements, antioxidants, vitamins, minerals, and natural compounds in food produce physiologic effects that mimic specific classes of
antihypertensive medications, improve vascular biology, and decrease BP.2,3,4,5,6,7,8,9,10,11,12,13,14 These natural compounds can be classified into the major antihypertensive drug groups such as diuretics, beta blockers, central alpha agonists (CAAs), calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs)2,3,4,5,6,7,8,9,10,11,12,13,14 (Table 21.2). Numerous clinical nutrition studies have demonstrated the efficacy of dietary interventions for the prevention and treatment of hypertension. These include Dietary Approaches to Stop Hypertension (DASH 1 and DASH 2), the Mediterranean diet, Trials of Hypertension Prevention (TOHP 1 and TOHP 2), Trial of Nonpharmacologic Intervention in the Elderly (TONE), Treatment of Mild Hypertension (TOMHS), INTERMAP, INTERSALT, Premier, Vanguard, and others.2,3,4,5,10,11,12,13,14,51,52
antihypertensive medications, improve vascular biology, and decrease BP.2,3,4,5,6,7,8,9,10,11,12,13,14 These natural compounds can be classified into the major antihypertensive drug groups such as diuretics, beta blockers, central alpha agonists (CAAs), calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs)2,3,4,5,6,7,8,9,10,11,12,13,14 (Table 21.2). Numerous clinical nutrition studies have demonstrated the efficacy of dietary interventions for the prevention and treatment of hypertension. These include Dietary Approaches to Stop Hypertension (DASH 1 and DASH 2), the Mediterranean diet, Trials of Hypertension Prevention (TOHP 1 and TOHP 2), Trial of Nonpharmacologic Intervention in the Elderly (TONE), Treatment of Mild Hypertension (TOMHS), INTERMAP, INTERSALT, Premier, Vanguard, and others.2,3,4,5,10,11,12,13,14,51,52
 Figure 21.6 The blood vessel structure: endothelium, smooth muscle, and adventitia. (Modified from Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1999;340:115-126 and Mulvany MJ, et al. Structure and function of small arteries. Physiol Rev. 1990;70:921-961.) |
 Figure 21.7 The endothelium has a strategic location and function to maintain communication and homeostasis between the circulating blood elements and the vascular smooth muscle. (Adapted from Houston MC. Vascular Biology in Clinical Practice. Hanley & Belfus: Philadelphia, PA; 2000 and Houston MC. Handbook of Hypertension. Wiley- Blackwell: Oxford, UK; 2009.) |
Sodium (Na+)
Increased dietary sodium intake is associated with hypertension, CVA, left ventricular hypertrophy (LVH), diastolic dysfunction (DD), CHD, MI, renal insufficiency, proteinuria, arterial stiffness, platelet dysfunction, and increased
sympathetic nervous system (SNS) activation. A reduction in dietary sodium intake lowers BP and the risk of all of these diseases.2,3,4,5,10,11,12,13,14,15,18,19,53,54,55,56,57,58,59,60,61 Decreasing dietary sodium intake in hypertensive patients, especially the salt-sensitive patients, lowers BP by 4 to 6/2 to 3 mm Hg proportional to the amount of sodium restriction54 and may prevent or delay hypertension in high-risk patients.
sympathetic nervous system (SNS) activation. A reduction in dietary sodium intake lowers BP and the risk of all of these diseases.2,3,4,5,10,11,12,13,14,15,18,19,53,54,55,56,57,58,59,60,61 Decreasing dietary sodium intake in hypertensive patients, especially the salt-sensitive patients, lowers BP by 4 to 6/2 to 3 mm Hg proportional to the amount of sodium restriction54 and may prevent or delay hypertension in high-risk patients.
Table 21.2 NATURAL ANTIHYPERTENSIVE COMPOUNDS CATEGORIZED BY ANTIHYPERTENSIVE CLASS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Salt sensitivity, defined as a >10% increase in mean arterial pressure (MAP) with salt loading, increases the BP response to dietary salt intake in 51% of hypertensive patients.57,58 Cardiovascular events may be more common in salt-sensitive patients compared with salt-resistant patients, independent of BP level.57,58 Decreasing sodium intake to below 1500 to 2300 mg/d was associated with lower BP and a decrease in all-cause mortality, whereas increasing the intake to >2300 mg/d was associated with an increase in all-cause mortality and CVD.56
Sodium promotes hypertension by increasing endothelial cell stiffness; reducing the size and pliability of endothelial cells; decreasing eNOS and NO production; elevating asymmetric dimethyl arginine (ADMA), oxidative stress, and TGF-β; and abolishing the AT 2 receptor-mediated vasodilation.59,60,62 All of these effects are increased in the presence of aldosterone, which mimics these same pathophysiologic changes.59,60,63 Endothelial cells act as vascular salt sensors.59,60
A balance of sodium with potassium and magnesium improves BP control and lowers cardiovascular and cerebrovascular events.2,63,64,65,66,67 Increasing the sodium to potassium ratio increases BP and the risk of CVD, but increasing the potassium to sodium ratio lowers BP and CVD risk.64,65,66,67 A potassium/sodium ratio of 4:1 is recommended with a daily dietary sodium intake of 1500 mg and a dietary potassium intake of 6000 mg.2,64,65,66,67
Potassium
Increased dietary potassium intake reduces BP and CVD.64,65,66,67,68,69,70,71 The minimal recommended intake of K+ is 4700 mg/d (120 mmol) with a K+/Na+ ratio 4-5:1.64,65,66,67,68,69,70,71 Potassium supplementation at 60 mmol of KCl per day for 12 weeks significantly reduced SBP −5.0 mm Hg in 150 Chinese subjects.68 Prospective studies in a meta-analysis found that 1.64 g or more per day of potassium intake resulted in a 21% lower
risk of stroke (P = .0007) and a lower risk of CHD and total CVD. In another meta-analysis, potassium supplementation resulted in modest but significant reductions in both SBP −4.25 mm Hg and DBP 2.53 mm Hg.70 Studies indicate a dose-related reduction in BP of 4.4/2.5 mm Hg to 8/4.1 mm Hg with potassium supplementation with doses between 60 to 120 mmol per day.2,3,4,5,6,7,8,9,10,11,12,13,14,64,65,66,67,68,69,70,71 Increased dietary potassium reduces CHD, MI, CHF, LVH, diabetes mellitus (DM), and cardiac arrhythmias independent of BP reduction.68 The incidence of CVA is reduced proportional to BP reduction but also is independent of the BP reduction.2,3,4,5,6,7,8,9,10,11,12,13,14,64,65,66,67,68,69,70,71 Chronic serum levels of potassium below 4.0 meq/dL increase CVD mortality, ventricular tachycardia, ventricular fibrillation, and CHF.2,3,4,5,6,7,8,9,10,11,12,13,14,64,65,66,67,68,69,70,71 Red blood cell potassium is a better indication of total body stores than serum potassium,2,3,4,5,6,7,8,9,10,11,12,13,14 and it lowers NADPH oxidase, which reduces oxidative stress and inflammation.2,3,4,5,6,7,8,9,10,11,12,13,14,64,65,66,67,68,69,70,71
risk of stroke (P = .0007) and a lower risk of CHD and total CVD. In another meta-analysis, potassium supplementation resulted in modest but significant reductions in both SBP −4.25 mm Hg and DBP 2.53 mm Hg.70 Studies indicate a dose-related reduction in BP of 4.4/2.5 mm Hg to 8/4.1 mm Hg with potassium supplementation with doses between 60 to 120 mmol per day.2,3,4,5,6,7,8,9,10,11,12,13,14,64,65,66,67,68,69,70,71 Increased dietary potassium reduces CHD, MI, CHF, LVH, diabetes mellitus (DM), and cardiac arrhythmias independent of BP reduction.68 The incidence of CVA is reduced proportional to BP reduction but also is independent of the BP reduction.2,3,4,5,6,7,8,9,10,11,12,13,14,64,65,66,67,68,69,70,71 Chronic serum levels of potassium below 4.0 meq/dL increase CVD mortality, ventricular tachycardia, ventricular fibrillation, and CHF.2,3,4,5,6,7,8,9,10,11,12,13,14,64,65,66,67,68,69,70,71 Red blood cell potassium is a better indication of total body stores than serum potassium,2,3,4,5,6,7,8,9,10,11,12,13,14 and it lowers NADPH oxidase, which reduces oxidative stress and inflammation.2,3,4,5,6,7,8,9,10,11,12,13,14,64,65,66,67,68,69,70,71
For each 1000 mg increase of daily dietary potassium, the all-cause mortality is reduced by 20% and for each 1000 mg decrease of daily dietary sodium intake all-cause mortality is decreased by 20%.64 The recommended daily dietary intake of potassium is 6 g in hypertensive patients with normal renal function, those not taking potassium-retaining medications, or in those with some other contraindication.2,3,4,5,6,7,8,9,10,11,12,13,14,64,65,66,67,68,69,70,71 Potassium sources include dark green leafy vegetables and fruits, nutritional supplements such as “No Salt” (KCL) substitutes, pure potassium powders or capsules or combined potassium/magnesium powders or capsules, and prescription KCL.2,3,4
Magnesium (Mg++)
There is an inverse relationship between dietary magnesium intake and BP.65,72,73,74,75,76 In clinical trials an increased dietary magnesium of 500 to 1000 mg/d lowers BP, but compared with dietary potassium intake the BP results are less.65,72,73,74,75,76 Significant reductions in BP of 5.6/2.8 mm Hg, as documented by 24-hour ambulatory BP monitoring, home and office blood BP readings, usually take about 2 months.72 A meta-analysis of trials found that Mg++ supplementation of over 370 mg daily reduced BP 3 to 4 ± 2 mmHg/2.5 ± 1 mm Hg.75 A more recent meta-analysis (34 trials and 2028 participants) showed that Mg++ supplementation dosed at 368 mg/d for 3 months reduced BP 2.00/1.78 mm Hg74. The combination of high potassium and magnesium combined with a low sodium intake potentiates the antihypertensive effects in both treated and untreated hypertensive subjects.65,72,73,74,75,76 Magnesium also competes with Na+ and calcium on vascular smooth muscle binding sites, simulates the effects of CCBs, and increases nitric oxide levels and endothelial function.2,72,73,74,75,76
Intracellular erythrocyte levels of magnesium are a more accurate assessment of total body stores compared to serum levels.2,65,76 Magnesium formulations chelated to an amino acid, especially magnesium with taurine provides additional BP reduction.2,65,76 Transdermal preparations of magnesium and magnesium salt baths are also effective.2,65,76 A high-magnesium diet or magnesium supplements must be used with caution in patients taking medications that promote magnesium retention, in those with known renal insufficiency or those with other contraindications to high doses of magnesium intake.2,65,76
Calcium (Ca++)
Calcium supplementation is not recommended as an effective means to reduce BP until more studies are done on specific populations and age groups and the proper formulation and dose is identified.77,78,79,80 The only exception is that calcium may reduce the risk of preeclampsia and its comorbidities for both mother and fetus.80
Zinc (Zn++)
Low serum zinc levels correlate with hypertension and other CV problems.2,81,82 There is an inverse correlation between BP, serum Zn++, and Zn++-dependent enzyme-lysyl oxidase activity in hypertensive subjects.2,82 Zinc is transported into cardiac and vascular muscle and other tissues by metallothionein.81 Genetic deficiencies of metallothionein lead to intramuscular zinc deficiencies and hypertension.81 Zinc reduces the oxidative stress, inflammation, and immune dysfunction and balances the RAAS (renin-angiotensin-aldosterone system) and SNS.1,2,57,58,81,82 Dietary zinc intake should be approximately 50 mg per day and levels should be monitored.1
Protein
Lower blood pressure is associated with an increased intake of animal protein and plant-based protein depending on the type of fat present in animal protein.2,6,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113 Lean or wild animal protein with a higher content of essential omega-3 fatty acids and reduced saturated fats improves hypertension.84,85,86,87,113 Dietary protein intake 30% above the mean had a 3.0/2.5 mm Hg lower BP compared to protein intake 30% below the mean (81 vs. 44 g/d).2,83
In a meta-analysis of 40 RCTs compared with carbohydrate, dietary animal and vegetable protein intake was associated with significant changes in mean BP 1.2/0.6 mm Hg.6,86
In a randomized crossover study of 352 prehypertension and stage I hypertension subjects, soy protein and milk protein significantly reduced SBP 2.0 and 2.3 mm Hg, respectively with no change in DBP compared to a high-glycemic index diet.87 Soy protein intake of 25 g/d over 3 years was associated with lower BP of 1.9/0.9 mm Hg in 45,694 Chinese women.99 Randomized clinical trials and meta-analysis of soy protein in hypertensive subjects indicate an average reduction in BP of 5.9/3.3 mm Hg.99,100,101,103,104,106 The recommended daily intake of fermented soy is 25 g.2
Whey protein, milk peptides, fermented milk, and casein significantly lower BP in humans.2,6,88,89,90,91,92,93,102,108,109,110,111,112,113 Administration of 20 g/d of hydrolyzed whey protein lowered BP within 6 weeks by 8.0/5.5 mm Hg.89 Milk peptides are rich
in ACEI peptides which lower BP approximately 4.8/2.2 mm Hg with doses of 5 to 60 mg/d.2,6,88,89,90,91,92,93,102 Powdered fermented milk containing Lactobacillus helveticus and active ACEI peptides dosed at 12 g daily significantly reduced BP by 11.2/6.5 mm Hg in 1 month.90
in ACEI peptides which lower BP approximately 4.8/2.2 mm Hg with doses of 5 to 60 mg/d.2,6,88,89,90,91,92,93,102 Powdered fermented milk containing Lactobacillus helveticus and active ACEI peptides dosed at 12 g daily significantly reduced BP by 11.2/6.5 mm Hg in 1 month.90
Administration of 20 g of hydrolyzed whey protein to hypertensive subjects lowered BP 11/7 mm Hg compared to controls within 1 week.93 The WHEY2Go trial108 was a double-blinded, randomized, 3-way-crossover, controlled intervention study of 42 participants who were randomly assigned to consume 56 g of whey protein, 56 g of calcium caseinate, or 54 g of maltodextrin (control)/day for 8 weeks separated by a 4-week washout.
The 24-hour ambulatory blood pressure monitoring (ABM) reductions in BP were 3.9/2.5 mm Hg (P = .05); the peripheral and central SBP fell 5.7 mm Hg (P = .007) and −5.4 mm Hg (P = .012), respectively, after whey protein consumption compared with the control group.108 Whey protein improves endothelial function, stimulates opioid receptors, and improves PWV.
Marine collagen peptides (MCPs) derived from deep sea fish have antihypertensive activity.94,95,96 Bonito protein (Sarda orientalis) from the tuna and mackerel family has natural ACEI inhibitory peptides and lowers BP 10.2/7 mm Hg with a dose of 1.5 g daily.95 Administration of MCPs in a double-blind placebo-controlled trial of 100 hypertensive-diabetic subjects for 3 months significantly reduced DBP and MAP (mean arterial pressure).94
Sardine muscle protein lowered BP 9.7/5.3 mm Hg (P < .05) over 4 weeks in 29 hypertensive subjects at a dose of 3 mg of VAL-TYR (a sardine muscle concentrated extract).97 A vegetable drink with sardine protein hydrolysates also reduced BP by 8/5 mm Hg over 13 weeks.98
The daily recommended intake of protein from all sources is 1.0 to 1.5 g/kg body weight, depending on exercise level, gender, age, hepatic and renal function, medications such as proton pump inhibitors and H2 blockers, and concomitant medical diseases.2
L-Arginine
L-arginine lowers BP in humans with a low side effect profile and to levels similar to the DASH diet.114,115,116,117,118,119,120,121,122,123,124,125,126 L-arginine and endogenous methylarginines are the primary precursors for the eNOS to produce nitric oxide (NO).114,115,116,117,118,119,120
Intracellular arginine levels far exceed the K(m) of eNOS under normal physiological conditions, but endogenous NO formation depends on extracellular arginine concentration. NO production by endothelial cells is closely coupled to cellular arginine transport mechanisms to regulate NO-dependent functions such as increasing renal vascular flow, renal perfusion, renal tubular NO bioavailability, and BP.119
Parenteral and oral L-arginine administration in hypertensive and normotensive subjects lowers BP significantly at doses of 10 to 12 g/d in food or as a supplement lowers BP by about 6.2/6.8 mm Hg in both office and 24-hour ABM readings.114,115,121,123,124 Arginine administered at 4 g daily significantly lowered BP in gestational hypertension, reduced concomitant antihypertensive, therapy and improved maternal and neonatal outcomes with normal delivery time.121,122 The combination of arginine (1200 mg per day) and N-acetylcysteine (600 mg bid) administered over 6 months to hypertensive patients with type 2 diabetes lowered SBP and DBP (P < .05).123 Arginine may have a pro-oxidative effect and increase in mortality in patients with advanced atherosclerosis, CHD, acute coronary syndrome, or MI125. Pending more studies, arginine is best avoided in these situations.
Taurine
Taurine is a conditionally essential sulfur-based amino acid that is efficacious for the treatment of hypertension and a variety of CVDs by reducing SNS activity, plasma norepinephrine, plasma and urinary epinephrine.2,3,4,5,14,127,128,129,130,131,132,133 In addition, taurine increases urinary sodium and water excretion, atrial natriuretic factor, NO bioavailability, improves ED, and increases EPCs, while it decreases plasma renin activity (PRA), A-II, and aldosterone.2,3,4,5,127,128,129 Nineteen hypertensive subjects administered 6 g of taurine resulted in lowered BP by 9/4.1 mm Hg (P < .05) in 7 days.128 In a randomized, double-blind, placebo-controlled study over 12 weeks in 120 prehypertensive individuals, taurine supplementation (1.6 g/d) significantly improved endothelial function and decreased the clinic and 24-hour ambulatory BP reading 7.2/2.6 mm Hg and 4.7/1.3 mm Hg, respectively.132 In another 4-month study of 97 prehypertensive individuals, 1.6 g/d of taurine significantly decreased the clinic and 24-hour ambulatory BPs, improved endothelium-vasodilation, and reduced the carotid IMT.132
In a DBRPC study of 42 hypertensive subjects evaluated over 1 month, a combination powder dietary supplement was given once daily.133 The supplement included 6 g of taurine, vitamin C (as magnesium ascorbate) at 1000 mg, grape seed extract at 150 mg, magnesium ascorbate at 87 mg, vitamin B6 (pyridoxine HCl) at 100 mg, vitamin D 3 at 2000 IU, and biotin at 2 mg. The active group had a reduction in BP of 16/11.35 mm Hg (P < .001) at week 4. The recommended dose of taurine is 1.5 to 6 g/d as a single dose or as divided doses.2,127,128,129,130,131,132,133
Omega-3 Fats and Selected Omega-6 Fats
Omega-3 fatty acids derived from food or nutritional supplements produce a dose-related reduction in BP and CVD in published human studies.2,3,4,5,6,7,8,9,10,11,12,13,14,113,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149
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