Nutraceuticals, Vitamins, Antioxidants, and
Minerals in the Prevention and Treatment of
Hypertension
Mark C. Houston
Vascular biology assumes a pivotal role in the
initiation and perpetuation of hypertension and
target organ damage sequelae. Endothelial activa-
tion, 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 prob-
lems and hypertension. Optimal nutrition, nutra-
ceuticals, 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 vascu-
lar 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
From the Department of Medicine, Division of General
Internal Medicine, Vanderbilt University School of Medi-
cine, Nashville, TN, Hypertension Institute and Vascular
Biology, American Society of Hypertension (ASH), Nash-
ville, TN, and Saint Thomas Medical Group, Saint Thomas
Hospital and Health Services, Nashville, TN.
Address reprint requests to Mark C. Houston, MD, MS,
FACP, FAHA, Clinical Professor of Medicine, Director,
Specialist in Clinical Hypertension, Suite 400, 4230 Har-
ding Rd, Nashville, TN 37205.
E-mail: mhoustonhisth@yahoo.com
0033-0620/$ - see front matter
n 2005 Published by Elsevier Inc.
doi:10.1016/j.pcad.2005.01.004
396 Progress in Cardiovascular Diseases, Vol 47, No 6 (May/June), 2005: pp 396-449
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 Euro-
pean Society of Cardiology, the International
Society of Hypertension, the Canadian Society of
Hypertension, and other hypertension guidelines.
n 2005 Published by Elsevier Inc.
H ypertension is a consequence of the inter-
action of genetics and the environment.
Macronutrients and micronutrients are crucial in
the regulation of blood pressure (BP) and sub-
sequent target organ damage (TOD). Nutrient-
gene interactions, subsequent gene expression,
oxidative stress, and inflammation have positive
or negative influences on vascular biology in
human beings. Endothelial dysfunction (ED) and
vascular smooth muscle dysfunction initiate and
perpetuate essential hypertension. The optimal
combination of macronutrients and micronu-
trients significantly impacts hypertension pre-
vention, treatment, and potential vascular
complications. Our lifestyle and nutritional
choices will influence our physical and mental
health and, ultimately, our fate.1
Nutritional needs have been imposed on the
world population after evolution from a preagri-
cultural, hunter-gatherer milieu to a highly
technological agricultural industry that is exceed-
ingly dependent on mechanical processing for
food supply.1,2 The transition from the Paleolithic
diet composed of low Na, high K, high fiber, low
fat and cholesterol, lean animal protein (wild
game), low refined carbohydrate, and a high
intake of fruits, vegetables, berries, nuts, fiber,
fish, and fowl to our modern diet has produced an
epidemic of nutritionally related diseases. Hyper-
tension, atherosclerosis, coronary heart disease
NUTRACEUTICALS AND HYPERTENSION
(CHD), myocardial infarction (MI), congestive
heart failure (CHF), cerebrovascular accidents
(CVAs), renal insufficiency (RI), renal failure,
type II diabetes mellitus (DM), metabolic syn-
drome, and obesity are some of these diseases.2
Short-term reduction in BP using nutrition
results in intermediate and long-term improve-
ments in morbidity and mortality, including
CVAs, CHD, and MI.3,4 In the Health Profes-
sionals Follow-up Study,3 diets rich in K
reduced CVAs by 41% in hypertensive subjects.
In the Lyon Diet Heart Study,4 a Mediterranean-
type diet reduced the incidence of a second MI
by 76%. These studies and others reveal the
importance of micronutrients, macronutrients,
and nutraceuticals for preventing and treating
hypertension and the cardiovascular complica-
tions of this disease. Many national and global
organizations and policy directives on nutrition
and hypertension such as the Joint National
Committee on Prevention, Detection, Evalua-
tion, and Treatment of High Blood Pressure
(seventh report),5 the Nutrition Committee of
the American Heart Association,6 the World
Health Organization, the Canadian Hyperten-
sion Society, and the Institute of Medicine
Report to Congress7 on the nutritional needs
of aging adults, INTERSALT,8 the recently
published European Society of Hypertension-
397
European Society of Cardiology guidelines, and
the International Society of Hypertension guide-
lines9 recognize the impact of nutrition on
hypertension, CHD, atherosclerosis, and CVAs
in overall disease prevention.
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 phar-
macological therapy is the best means to
reduce BP and TOD in most hypertensive
patients. Lower BP goals will require a combi-
nation of lifestyle modifications and drug
therapy, especially for those patients5 with
multiple risk factors, TOD, or clinical cardio-
vascular disease (CCD). These risk factors and
diseases include DM, RI, proteinuria or micro-
albuminuria, present or previous TOD (CVAs,
MI, CHF, CHD, coronary artery bypass graft,
left ventricular hypertrophy [LVH], transient
ischemic attack, nephropathy, peripheral arte-
rial disease, retinopathy), and concomitant
CHD risk factors such as dyslipidemia, homo-
cystinemia, insulin resistance, hyperglycemia,
tobacco use, advanced age, male sex, postme-

Table 1. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure Classification of BP for Adults5 Aged 18 Years and Older
ManagementT
Initial Drug Therapy
SBP DBP Lifestyle Without Compelling With Compelling
BP Classification (mm Hg)T (mm Hg)T Modification Indication Indicationsy
Normal b120 and b80 Encourage
Prehypertension 120-139 or 80-89 Yes No antihypertensive Drug(s) for the
drug indicated compelling indicationsz
Stage 1 140-159 or 90-99 Yes Thiazide-type diuretics Drug(s) for the compelling
hypertension for most; may consider indications. Other
ACEI, ARB, b-blocker, antihypertensive drugs
CCB, or combination (diuretics, ACEI, ARB,
b-blocker, CCB) as needed
Stage 2 z160 or z100 Yes Two-drug combination Drug(s) for the compelling
hypertension for most (usually indications. Other
thiazide-type diuretic antihypertensive drugs
and ACEI or ARB or (diuretics, ACEI, ARB,
b-blocker or CCB)§ b-blocker, CCB) as needed

Abbreviation: ARB, angiotensin-receptor blocker.

TTreatment determined by highest BP category.
ySee Table 6.
zTreat patients with chronic kidney disease or diabetes to BP goal of less than 130/80 mm Hg.
§Initial combined therapy should be used cautiously in those at risk for orthostatic hypertension.
398
(<140/90 mmHg or <130/80 mmHg for those with diabetes
Hypertension without
compelling indications
Stage 1 hypertension
(systolic BP 140-159 mmHg
or diastolic BP 90-99 mmHg)
thiazide-type diuretics for most
may consider ACE inhibitor, ARB,
ß-blocker, CCB or combination
Optimize dosages or add additional drugs until goal BP is achieved
consider consultation with hypertension specialist
nopause for women, and a family history of
premature cardiovascular disease (women b65;
men b55) (Tables 1 and 2).
Such lifestyle changes may prevent or delay
the onset of hypertension and reduce BP levels
and the progression of this disease in those
patients who have already been diagnosed. In
addition, the effects of antihypertensive drugs
are potentiated, allowing for fewer drugs and/or
lower doses. Finally, there may be additive or
synergistic improvements in cardiovascular risk
factors, vascular function, structure, and
health.10,11 Patients with a BP below 140/90
mm Hg who have no risk factors, TOD, or CCD
may be initially and successfully treated with
lifestyle modifications5 (Tables 1 and 2).
A large percentage of essential hypertensive
patients are excellent and appropriate candidates
for preliminary and prolonged lifestyle modifi-
cations as long as the BP is frequently evaluated
and clinical TOD, CCD, DM, or significant risk
factors are not present at that time and do not
develop later. As many as 50% to 60% of
essential hypertensive patients are included in
MARK C. HOUSTON
Table 2.
Lifestyle modifications
Not at goal BP
or chronic kidney disease)
Initial drug choices
Hypertension with
compelling indications
Stage 2 hypertension Drug(s) for the compelling indications
(Systolic BP ≥ 160 mmHg (See Table 6)
diastolic BP ≥ 100 mmHg) other antihypertensive drugs
2-drug combination for most (diuretics, ACE inhibitor, ARB,
(usually thiazide-type diuretic ß-blocker, CCB) as needed
and ACE inhibitor or ARB or
ß-blocker or CCB)
Not at goal BP
this classification.11-13 Nutrition, antioxidants,
vitamins, minerals, functional food, and nutra-
ceutical supplements are effective therapies in
these patients and provide excellent adjunctive
treatment in patients taking antihypertensive
drugs. The lifestyle modifications mentioned
above should always be continued after initiation
of drug therapy.10-13
This paper will review the basic science and
clinical studies of nutraceutical supplements,
vitamins, antioxidants, minerals, macronutrients
and micronutrients, and their impact on the
prevention and treatment of hypertension.
Correlations and mechanisms of action based
on vascular biology will provide a unique
framework for understanding the clinical use
of these therapeutic interventions. Pharmaco-
logical therapy with antihypertensive drugs is
beyond the scope of this paper, but a general
discussion is provided to emphasize the impor-
tance of bbalanceQ when treating essential
hypertension. It is important to integrate nutri-
tion and nutraceutical science with traditional
drug therapy to reduce BP and TOD and
NUTRACEUTICALS AND HYPERTENSION
improve the dismal statistics of BP control
worldwide.5,14-17
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 vas-
cular relaxation in spontaneously hypertensive
rats (SHRs).18 In SHRs, an increase in ROS pre-
cedes the development of hypertension.19 In-
creased 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 mainte-
nance of hypertension in SHRs. These ROS may
also be an early event in the pathogenesis of
human hypertension.
The increased ROS in SHRs inactivate nitric
oxide (NO), which reduces bioactive NO, leading
to vasoconstriction and hypertension. 20-30
Superoxide anion (O2) and other ROS have been
shown to act avidly with NO and cause its
inactivation with subsequent ED.27-35 There is
marked upregulation of renal, cardiac, and
vascular expressions of endothelial NO synthase
(eNOS), inducible NOS, and NOS proteins
in young SHRs.20-26 This is caused by ROS-
mediated reduction in NO bioavailability and
reduced negative feedback on the regulation of
NOS expression.
The proposed mechanisms of ROS-induced
hypertension in SHRs include inactivation of
endothelium-derived NO,27,29,35 nonenzymatic
generation of vasoconstrictive F-2-isoprostanes
from arachidonic acid (AA) peroxidation,30 and
depletion of the NOS cofactor-tetrahydro-
biopterin (BH4).28 Angiotensin II (A-II) will
increase superoxide production (O2) by the
nicotinamide adenine dinucleotide phosphate
(NAD(P)H) oxidase in endothelial cells.19,36,37
Antioxidant administration ameliorates hyper-
tension in SHRs, supporting the concept that ROS
play a role in the genesis and maintenance of
hypertension.29,30,38-41 Administration of tempol,
a cell-permeable superoxide dismutase (SOD), to
SHRs lowers BP and increases NO.29 Antioxidant
treatment with ascorbic acid, glutathione, amino-
triazol, and vitamin E also reduces BP in SHRs.18
399
The vitamin E–fortified diet in SHRs will increase
NO, reduce eNOS, and lower BP.20 Numerous
antioxidants have the same effect, but these effects
are not caused by a nonspecific action of the
antioxidant therapy. Antioxidant administration
in the normotensive animal in the absence of
oxidative stress does not change BP, urinary NO
excretion, or NOS expression.20,34,42
There is emerging evidence that dietary
factors, nutrients, vitamins, and antioxidants
play an important role in modulating ED.
Specifically, essential fatty acids (EFAs), vita-
mins C and E, folic acid, arginine, coenzyme
Q-10 (Co-Q-10), and others have a beneficial
effect on endothelial function and possibly in
preventing cardiovascular disease.43,44
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 hyperten-
sion as well as its initiation, maintenance,
pathogenesis, pathophysiology, and cardiovascu-
lar complications.44 Oxidative stress has been
implicated in many hypertensive disorders
including lead-induced,34,45-47 uremic, cyclo-
sporin-induced, 48-51 salt-sensitive, 52,53 pre-
eclampsia, essential hypertension,54-58 DM,59,60
and in hypertension induced by high-fat, high-
refined-carbohydrate diets.61-64
Hypertensive patients have an impaired en-
dogenous and exogenous antioxidant defense
mechanism.56,65-71 This includes increased lipo-
fuscin,65 increased lipid peroxidation,66,67 ele-
vated plasma malondialdehyde (MDA) ( P b
.05),65,67 reduced SOD in erythrocytes ( P b
.005)66,67 and plasma-reduced67 glutathione per-
oxidase ( P b .05),67,69 reduced vitamin A ( P b
.05),65,67 reduced vitamin C,65 reduced copper
( P b .005),67 reduced vitamin E ( P b .001),65,67
lower NO levels26,27 and polyunsaturated fatty
acids (PUFAs) in red cell membranes,70 re-
duced glutathione,67,71 normal-to-reduced sele-
nium levels, 6 7 , 7 1 and increased plasma
hydrogen peroxide (H2O2) production.55,56
In addition, hypertensive patients have more
oxidative stress with more ROS produced and a
greater-than-normal response to oxidative
stress. 18,19,36,37,55,56,66,67,72 This response
400 MARK C. HOUSTON

Table 3. Hypertension and Oxidative Stress Table 4. Hypertension and Oxidative Stress
ROS in Hypertension73-75 (Animal Models and Human Studies)
Mechanisms of ROS in HBP ! Impaired antioxidant status (endogenous and
exogenous)
A. Direct action on endothelial cell with structural and ! More oxidative stress, more ROS production
functional damage ! Greater-than-normal response to oxidative stress
B. Degradation of NO by ROS ! ROS contribute to ED in aorta and resistance arteries
C. Effects on eicosanoid metabolism in endothelial cell with imbalance of vasoconstrictors and vasodilators
D. Oxidative modification of LDL-C (oxLDL) ! ROS is both cause and consequence of hypertension
E. Hyperglycemia ! Antioxidants as single or combined agents reduce BP
F. Hyperinsulinemia ! Inverse relationship between BP and antioxidant intake
G. zFA mobilization in observational and interventional studies
H. zCatecholamines ! ED leads to vascular smooth muscle contraction,
I. A-II increase O2 via NAD(P)H oxidase increased SVR and BP

includes increased lipid peroxidation in serum cyclosporin-induced hypertension.48 An imbal-

and urine,66,67 increased MDA in serum and
urine,65 elevated H2O2,56 increased production
of O2 by polymorphonuclear leukocytes,19,66
increased NAD(P)H oxidase activity,84 and in-
creased plasma Zn ( P b .001).67
The proposed mechanisms of ROS-induced
hypertension in human beings are shown in
Table 3.73-75 Nitric oxide exerts a negative
feedback on NOS expression in cultured human
endothelial cells. 76 This negative feedback
leads to a compensatory upregulation of NOS
by reducing NO bioavailability similar to
that seen in lead-induced,34,42,45 uremic,51 and
ance of vasodilators (such as NO) and vaso-
constrictors (such as A-II) and their interaction
with ROS contribute to the initiation and
perpetuation of hypertension (Fig 1).77
Antioxidant deficiency and excess free radical
production have been implicated in human hyper-
tension in numerous epidemiological, observa-
tional, and interventional studies. 35,37,44,72,78-83
Serum ascorbic acid has the highest inverse
association with systolic BP (SBP) among risk
factors for CVAs, cardiovascular disease (CVD),
hypertension, and hyperlipidemia.80,84 Ceriello
et al81 demonstrated significant hypotensive

Fig 1. Reactive oxygen species and NO. Some of the complex interactions involved in regulating the balance of NO
and superoxide (O2) within the vasculature. Abbreviations: NOS I, neuronal NOS; NOS II, inducible NOS; NOS III,
endothelial NOS; EC-SOD, extracellular SOD; Mn SOD, manganese SOD; Cu/Zn SOD, copper/zinc SOD; sGC,
soluble guanylate cyclase; ONOO, peroxynitrite; H2O2, hydrogen peroxide; GTP, guanosine 5 V-triphosphate; COX,
cyclooxygenase; and VP, vasoconstrictor prostanoids.77
NUTRACEUTICALS AND HYPERTENSION 401

Fig 2. Role of different extracardiac and extravascular systems in the genesis of oxidative stress and development
of cardiovascular abnormalities. Abbreviation: RAS, renin-angiotensin system.87

effects with various antioxidants including patients.85 Intravenous vitamin C, thiopronine,

ascorbic acid, glutathione, and thiopronine in
subjects with hypertension and DM. Normoten-
sive control subjects had no significant change
in BP.
Vitamin C increases endothelial vasodilation
of epicardial coronary arteries in hypertensive
and glutathione each significantly reduced BP in
hypertensive patients.81 In an 8-week placebo-
controlled study of hypertensive subjects vs
normotensive subjects,86 the SBP was signifi-
cantly reduced by 9 mm Hg ( P b .01) and
urinary NO was reduced with a regimen of

Table 5. The Cytotoxic ROS and the Natural Defense Mechanisms87

ROS Antioxidant Defense Mechanisms
Free radicals Enzymatic scavengers
O2S Superoxide anion radical SOD SOD
OHS Hydroxyl radical 2O2S + 2H+ Y H2O2 + O2
ROOS Lipid peroxide (peroxyl) CAT Catalase (peroxisomal bound)
ROS Alkoxyl 2H2O2 Y O2+H2O
RSS Thiyl GTP Glutathione peroxidase
NOS NO 2GSH + H2O2 Y GSSG + 2H2O
NO2S Nitrogen dioxide 2GSH + ROOH Y GSSG + ROH + 2H2O
ONOO Peroxynitrite
CCl3S Trichloromethyl

Nonradicals Nonenzymatic scavengers

H2O2 Hydrogen peroxide Vitamin A
HOCl Hypochlorous acid Vitamin C (ascorbic acid)
ONOO Peroxynitrite Vitamin E (a-tocopherol)
1
O2 Singlet oxygen b-Carotene
Cysteine
Coenzyme Q
Uric acid
Flavonoids
Sulfhydryl group
Thioether compounds

The superscripted bold dot indicates an unpaired electron and the negative charge indicates a gained electron. Singlet
oxygen is an unstable molecule caused by the 2 electrons present in its outer orbit spinning in opposite directions.
Abbreviations: R, lipid chain; CAT, catalase.
402
Table 6. Oxidative Stress and CVD135,137
ROS Effects
! Lipid peroxidation: PUFAs in membrane lipid bilayer
! Protein oxidation: induces lipid and CHO autooxidation
proteolysis
! Carbohydrate oxidation
! DNA oxidation and damage
! Organic molecule oxidation
! Genetic machinery and gene expression. Transcription
factors and DNA synthesis
vitamin C 500 mg QD, vitamin E 600 IU QD,
b-carotene 30 mg QD, and Zn 200 mg QD.
Combinations of various antioxidants may have
additive or synergistic effects in neutralizing
ROS, increasing NO, improving endothelial
vasodilation, and lowering BP.
A summary of the present research and con-
clusions of the role of oxidative stress in animal
and human hypertension are shown in Table 4.
The interrelations of neurohormonal systems,
oxidative stress, and cardiovascular disease are
shown in Fig 2.87 The increased oxidative stress
in human hypertension is thus a combination of
increased generation of ROS, an exacerbated
response to ROS, and a decreased antioxidant
reserve.87,88 The ED, AA metabolites, renin
angiotensin aldosterone system, and sympathetic
nervous system (SNS) contribute to increased
ROS. Reduced antioxidant reserve is caused by
low intracellular, extracellular, enzymatic, and
nonenzymatic antioxidants (Table 5).87
Reactive oxygen species damage virtually
every organelle, cell, and tissue in the body
(Table 6).87,88 The primary and ultimate mecha-
nism of ROS damage is intracellular Ca overload
secondary to injury of subcellular organelles.87,88
Reactive oxygen species are actually second
messengers that are involved in redox-sensitive
transcription pathways modulating early and late
gene induction with production of adhesion
molecules, chemokines, cytokines, growth stim-
ulatory genes, apoptotic genes, and kinases in
virtually all cells (Fig 3).89
Touyz and Schiffrin90 studied vascular smooth
muscle cells (VSMCs) from peripheral resistance
arteries of normotensive and hypertensive sub-
jects. The generation of ROS, particularly H2O2
by A-II, is augmented in the VSMC of the
hypertensive subjects. These NAD(P)H oxidase-
dependent processes are associated with in-
MARK C. HOUSTON
creased activation of phospholipase D, which
may influence the redox-sensitive pathways
through protein kinase C (PKC) and phospha-
tidic acid that contribute to vascular structural
changes in human hypertension.
Not only essential hypertension but also the
level of BP (partially) is related to the level of
oxidative stress.91 Hypertensive patients, com-
pared with normotensive control subjects, have a
significantly elevated oxidized/reduced glutathi-
one index (a measure of oxidative stress status),
increased MDA, a lipid peroxidation product,
elevated 8-OXO-2V deoxyguanosine (a measure
of DNA damage), and decreased activity of 3 major
enzymatic antioxidants including SOD, catalase,
and glutathione peroxidase. These indicators of
oxidative stress correlate with urinary albumin
excretion, left ventricular mass index, and, par-
tially, BP. Hypertension-induced TOD is related
to the level of oxidative stress, but this damage is,
in part, independent of BP levels.92
Evolutionary Nutrition
Human beings have evolved from a preagricul-
tural, hunter-gatherer society to a commercial
agriculture society with highly processed, re-
frigerated, 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
Fig 3. Redox-sensitive transcriptional factors. Reac-
tive oxygen species are intracellular signal transduc-
tion systems and modulators of transcriptional
pathways.89
NUTRACEUTICALS AND HYPERTENSION 403

Table 7. Evolutionary Nutritional Impositions2

Human beings are genetically geared to a
preagricultural, hunter-gatherer nutritional and
Paleolithic Intakes Modern Intakes exercise lifestyle. This includes, at a minimum,
K+
N10 000 mEq/d 150 mEq/d (6 g) a low Na+ intake (b2 g/d), high K+ intake
+
(256 g) (N500 mEq/d), a K+/Na+ ratio higher than 5:1,
Na b50 mmol/d 175 mmol/d (4 g)
(1.2 g) low saturated fat (b10% total calories), high x-3
Na+/K+ ratio b0.13/d N0.67/d PUFAs, more monounsaturated fats (MUFAs)
Fiber N100 g/d 9 g/d with a total fat intake of 20% to 25% of total
Protein 37% 20%
Carbohydrate 41% 40%-50% calories, high fiber (N50 g/d), moderate protein
Fat 22% 30%-40% (30%-35% total calories), moderate unrefined
P/S ratio 1.4 0.4 carbohydrate (35%-40% total calories), no TFAs,
Evolution from preagricultural, hunter-gatherer milieu to and regular aerobic and resistance exercises
an agricultural, refrigeration society has imposed an performed daily.93,97-104
unnatural and unhealthy nutritional selection process.
Nutritionally related diseases such as DM,
metabolic syndrome, CHD, hypertension, CVAs,
CHF, cancer, and hyperlipidemia have reached
protein, fats, carbohydrates, fiber, Na, K, Mg, epidemic levels in the United States.93,95 This
and various vitamins and minerals contribute epidemic level of nutritionally related diseases is
to the higher incidence of hypertension and caused, in part, by the drastic change in the
other cardiovascular diseases through a com- amount and frequency of human exposure to
plex nutrient-gene interaction (Table 7).2,93-95 selected undesirable and unhealthy macronu-
Poor nutrition, coupled with obesity and a trients and micronutrients.94
sedentary lifestyle, has resulted in an exponen- Nutrients are powerful, influential factors to
tial increase in nutritionally related diseases.93 which the human genome is exposed. These
In particular, the high Na+/K+ ratio of modern nutrients determine the amount and activity of
diets has contributed to hypertension, stroke, specific proteins by functioning as regulators of
CHD, CHF, and renal disease.96-98 In addition, gene transcription,93,95,105,106 nuclear RNA pro-
the relatively low intake of x-3 PUFAs and cessing,93,95,107 and messenger RNA stability and
increase in x-6 PUFAs saturated fat and trans- degradation.93,95,108 These factors, in turn, de-
fatty acids (TFAs) have contributed to the termine and influence energy metabolism, cell
increased incidence of CHD, hypertension, differentiation, and cell growth93 (Fig 4).
DM, and hyperlipidemia.99-103 The clinical outcomes of nutrient regulation
of gene expression may be beneficial by decreas-
ing cardiovascular disease, BP, glucose, and
Nutrient-Gene Interactions lipids or detrimental by increasing cardiovascu-
The human genetic pool has remained essen- lar disease, BP, glucose, and lipids95 (Fig 5). The
tially unchanged for the past 35 000 years.2 x-3 PUFAs are strong determinants of cell

Fig 4. Nutrient-gene interactions and gene expression (bb The interaction of nature and nurtureQQ ).93-95,105-108
404
Fig 5. Nutrient regulation of gene expression.181
growth, energy metabolism, energy balance, and
insulin sensitivity.93,109,110 A ratio of x-3 to x-6
PUFAs of between 1:2 and 1:1 is considered
beneficial to cardiovascular health and
approaches that of our Paleolithic ancestors
and the Inuit Eskimos.2
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, observation-
al, 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.98,112-114 The BP reduction is proportional to
the severity of Na restriction.98,115,116
In the TOHP-I Trial,117 a 100 mmol Na intake
per day (2400 mg) reduced the incidence of
hypertension by 20% in a group of high-risk
subjects, improved hypertension control in
elderly subjects taking medication in the TONE
Study,118 reduced cardiovascular disease in
obese subjects,97 and reduced proteinuria and
progression of renal disease.116,119 The TOHP-II
Trial had a mean BP reduction of 2.9 F 1.6 mm
Hg with moderate Na restriction.120 There was
no rebound increase in Na excretion at the end
of intervention in TONE, indicating that the
MARK C. HOUSTON
preferred amount of Na in food is smaller after
reduction in the Na intake.121
The effect of dietary Na on BP is modulated by
other components of the diet.122-124 A severe Na
restriction may concomitantly decrease other
essential dietary components such as Ca, K, fiber,
and protein that would adversely affect BP and
cardiovascular risk.124,125 Na chloride–induced
hypertension is augmented by diets low in
K,122,123 Ca, and Mg122,124,126 and attenuated by
high K, Mg, and Ca (especially Na+ sensitive).
This is true only of Na with chloride but not of
other anions.124 An increased dietary intake of
simple carbohydrates also augments the BP
response to Na chloride. The DASH-II diet is
particularly instructive in this regard.98 Gradual
reductions in Na from 150 to 100 to 50 mmol/d
in association with a high fruit and vegetable
and low-fat dairy intake with adequate K, Ca, Mg,
and fiber intake were the most effective in
reducing BP.
Despite the enormous body of literature on
bsalt and hypertension,Q debate still exists as to a
true causal relationship.124,125 Nevertheless, Na
does have a major impact on cardiovascular,
cerebrovascular, and renal diseases.125-140 Stud-
ies have documented a direct relationship
between Na intake and increased platelet reac-
tivity,126 stroke (independent of BP),127,128
LVH,129 MI,129 CHF,129 sudden death,129 and
left ventricular filling.130 The renal plasma flow
falls and glomerular filtration rate and glomer-
ular filtration increase, leading to an increase in
NUTRACEUTICALS AND HYPERTENSION
intraglomerular capillary pressure, microalbu-
minuria, proteinuria, glomerular injury, and
RI.129,131-134 Na also reduces arterial compliance
independent of BP changes.135,136
Salt sensitivity (z10% increase in mean
arterial pressure with salt loading) is a key
factor in determining the cardiovascular, cere-
brovascular, renal, and BP response to dietary
salt intake.137-140 Cardiovascular events are
more common in salt-sensitive patients than
in salt-resistant ones, independent of BP.139,140
These cerebrovascular events may reflect spe-
cific target organ sensitivity and vulnerability
to Na that are unrelated to BP. In addition, salt
sensitivity is most pronounced in elderly
patients with isolated systolic hypertension
and is modified by polymorphisms of the
angiotensinogen gene. 141-143 Salt-sensitive
patients do not inhibit their SNS activity143
or increase NO production with salt loading.144
The evidence is very suggestive that reduction
of dietary salt intake reduces TOD (brain, heart,
kidney, and vasculature), which is both depen-
dent on the small BP reduction and independent
of the decreased BP. However, it should be noted
that higher Na consumption has actually been
associated with lower BP, suggesting that nutri-
tional deficiencies and relative serum levels or
total body stores (K+, Mg2+, Ca2+, vitamins,
antioxidants, and EFAs) and not excess Na cause
hypertension.122,145-148 On the other hand, strict
dietary Na restriction may increase the risk of
nutrient, mineral, vitamin, and antioxidant defi-
ciencies owing to a narrow and limited nutri-
tional intake that could elevate BP. 145-148
Clearly, a balance of Na with other nutrients is
important not only in reducing and controlling
BP but also in decreasing cardiovascular and
cerebrovascular events.
In the Montreal Study,122 salt intake influ-
enced BP only in those with a low Ca2+ intake.
Increased Ca intake has a depressor effect on
increased Na+ intake.122 Other studies149-151
have demonstrated that the response to Ca is
closely linked to the effect of salt; the more that
salt elevated BP, the more Ca2+ lowered it. A
decreased Ca2+/Na + ratio in the diet or a
decreased urinary Ca2+/Na+ ratio may predispose
to higher BP in salt-sensitive hyperten-
sive patients, which can be reversed by restrict-
ing Na+ intake and/or increasing Ca2+ intake.122
405
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 signifi-
cant 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 patients.154,155
A meta-analysis of all K+ supplementation
clinical trials in the treatment of hypertension
demonstrated a racial difference—with black
subjects having a more substantial reduction in
BP compared with white subjects.154 A high K
intake is most effective in reducing BP in patients
with diuretic-induced hypokalemia, in those
with a high Na+ intake,154,156,157 in patients with
salt-sensitive hypertension,157 severe hyperten-
sion, or a positive family history,157 as well as in
African Americans157 and Chinese.156 Alteration
of the K+/Na+ ratio to a higher level is important
for both antihypertensive as well as cardiovas-
cular and cerebrovascular effects.126,156 High K
intake reduces the incidence of cardiovascular
and CVAs independent of BP reduction.70,96,155
Proposed mechanisms include improvements in
vascular smooth muscle function and structure,
natriuresis, modulation of baroreflex sensitivity,
direct vasodilation, reduced vasoconstrictive
sensitivity to norepinephrine (NE) and A-II,
increased serum and urinary kallikrein, in-
creased Na+/K+ adenosine triphosphatase activi-
ty, and DNA synthesis and proliferation in
VSMCs and SNS cells.70,157,158
Gu et al156 recently demonstrated for the first
time that K supplementation at 60 mmol of KCI
per day for 12 weeks significantly reduced SBP
5.0 mm Hg (range, 2.13 to 7.88 mm Hg) ( P
b .001) in 150 Chinese men and women aged 35
to 64 years. This study confirmed that the higher
the initial BP, the greater the response. Finally, it
showed that the urinary Na/K ratio correlates
best with BP reduction as does the dietary Na/K
ratio126 compared with either urinary Na or K
individually.156
In addition, K+ may have a Ca2+-conserving
effect that would further minimize the effects
406
of a high Na+ intake.159 The interactions of
Na+, Ca2+, K+, and Mg2+ are more important in
BP control than isolated changes in one
mineral.98,104,122,149,151,159
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 tri-
als, but the results are less consistent than those
seen with Na+ and K+.14,111,155,160-166 In most
epidemiological studies, there is an inverse
relationship between dietary Mg intake and
BP.147,155,162,163,166-171 A study of 60 essential
hypertensive subjects given Mg supplements
showed a significant reduction in BP over an 8-
week period documented by 24-hour ambulatory
BP and home and office blood BP.161 The intake
of multiple minerals in a natural form such as
Mg2+, K+, and Ca2+ is more effective than Mg2+
alone in reducing BP. Mg may also be effective in
acute MI and atherosclerosis.160
Mg competes with Na+ for binding sites on
vascular smooth muscle and acts like a
calcium-channel blocker (CCB), increases
PGE, and binds in a necessary cooperative man-
ner with K, inducing vasodilation and BP
reduction.14,111,147,171-173
Witteman et al174 treated 91 middle-aged and
elderly women with mild-to-moderate hyperten-
sion taking no antihypertensive medication in a
double-blind placebo controlled study given Mg
aspartate-HCL, 20 mmol/d (484 mg of Mg2+), vs
placebo for 6 months. The SBP fell 2.7 mm Hg
( P b .18), diastolic BP (DBP) fell 3.4 mm Hg
( P b .003), urinary Mg2+ increased, but the lipid
profile did not change. The BP response was not
associated with baseline Mg status.
Mg is an essential cofactor for the delta-
6-desaturase enzyme that is the rate-limiting
step for conversion of linoleic acid (LA) to
c-linolenic acid (GLA).147,175-177 The GLA elon-
gates to form dihomo-c-linoleic acid (DGLA),
the precursor of prostaglandin E1 (PGE1), a
vasodilator and platelet inhibitor.147,175 In hypo-
magnesemic states, insufficient amounts of
PGE1 are formed, leading to vasoconstriction
and increased BP.147,176
Mg regulates SBP, DBP, intracellular Ca2+, Na+,
+
K , and pH as well as left ventricular mass,
MARK C. HOUSTON
insulin sensitivity, and arterial compliance.170,171
Newer techniques such as phosphorus nuclear
magnetic resonance and Mg 2+ -specific ion-
selective electrodes that measure intracellular
and extracellular free levels of Mg will enhance
the understanding of the role of Mg 2+ in
hypertension.170
Calcium (Ca2+)
Population studies show a link between hyper-
tension 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.155,182
A recent meta-analysis of the effect of Ca2+
supplementation in hypertensive patients found a
reduction in the SBP of 4.3/1.5 mm Hg.151,183,184
Food containing Ca2+ were more effective than
supplements in reducing BP.151,184 Karanja
et al185 assessed the effects of CaCO3 vs Ca
contained in the diet and found significant
increases in Mg, riboflavin, and vitamin D
in the dietary group that correlated with
Ca2+ intake. There is an additive or synergistic
effect on BP reduction with a combination of
minerals and vitamins as compared with
Ca2+ alone.98,104
The response to Ca2+ intake may be dependent
on the population or hypertensive subtype that
has been studied.181,186 Those patients with the
most reduction in BP with Ca2+ supplements
include black subjects, those with low-renin
hypertension, aging adults, pregnant women
(pregnancy-induced hypertension), Na + -
sensitive hypertensive subjects, those with a high
Na+ intake, those with type II DM, and postmen-
opausal women.181,186
The heterogeneous responses to Ca supple-
mentation have been explained by Resnick.187
There are 2 underlying Ca-related mechanisms.
One is salt sensitive, low renin, and Ca antago-
nist sensitive, which is dependent on impaired
cellular Ca uptake from the extracellular space.
The other is salt sensitive, renin dependent, and
NUTRACEUTICALS AND HYPERTENSION
Ca antagonist insensitive, which is dependent on
increased cellular Ca released from intracellular
sites. Reduced dietary Ca may deplete Ca from
all membrane storage sites, causing a less stable
membrane of VSMCs.187,188
When Ca is present in optimal concentrations,
it stabilizes vascular membranes, blocks its own
entry into cells, and reduces vasoconstric-
tion.176,189 Ca in combination with other ions
such as Na+, K+, and Mg2+ provides ionic balance
to the vascular membrane, vasorelaxation, and
reduced BP.147,190
This bionic hypothesisQ191 of hypertension,
cardiovascular disease, and associated metabolic,
functional, and structural disorders is character-
ized by the following191-204:
1. Increased intracellular free Ca2+ and reduced
intracellular free Mg2+ that determine rela-
tive vasoconstriction or vasodilation.192,193
2. Elevated glucose and low-density lipoprotein
cholesterol (LDL-C) increase the intracellular
Ca2+ and/or lower intracellular Mg2+ in
VSMCs.194,195
3. Hypertension, insulin resistance, and type II
DM are characterized by increased intracel-
lular Ca2+ and decreased intracellular Mg2+
and all respond to weight loss.196-198
4. Weight loss decreases intracellular Ca2+
levels.196-198
5. Dietary Ca2+–suppressible hormones such as
PTH and 1,25 vitamin D are vasoactive and
promote Ca2+ uptake in VSMCs and cardiac
muscle.199-201
6. The higher the PTH level, the greater the fall in
BP; the greater the reduction in PTH and 1,25
vitamin D, the greater the BP reduction.187
7. Salt-sensitive hypertension and Ca2+-
sensitive hypertension have elevated intracel-
lular Ca2+, PTH, and 1,25 vitamin D but low
intracellular Mg2+.202
8. Dietary Ca2+ reverses the abnormal Ca
indices and lowers BP.203
9. Mg2+ intake reduces tissue Ca2+ accumula-
tion.204
The overall effect of nutrition and diet on BP is
thus determined by the net contribution of
multiple nutritional components on cytosolic
free mineral ions such as Ca2+ and Mg2+. Direct
ionic effects on glucose or Ca2+ and ionic effects
407
on hormones (PTH, 1,25 vitamin D) regulate
these steady-state mineral concentrations.
Zinc (Zn2+)
Low serum Zn levels in observational studies
correlate with hypertension as well as CHD,
type II DM, hyperlipidemia (especially hyper-
triglyceridemia 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 than 800 mg/d.206
There is a close relationship between Zn2+, Ca2+,
Na2+, Mg2+, and K+ in various hormonal systems
(SNS, RAAS) that modulate BP.206,207
Galley et al86 administered antioxidants to
40 hypertensive and normotensive adult sub-
jects in a randomized, double-blind, crossover
design placebo-controlled study for 8 weeks.
The antioxidants administered were Zn sulfate
200 mg/d, ascorbic acid 500 mg/d, a-tocoph-
erol 600 mg/d, and b-carotene 30 mg/d. The
SBP decreased significantly in the hypertensive
subjects ( P b .01) but not in the normotensive
subjects ( P b .067). Increases in plasma levels
of antioxidants and increased urine nitrate
excretion occurred in the hypertensive sub-
jects, suggesting an increased bioavailability
of NO.86
Bergomi et al208 evaluated Zn2+ and Ca2+ status
in 60 hypertensive compared with 60 normoten-
sive control subjects. An inverse correlation of BP
and serum Zn2+ was observed, but there was a
direct correlation with serum Ca2+. The BP was
also inversely correlated with a Zn2+-dependent
enzyme-lysyl oxidase activity. Zn2+ inhibits gene
expression and transcription through nuclear
factor j-b (NF-KB) and activated protein-1.205
These effects plus those on insulin resistance,
membrane ion exchange, and RAAS and SNS may
account for Zn2+-antihypertensive effects.205,207
Zn intake should be between 15 and 30 mg/d.
Protein
Observational and epidemiological studies dem-
onstrate a consistent association between a high
408
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.209-212 The protein source is an impor-
tant factor in the BP effect, animal protein being
less effective than nonanimal protein.213 How-
ever, lean or wild animal protein with less
saturated fat and more essential x-3 and x-6
FAs may reduce BP, lipids, and CHD risk.212-214
The Intermap Study, a large international obser-
vational study, showed an inverse correlation of
BP with total protein intake and with protein
intake from nonanimal sources.213
The INTERSALT Study210 supported the hy-
pothesis that higher dietary protein intake has
favorable influences on BP. The study evaluated
10 020 men and women in 32 countries world-
wide and found that the average SBP and DBP
were 3.0 and 2.5 mm Hg lower, respectively, for
those whose dietary protein was 30% above the
overall mean than for those 30% below the
overall mean (81 g/d vs 44 g/d).
Fermented milk supplemented with whey
protein concentrate significantly reduced BP in
animal models (rats) and human studies.215
Kawase et al215 studied 20 healthy men given
200 mL of fermented milk/whey protein twice
daily for 8 weeks. The SBP was reduced ( P b .05),
HDL-C increased ( P b .05), and triglycerides fell
( P b .05) in the treated group compared with the
control group. Natural bioactive substances in
milk and colostrum including minerals, vitamins,
and peptides have been demonstrated to reduce
BP.216 Milk ingestion increases protein, vitamins
A, D, and B12, riboflavin, pantothenate, Ca,
phosphorous, Mg, Zn, and K.217 These findings
are consistent with the combined diet of fruits,
vegetables, grains, and low-fat dairy in the DASH-
I and DASH-II studies in reducing BP.98,104
Soy protein at intakes of 25 to 30 g/d lowers
BP and increases arterial compliance218,219 and
reduces LDL-C and total cholesterol by 6% to 7%
and LDL-C oxidation.218,219 Soy contains many
active compounds that produce these antihyper-
tensive and hypolipidemic effects including
isoflavones, amino acids, saponins, phytic acid,
trypsin inhibitors, fiber, and globulins.218,219
Laplante et al220 recently evaluated the effects
of genistein, an active ingredient in soy, on the BP
MARK C. HOUSTON
of angiotensin-treated hypertensive rats. Block-
ade of the tyrosine kinase (TK) pathway with
genistein significantly reduced SBP ( P b .05)
when exposed to A-II infusion. In addition, the
superoxide anion radical concentration in aortic
tissue decreased ( P b .05) and the extracellular
signal-regulated kinases/mitogen-activated pro-
tein kinases pathway activity was suppressed
( P b .05). These results suggest that genistein
lowers BP by decreasing extracellular signal-
regulated kinase/mitogen-activated protein
kinase activity and superoxide anion radical in
A-II related hypertension. Other studies have
shown that genistein inhibits TK activity, reduces
ROS by a direct antioxidant effect, or protects
tyrosine phosphatases, which shifts the balance of
protein phosphorylation-dephosphorylation
reactions.221 Phosphorylation of proteins by TKs
and other protein kinases escalates signal trans-
duction pathways, which induces growth promo-
tion, platelet aggregation, vascular smooth
muscle hyperplasia and hypertrophy, increased
vascular resistance, and BP.221 Numerous food
are abundant in genistein and daidzein such as
currants, raisins, hazelnuts, peanuts, coconuts,
passion fruit, prunes, as well as many other fruits
and nuts.222
In 2 unpublished studies by Pitre et al223 in
SHRs, hydrolyzed ion-exchange whey protein
isolate (BioZate-1, Davisco, Eden Prairie, Minn)
demonstrated significant reductions in mean
arterial pressure and heart rate (HR) compared
with an ion-exchange whey protein isolate. Bio-
Zate-1 at an oral dose of 30, 75, and 150 mg/kg
reduced mean arterial pressure by 10% to 18%
and HR 10%, which was sustained for 24 hours
( P b .05 for both). The maximum effect occurred
1 to 6 hours after dosing. Pins and Keenan224
administered 20 g of hydrolyzed whey protein to
30 hypertensive subjects and noted a BP reduc-
tion of 11/7 mm Hg compared with control
subjects at 1 week that was sustained throughout
the study. The antihypertensive effect was
thought to be mediated by an angiotensin-
converting enzyme inhibitor (ACEI) mechanism.
These data indicate that the whey protein must
be hydrolyzed to exhibit an antihypertensive
effect and that the maximum BP response is
dose dependent.
Bovine casein–derived peptides and whey
protein–derived peptides exhibit ACEI activi-
NUTRACEUTICALS AND HYPERTENSION
ty. 215,216,224,225 These components include
B-caseins, B-Ig fractions, B2-microglobulin,
and serum albumin. Whey protein hydrolysates
exhibit both in vitro and in vivo ACEI and
antihypertensive activity in in vivo animal and
human studies.215-217,223-225 The enzymatic
hydrolysis of whey protein isolates releases
ACEI peptides.223 The relative in vitro ACEI
activity (IC50-the amount of the substance that
causes a 50% inhibition of ACE activity) is
0.45 mg/mL for BioZate-1 and 376 mg/mL for
whey protein isolate compared with 1.3 
106 for captopril.
Sardine muscle protein, which contains valyl-
tyrosine (VAL-TYR), significantly lowers BP in
hypertensive subjects.226 Kawasaki et al treated
29 hypertensive subjects with 3 mg of VAL-TYR
sardine muscle concentrated extract for 4 weeks
and lowered BP 9.7/5.3 mm Hg ( P b .05).79
Levels of A-I increased as serum A-II and
aldosterone decreased, indicating that VAL-TYR
is a natural ACEI. No adverse effects were noted
during the clinical study.
A similar study using a wheat germ hydroly-
sate, which contains ILE-VAL-TYR, significantly
reduced BP in the SHR model.227 The mean
arterial pressure MAP fell between 10.3 and 19.2
mm Hg after intravenous injection of 5 to 50
mg/kg of the wheat germ hydrolysate. The wheat
germ hydrolysate has the natural ACEI (ILE-
VAL-TYR), which is also metabolized by amino-
peptidase to VAL-TYR, an ACEI.
In addition to ACEI effects, protein intake
may also alter catecholamine responses and
induce natriuresis.228 The optimal protein in-
take, depending on level of activity, renal
function, stress, and other factors, is about 1.0
to 1.5 g/(kgd d).229,230
Fats
Observational, epidemiological, biochemical,
cross-sectional studies and clinical trials on the
effect of fats on BP have been disappointing and
inconsistent.231-235 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
409
review of these studies is reported by Morris231
(Table 8).
In the National Diet Heart Study, there was no
change in BP with a polyunsaturated to saturated
fat ratio (P/S ratio) in the range of 0.3 to 4.5 in
1218 subjects over a 52-week study peri-
od.231,232 The Multiple Risk Factor Intervention
Trial demonstrated that consumption of an extra
6 g of TFAs per day increased SBP 1.4 mm Hg
and DBP 1.0 mm Hg.233 However, the addition
of 2 g/d of linolenic acid reduced mean BP by
1.0 mm Hg.
Two large prospective clinical studies, the
Nurses Health Study234 and the US Male Study
(USMS),235 showed a neutral effect on BP by all
the fats studied. In the Nurses Health Study,
58 218 disease-free nurses were evaluated for the
incidence of hypertension over a 4-year period.
A diet questionnaire was used; all confounding
factors were controlled during the study. Multi-
variate analysis showed that the incidence of
hypertension was not associated with total fat,
saturated fat, and polyunsaturated fat (LA) or
TFAs.234 Similarly, in the US Male Study, which
was also a 4-year study that controlled for
confounding factors, of 30 681 American male
health professionals, the incidence of hyperten-
sion was not associated in multivariate analysis
by total fat, saturated fat, polyunsaturated fat,
or TFAs.235
However, the type of fat, total daily intake,
and relative ratios of fat intake may be more
important in determining BP effect in patients.
This is particularly true of the PUFAs and
MUFAs, which include x-3 fatty acids (FAs),
x-6 FAs, and x-9 FAs (Tables 9 and 10). The
Table 8. Fat and BP Meta-Analysis and
Study Review 1994231
! Total fat 1 A SBP
2 z BP
8 No change BP
! PUFAs 9 No change BP
1 A BP
! N-6 PUFAs 1 A BP
1 No change BP
! N-3 PUFAs 1 A BP
! PUFA/SFA ratio 5 No change in BP
! MUFAs 2 A BP
5 No change in BP
! SFA No change in BP
Abbreviation: SFA, saturated FA.
410 MARK C. HOUSTON

Table 9. Nomenclature of Major Families of

x-3 PUFAs
Unsaturated FAs a-Linolenic acid (ALA), eicosapentaenoic acid
No. of (EPA), and docosahexaenoic acid (DHA) are
Parent Double Family primary members of the x-3 PUFA family
Compound Bonds NameT Structural Abbreviationsy
(Table 10). x-3 Fatty acids are found in cold-
Oleic acid 1 x-9 18: 1n-9 or 18: 1x-9 water fish (herring, haddock, Atlantic salmon,
Palmitoleic 1 x-7 16: 1n-7 or 16: 1x-7
acid
trout, tuna, cod, and mackerel), fish oils, flax, flax
LA 2 x-6 18: 2n-6 or 18: 2x-6 seed, flax oil, and nuts.14,236 x-3 PUFAs signifi-
ALAz 3 x-3 18: 3n-3 or 18: 3x-3 cantly lower BP in observational, epidemiolo-
TThe family name denotes the position of the first gical, and some small prospective clinical
double bond as the number of carbon atoms from the
methyl end of the fatty acid chain. trials.14,231,237-243 A meta-analysis of 31 studies
yNumber of carbon atoms: number of double bonds of the effects of fish oil on BP has shown a dose-
(fatty acid family).
zAlso designated a-linolenic acid; a-linolenic acid is related response in hypertension as well as a
distinct from c-linolenic acid (18: 3n-6), which is an relationship to the specific concomitant diseases
intermediate in the x-6 metabolic pathway and is a major
component of evening primrose, borage, and block associated with hypertension.147,244-250 At fish
currant oils. oil doses of b4 g/d, there was no change in BP in
the mildly hypertensive subjects. At 4 to 7 g of
fish oil per day, BP fell 1.6 to 2.9 mm Hg; at 15 g of
x-3 FAs and x-6 FAs are EFA families; fish oil per day and greater, BP decreased 5.8 to
whereas x-9 FAs (oleic acid) can be manufac- 8.1 mm Hg.147,244-250 There was no change in BP
tured by the body from the dietary precursor in the normotensive subjects. However, in those
stearic acid. subjects with atherosclerotic disease and hyper-

Table 10. Metabolic Pathways of the x -3 and x -6 FAs

Omega-3 Omega-6
Fatty Acids Fatty Acids

Alpha-linolenic acid (ALA) Linoleic acid (LA)

18:3n-3 18:2n-6
delta-6-desaturase

Gamma-linolenic acid (GLA)

Stearidonic acid
18: 3n-6
18:4n-3

Dihoma-gamma-
20: 4n-3 linolenic acid (DGLA)
20: 3n-6
delta-5-desaturase

Eicosapentaenoic acid Arachidonic acid (AA)

20: 5n-3 20: 4n-6

Adrenic acid
22: 5n-3 22: 4n-6
delta-4-desaturase

Docosahexaenoic acid (DHA) 22: 5n-6

22: 6n-3
NUTRACEUTICALS AND HYPERTENSION
tension, hyperlipidemia, and CHD, BP was re-
duced as shown below:
Mean Fish Mean BP
Oil Dose Reduction
Disease g/d mm Hg
Hypertension 5.6 2.3-3.4
Hyperlipidemia 4.0 4.1
CHD 4.8 2.9-6.3
A study of 399 healthy men showed that a 1%
increase in adipose tissue ALA content was
associated with a 5 mm Hg decrease in SBP,
DBP, and MAP.161
Knapp and FitzGerald242 demonstrated a sig-
nificant reduction in BP ( P b .01) in a group of
hypertensive subjects given 15 g/d of fish oil.
Bao et al236 studied 69 obese hypertensive
subjects for 16 weeks treated with fish oil
(3.65 g x-3 FAs per day), evaluated by 24-hour
ambulatory BP monitoring (24-hour ABM).
Group I subjects taking 3.65 g/d of x-3 FAs
alone reduced 24-hour ABM by 6/3 mm Hg
( P b .01). Group II subjects who lost an average
of 5.6 kg of weight, but received no fish oil, had a
5.5/2.2 mm Hg reduction in BP ( P b .01). The
best BP results were seen in group III subjects
with combined fish oil (x-3 FAs) and weight loss
whose BP and HR fell 13.0/9.3 mm Hg and an
average of 6 beats/min, respectively.
Mori et al109 studied 63 hypertensive and
hyperlipidemic subjects treated with x-3 FAs
(3.65 g/d for 16 weeks) and found significant
reductions in BP ( P b .01), increase in HDL2-C
( P b .0004), decrease in HDL3-C ( P b .026),
decrease in triglycerides (29%), but no change in
LDL-C, TC, or total HDL-C. Serum glucose and
insulin levels also declined.
Studies indicate that DHA is very effective in
reducing BP and HR.237,238 However, formation
of EPA and ultimately DHA from ALA is
decreased in the presence of increased LA in the
diet (x-6 FAs), increased dietary saturated fats
and TFAs, alcohol, and aging through inhibitory
effects or reduced activity of delta-6-desaturase,
delta-5-desaturase, or delta-4-desaturase (Table
10).237,238 Eating cold-water fish 3 times per week
is as effective as high-dose fish oil in reducing BP
in hypertensive patients, and the protein in the
fish may also have antihypertensive effects.14,243
411
The BP is usually unaffected in healthy non-
hypertensive patients.243,249
x-6 FAs
The x-6 FA family, which includes LA, GLA,
DGLA, and AA, does not usually lower BP
significantly231 (Table 10), but it may prevent
increases in BP induced by saturated fats.146,251
The x-6 FAs are found in flax, flax seed, flax
seed oil, conjugated LA, canola oil, nuts, evening
primrose oil, borage oil, and black current oil.
The ideal ratio of x-3 FAs to x-6 FAs is between
1:1 and 1:2 with a P/S fat ratio greater than 1:5 to
2:0.252 Hydrogenated or partially hydrogenated
vegetable oils with TFAs should be avoided
because they will increase BP and CHD risk.233
These vegetable oils also have high x-4 FA
concentrations with little or no x-3 FAs.14
The GLA and DGLA will enhance synthesis of
vasodilating prostaglandins (PG) PGE1 and
PGI2, preventing the increase in BP by feeding
saturated fats.147,251 The GLA also completely
blocks stress-induced hypertension253,254 caused
by increased PGE1,255 decreased plasma aldoste-
rone, and reduced adrenal A-II receptor density
and affinity.254 Both PGE1 and PGI2 regulate
nerve conduction, mental function, and neuro-
transmitter release, an action that will potentially
normalize stress-induced changes in the hypo-
thalamus and endocrine organs in hypertensive
patients given GLA supplementation.147,254-257
The conversion from LA to GLA and DGLA
requires cofactors such as Mg, K, Zn, Ca, vitamin
B6, vitamin A and b-carotene, vitamin C, niacin,
selenium, and Na.147,175-177,255
x-3 FAs—Other Clinical Effects
The x-3 FAs have a multitude of cardiovascular
consequences whose interplay modulates BP.
These cerebrovascular effects include reduction
in fibrinogen,242 anti-inflammatory,238 antiplate-
let,238 antiarrhythmic,238,239 hypolipidemic,258
antiatherosclerotic,238 and vasodilatory effects
(increases NO levels).238
x-3 FAs: Mechanism of action
The proposed mechanisms of action of x-3 FAs
are outlined in Table 11.93,109,110,231,259-271
a-Linolenic acid competes for the same enzyme
412
as LA (ie, delta-6-desaturase), thus reducing AA
formation and eicosanoid production of prod-
ucts such as thromboxane A2 (TxA2) (procoa-
gulation) and leukotrienes (proinflammatory)
while increasing production of vasodilatory
prostacyclin I (PGI2 and PGI3).147,231,259,260,272
In addition, there is a modification of membrane
phospholipids, improved membrane fluidity,
reduced Ca2+ exchange, and increased Na+/K+
adenosine triphosphatase activity. 259,268-271
Stimulation of NO production,370 improved
insulin sensitivity,93,109,110,261-265 and effects on
intracellular and intraorgan fuel partitioning of
FAs account for much of the observed BP-
lowering effect.93,262,266
Eicosapentaenoic acid blocks the activity of
delta-5-desaturase, which reduces levels of AA
and increases DGLA levels and thus PGE1.272
Arachidonic acid is necessary for the conversion
of EPA to PGI3 and EPA for the conversion of
DGLA to PGE1.248,272 Dietary caloric restriction
will increase the activity of delta-6-desaturase,
increasing levels of GLA, DGLA, EPA, and DHA
as well as PGE1, PGI2, and PGI3.147,177,272-274
The EFAs all have ACE inhibitory activity.
A critical and optimal balance of x-3 and x-6
EFAs with the nutrition cofactors of minerals,
vitamins, antioxidants, and electrolytes is impor-
tant in vasoregulation, thrombosis, BP, vascular
health, and CVD reduction.
x-9 FAs
Olive oil is rich in MUFAs (x-9 FAs) (oleic
acid), which have been associated with BP and
lipid reduction in Mediterranean and other
diets.14,275 Ferrara et al275 studied 23 hyperten-
sive subjects in a double-blind, randomized,
crossover study for 6 months comparing MUFAs
with PUFAs. Extra virgin olive oil (MUFAs) was
compared with sunflower oil (PUFAs) rich in LA
(x-6 FAs). The SBP fell 8 mm Hg ( P V .05) and
the DBP fell 6 mm Hg ( P V .01) in the MUFA-
treated subjects compared with the PUFA-trea-
ted subjects. In addition, the need for antihyper-
tensive medications was reduced by 48% in the
MUFA group vs 4% in the PUFA (x-6 FAs)
group ( P b .005).
Strazzullo et al276 found an increase in SBP
and DBP in patients when olive oil was replaced
with saturated FAs. Thomsen et al277 compared
MARK C. HOUSTON
Table 11. W-3 and PUFAs: Mechanism
of Action93,109,110,259-271
! Stimulates NO370,397,398 and PGI but decreases TxA2
and leukotrienes241,397,398
! Improves insulin sensitivity and lowers BP
! N-3 skeletal muscle phospholipid content196
! Membrane fluidity, membrane phospholipid
content 240,397,398 regulate gene expression394
! Mitochondrial up-coupling protein and FA oxidation
in liver and skeletal muscle392
! Thermogenesis gene induction (reduces body fat;
increases heat production) energy balance
improves197,388,392
! Mitochondrial and peroxisomal oxidation in skeletal
muscle179
! ATG droplets, zglucose uptake, glycogen
storage195-197,388,392
! Improved glucose tolerance182
! Intracellular and interorgan fuel partitioners directing FA
away from storage to oxidation179,395
! PPARa ligand activators (lipid oxidation)179
! SREBP-1 suppression (Alipogenic genes)395
! Improved cardiac function396
! Improved ED369,375,381,398,399
! Reduced plasma NE397
! Change calcium flux398
Abbreviations: PPAR, peroxisome proliferator–activated
receptor; SREBP-1, sterol response element–binding
protein.
16 hypertensive type II diabetics in a 3-week
crossover study comparing MUFAs (olive oil)
with PUFAs. There was a significant reduction in
clinic BP and 24-hour ABM. However, in 47
normotensive healthy subjects given an olive oil–
rich diet vs a carbohydrate-rich diet for 36 days,
there was no change in BP.278
Olive oil is rich in oleic acid (x-9 FAs).
Extra virgin oil has 5 mg of phenols in 10 g of
olive oil, a rich polyphenol antioxidant.275,279
About 4 tbsp of extra virgin olive oil is equal to
40 g. The MUFAs tend to increase HDL-C more
than PUFAs,280 and the oleate-rich LDL-C is
more resistant to oxidation than to oxidized
LDL-C (oxLDL-C).281 The combined antioxi-
dant and antilipid effect of MUFAs probably
accounts for the BP effects by improved
NO bioavailability, reduced ROS, improved
endothelial function, vasodilation, and inhibi-
tion of the oxLDL stimulation of the A-II
receptor.66,67,77,84,87,88
Palmitoleic acid
Palmitoleic acid reduces the incidence of stroke
in stroke-prone SHRs without any change in
NUTRACEUTICALS AND HYPERTENSION
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 intracra-
nial hemorrhage in women.283 This is also
independent of BP. Perhaps some saturated fat
and x-6 FAs from dairy products and red meat
are essential for membrane integrity and reduc-
tion 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, dia-
betic subjects, and hypertensive-diabetic sub-
jects.284- 287 Vuksan et al285 reduced SBP 9.4
mm Hg in hypertensive subjects with the fiber
Glucomannan. Keenan gave oat bran (b-glucan)
to hypertensive patients and reduced BP
7.5/5.5 mm Hg. The doses required to achieve
these BP reductions are approximately 60 g of
oatmeal per day, 40 gof oat bran (dry weight)
per day, 3 g of b-glucan per day, or 7 g of
psyllium per day.218 In addition, the soluble
and insoluble fibers reduce TC, TG, and LDL-C
and increase HDL.218 The mechanisms for the
BP reduction include improved insulin sensitiv-
ity,284,288 reduced ED,284,288 natriuresis and
reduced intravascular volume,284,289 decreased
SNS activity,284,289 reduced oxLDL,218 and
mitigation of postprandial high-fat meal–in-
duced hypertriglyceridemia, hyperglycemia with
ED, and vasoconstriction.218
Garlic
Good clinical trials using the correct type and
dose of garlic have shown consistent reductions
in BP in hypertensive patients. 14,238,290-299 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),300-310 and
aged 161 or fresh garlic will have variable
effects.14,290,291 Mohamadi et al301 found that
wild garlic had the greatest antihypertensive
effect in rats, probably mediated through the
413
reduction in A-II levels, increased NO, and
decreased ROS by the higher content of allicin
and other compounds. There is a consistent
dose-dependent reduction in BP with garlic
mediated through the RAAS and the NO sys-
tems.301 Allicin, a synthetic preparation of an
active constituent of garlic, lowered BP, insulin,
and TG to a similar degree as enalapril in the
Sprague-Dawley Rat Study by Elkayam et al.311
Approximately 10 000 lg of allicin per day,
the amount contained in 4 cloves of garlic (4 g),
is required to achieve a significant BP-lowering
effect.14,290,291 In human beings, the average
reduction in SBP is 5 to 8 mm Hg.312
Garlic contains numerous active compounds
that may account for its antihypertensive ef-
fects including c-glutamyl peptides (natural
ACEI),302,309,310 flavonolic compounds (natural
ACEI), 302,310 Mg (vasodilator and natural
CCB), 30 0,3 02 ajoenes, 16 1,30 0,3 02 phospho-
rous,300,302 adenosine,304-308 allicin,161,301 and
sulfur compounds.161 The proposed mecha-
nisms of action of garlic in reducing BP are
shown in Table 12. Garlic is probably a natural
ACEI and CCB that increases BK and NO-
inducing vasodilation, reducing systematic vas-
cular resistance (SVR) and BP and improving
vascular compliance.
Approximately 30 hypertensive clinical trials
have been completed to date and 23 reported
results with placebo control, 4 used nonplacebo
controls, and 3 did not report results.312 These
trials studied BP as the primary outcome and
7 excluded concomitant antihypertensive medi-
cations. Significant reductions in DBP of 2% to
7% were noted in 3 trials and reductions in SBP
of 3% in 1 trial when compared with placebo.
Other trials reported BP reductions in the garlic-
treated subjects (within-group comparisons).
Many studies did not provide numerical data
about BP or did not have an a priori hypothesis
regarding BP reduction.
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.313-318
However, green tea, black tea, and extracts of
active components in both teas have demonstrat-
ed reduction in BP in the SHR model.319-321
414
Table 12. Garlic: Mechanism
of Action161,293,300-310
! ACEI (c-glutamyl peptides, flavonolic
compounds)429-432,438,439
! Increase NO422,430
! Decrease sensitivity to NE422,430
! Increase adenosine422,430,433-437
! Vasodilation and reduced SVR297,430
! Inhibit AA metabolites (TxA2)297,430
! Reduced aortic stiffness297
! Mg (natural CCB vasodilator)429,431
! Decreased ROS430
Norwegians consuming black tea had a signif-
icant decrease in BP in an observational study.316
Normotensive subjects consuming 6 mugs of
black tea per day for 4 weeks had no change in
BP.317 Elderly hypertensive subjects had their
postprandial reduction in BP attenuated with
black tea,318 but there was no change in 24-hour
ABM in another study.313
Hodgson et al313 evaluated the effects of acute
and chronic ingestion of 4 to 5 cups of green tea,
black tea, caffeine, or water in a group of
normotensive, borderline hypertensive, or mild
systolic hypertensive (SBP, 130-150 mm Hg)
subjects in a Latin square and crossover study
design. In the acute study, there were increases in
BP of 5.5/3.1 mm Hg at 30 minutes with green tea,
but no change at 60 minutes. The black tea
group had an increase in BP of 10.7/5.1 mm Hg
at 30 minutes, but no change at 60 minutes. The
chronic study demonstrated no significant
change in office or 24-hour ABM, SBP, or DBP
with green or black tea. Tea contains many
active compounds that may alter BP including
flavonoids, which are polyphenolic compounds
with vasodilatory and antioxidant effects,314,315
theanine,321 theobromine,313 quercetin,313 epi-
gallocatechin-3-0-gallate, 322 c-glutamylme-
thylamide,323 thearubigins, and theaflavins.324
Additional studies in human beings will be
required to accurately assess these BP effects.
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.14,325-327 Mushrooms are low in
carbohydrates, have no sugar, but also have high
amounts of Zn and other vitamins and minerals
MARK C. HOUSTON
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 F 3 mm
Hg and the DBP 5 F 2 mm Hg ( P b .01).329 In a
study of 62 middle-aged male subjects with mild
hypertension given a K-oaded, ion-exchanging,
Na-adsorbing, K-releasing seaweed preparation
showed significant BP reductions at 4 weeks on
12 and 24 g/d of the seaweed ( P b .01).330 The
MAP fell 11.2 mm Hg ( P b .001) in the Na-
sensitive subjects and 5.7 mm Hg ( P b .05) in
the Na-insensitive subjects, which correlated
with PRA. The urinary Na excretion decreased,
urinary K increased, and the Na/K urinary
excretion ratio decreased, indicating that the
MAP reduction was dependent on the reduced
intestinal absorption of Na and increased ab-
sorption of K released from the seaweed prepa-
ration. A similar mechanism of BP and stroke
reduction was reported in SHRs given 10%
alginic acid in a seaweed fiber.282
Seaweed and sea vegetables contain most of the
seawater’s 771 minerals and rare earth elements,
fiber, and alginate in a colloidal form.328 Howev-
er, the concentration of these minerals and
alginate is lower than the effective dose needed
to reduce BP in most cases.328 The primary effect
of Wakame appears to be through its ACEI
activity from at least 4 parent tetrapeptides and
possibly their dipeptide and tripeptide metabo-
lites, especially those containing the amino acid
sequence TYR-LYS in some combination.328 Its
long-term use in Japan has demonstrated its
safety. Other varieties of seaweed may reduce BP
by reducing intestinal Na absorption and increas-
ing intestinal K absorption.282,330
Natural ACEIs
Many other food have demonstrated ACEI activ-
ity in vitro, but whether they are active after oral
ingestion in vivo remains to be proven in human
studies (Table 13).302,305,309,310,328,331-347
NUTRACEUTICALS AND HYPERTENSION 415
Vitamin C measured, the P value and CIs were not
reported, variable BP measurement techniques
Vitamin C is a potent water-soluble antioxidant
were used (clinic or office, home, 24-hour ABM),
that recycles vitamin E, improves ED, and
unknown genetic polymorphisms exist, or there
produces a diuresis.238,348-352 Numerous epide-
was publication bias.84
miological, observational, and clinical studies
Ness et al84 published in 1997 a systematic
have demonstrated that the dietary intake of
review of MEDLINE-listed peer review journals
vitamin C or plasma ascorbate concentration in
on hypertension and vitamin C and concluded
human beings is inversely correlated with SBP,
that if vitamin C has any effect on BP, it is small.
DBP, and HR.81,84,86,353-369 Studies in SHRs have
However, in the 18 studies that were reviewed
shown fairly uniform reductions in BP with
worldwide, 10 of 14 showed a significant BP
vitamin C administration.41 Long-term epidemi-
reduction with increased plasma ascorbate levels
ological and observational follow-up studies in
and 3 of 5 demonstrated a decreased BP with
human beings also show a reduced risk of
increased dietary vitamin C.84 In 4 small ran-
CVD, CHD, and CVAs with increased vita-
domized clinical trials of 20 to 57 subjects, 1 had
min C intake.79,362,370,371 However, controlled
significant BP reduction, 1 had no significant BP
intervention trials have been somewhat less
reduction, and 2 were not interpretable.84 In
consistent or inconclusive as to the relation-
2 uncontrolled trials, there was a significant
ship between vitamin C administration and
reduction in BP.84
BP.84,356,362-365,372 Numerous reasons exist for
Koh367 in 1984 evaluated 23 hypertensive
these variable results, including lack of a control
women with a BP range of 140 to 160/90 to
group, no baseline BP, small study population,
100 mm Hg over a 3-month period. Administra-
short trial duration, variable vitamin C doses,
tion of 1 g of vitamin C per day reduced office
variable demographics, and study population,
SBP 7 mm Hg (.05 b P b .10) and reduced DBP
unknown premorbid vitamin C status or pre-
4 mm Hg (.05 b P b .10). Ceriello et al81 in 1991
morbid general vitamin or antioxidant status,
gave intravenous vitamin C to hypertensive
concomitant or unknown multivitamin intake,
patients with DM and reduced BP significantly.
and unknown nutritional status. In addition,
Trout360 in 1991 gave 1 g of vitamin C orally
existing concomitant diseases, confounding fac-
to 12 hypertensive subjects in a randomized
tors such as smoking, alcohol, weight changes,
crossover study for 6 weeks. The plasma ascor-
and fiber, among others were not stated or
bate levels increased by 20 lmol/L ( P b .001),
evaluated, plasma ascorbic acid levels were not
SBP fell 5 mm Hg ( P b .05), and DBP fell 1 mm
Hg F 2 (NS).
Duffy et al356 in 1999 evaluated 39 hyperten-
Table 13. Angiotensin-Converting Enzyme sive subjects (DBP, 90-110 mm Hg) in a placebo-
Inhibitor Activity in Food and Nutraceuticals
controlled 4-week study. A 2000 mg loading dose
A. Sour milk will A BP in human beings331 of vitamin C was given initially followed by
B. Casein332,333 500 mg/d. The SBP was reduced 11 mm Hg
C. Zein334,335
D. Geletin336 ( P = .03), DBP decreased by 6 mm Hg ( P = .24),
E. Sake337 and MAP fell 10 mm Hg ( P b .02). The plasma
F. Sour milk 338 ascorbate increased to 49 lmol/L at 4 weeks
G. Sardine muscle339,340
H. Tuna muscle341 ( P b .001), showing an inverse correlation
I. Dried salted fish342 with MAP and plasma ascorbate levels ( P b .03).
J. Dried bonito343 There was no change in cyclic GMP, urinary
K. Fish sauce344
L. Porhyda yezoensis 345 6 keto-prostaglandin-FI a, or urinary 8 epi-
M. Hijikia fusiformis 346 and seaweed (wakame)328,329 prostaglandin-F2 a.
N. Garlic302,305,309,310 Fotherby et al366 studied 40 mild hypertensive
O. Hawthorne14,238,328
P. Pycnogenol347 and normotensive subjects in a double-blind,
Q. Egg yolk (chicken) randomized, placebo-controlled, crossover study
R. Hydrolyzed whey protein215,223 for 6 months. Men and women aged 60 to
S. x-3 Fas91,268,269
80 years (mean age, 72 F 4 years) were given
416
vitamin C 250 mg BID for 3 months, then
crossed over after a 1-week washout period.
The plasma ascorbate increased to 35 lmol/L
( P b .001), but clinic BP did not change
significantly. However, the 24-hour ABM
showed a decrease in SBP 2.0 F 5.2 mm Hg
( P b .05), but there was no significant change in
DBP. However, the higher the BP, the greater the
response to vitamin C. Therefore, when the
normotensive or borderline hypertensive sub-
jects were excluded, the BP reduction was more
pronounced and significant. An increase in HDL-
C was seen in women ( P b .007) but not in men.
The LDL-C did not change in either group. The
conclusion from this study was that vitamin C
reduced primarily daytime SBP as measured by
24-hour ABM in hypertensive but not in normo-
tensive subjects. In the hypertensive subjects,
SBP was reduced by 3.7 F 4.2 mm Hg ( P b .05)
and DBP fell 1.2 F 3.7 mm Hg (NS).
Block et al373 in an elegant depletion-repletion
study of vitamin C demonstrated an inverse
correlation of plasma ascorbate levels, SBP, and
DBP. During this 17-week controlled diet study
of 68 normotensive men aged 39 to 59 years with
mean DBP of 73.4 mm Hg and mean SBP of
122.2 mm Hg, vitamin C depletion at 9 mg/d for
1 month was followed by vitamin C repletion at
117 mg/d repeated twice. All confounders in-
cluding smoking, exercise, alcohol, weight
change, and other nutritional intake during the
study were eliminated. Plasma ascorbate was
inversely related to DBP ( P b .0001; correlation,
0.48) and to SBP in logistic regression. Persons
in the bottom quartile of plasma ascorbate had a
DBP 7 mm Hg higher than those in the top
quartile. One fourth of the DBP variance was
accounted for by plasma ascorbate alone. Of the
other plasma nutrients examined, only ascorbate
was significantly and inversely correlated with
DBP ( P b .0001; r = 0.48) for the 5-week
plasma ascorbate levels. Each increase at week 5
in the plasma ascorbate level was associated with
a 2.4 mm Hg lower DBP at week 9.
Hajjar et al374 evaluated 31 subjects with stage
I hypertension in a double-blind, randomized,
placebo, 4-week, run-in trial using 3 doses of
vitamin C at 500, 1000, or 2000 mg/d for
8 months. The mean age of the participants
was 62 F 2 years, 52% were men, 90% were
whites, with good compliance of 48% F 2%. The
MARK C. HOUSTON
SBP fell significantly by 4.5 F 1.8 mm Hg
( P b .05) and DBP fell by 2.8 F 1.2 mm Hg
( P b .05) at 1 month and persisted during the
study. No dose response was demonstrated. The
BP decrease was not significant but was lower in
the vitamin C group. There was no difference in
BP response between the 3 groups ( P = .48) and
no change in serum lipid levels from baseline or
between groups although the vitamin C group
had an overall trend of improved lipids: TC,
P = .75; TG, P = .87; HDL, P = .32; or LDL,
P = .52.
Ness et al354 evaluated subjects aged 45
to 74 years in a population-based cross-sectional
analysis and found that an increase in plas-
ma ascorbate of 50 lmol/L reduced BP by
3.6/2.6 mm Hg. Bates et al353 in a similar
cross-sectional analysis on 914 elderly patients
older than 65 years confirmed that an increase in
plasma ascorbate of 50 lmol/L reduced SBP
by 7 mm Hg. In most of the epidemiological
studies, there is a clear inverse relationship
between plasma ascorbate levels, dietary in-
take, and BP with a reduction in SBP of 3.6 to
17.8 mm Hg for each 50 lmol/L increase in
plasma ascorbate.79,84,353,354,358-361
In the post hoc analysis in the Arterial Disease
Multiple Intervention Trial,372 a prospective,
double-blind, placebo-controlled study of 363
subjects with peripheral arterial disease treated
with vitamin C 1000 mg/d, vitamin E 800 IU/d,
and b-carotene 24 mg/d vs placebo, there was no
difference in BP in the normotensive or hyper-
tensive subjects (n = 177). Other studies,
however, have shown synergy of combination
antioxidants and vitamins in reducing BP,
increasing NO, PGE1,147,177,375 and PGI2 lev-
els,86,366,376,377 and reducing TxA2 levels. The
study by Miller et al378 in 297 elderly patients
showed no difference in BP in the treated group
given vitamins C and E and b-carotene vs the
placebo group. However, 87% of all subjects
were permitted to take their own multivitamins.
Mechanism of Vitamin C on BP
Vitamin C improves ED in hypertensive238,350
and hyperlipidemic349 patients and reduces BP
in a dose-related manner with higher pharmaco-
logical doses.238,348 The improvement of ED in
hypertensive patients occurs in conduit arteries,
NUTRACEUTICALS AND HYPERTENSION
epicardial coronary arteries, and forearm resis-
tance 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 administration, there is an increase in
exhaled NO that correlates with BP reduction,
especially SBP.357 Acute oral or intravenous
administration of vitamin C reverses ED and
causes acute vasodilation in human beings with
CHD351 and in smokers.352 The multitude of
proposed mechanisms for vitamin C in hyper-
tension and other cardiovascular diseases is
outlined in Table 14. Grossman et al369 proposed
recently that ascorbic acid modulates the redox
state of soluble guanylyl cyclase, activating cyclic
GMP–dependent K channels that hyperpolarize
VSMC-inducing vasodilation.
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 shown an inverse relationship to vitamin
C intake and plasma ascorbate levels that is
Table 14. Mechanisms of Vitamin C353-369
! Reduces ED and improves endothelial vasodilation and
lowers BP and SVR in hypertension, hyperlipidemia,
CHD, smokers
! Diuresis
! Increase NO and PGI2
! Decrease adrenal steroid production
! Improve sympathovagal balance
! Decrease cytosolic Ca2+
! Antioxidant
! Recycles vitamin E, glutathione, uric acid
! Reduces neuroendocrine peptides
! Reduces thrombosis and decreases TxA2
! Reduces lipids (ATC, ALDL, ATG, zHDL)
! Reduces leukotrienes
! Improves aortic collagen, elasticity, and aortic
compliance
! Increase cyclic GMP and activate vascular
smooth muscle K+ channels
417
reasonably consistent among different study
groups, populations, and the variable study
designs.79,84,353,354,356,358-361,366,367,373 Hyper-
tensive subjects were found to have significantly
lower plasma ascorbate levels compared with
normotensive subjects (40 vs 57 lmol/L, respec-
tively).382 Evidence supports the fact that plasma
ascorbate is inversely correlated with BP even in
healthy normotensive individuals. 373 The
NHANES-II Study found that 20% of American
men have plasma ascorbate levels below
27 lmol/L and that those of 30% of African-
American men were below 27 lmol/L.383 This
increased prevalence of lower plasma ascorbate
levels in black men could partially account for the
higher prevalence of hypertension in African-
American men.
Pharmacokinetic studies have documented the
existence of at least 3 or more ascorbate com-
partments of which plasma is only one.384,385
Human organs such as the adrenal gland,
pituitary gland, liver, spleen, pancreas, brain,
and lens of the eye actively concentrate ascor-
bate against a concentration gradient and
achieve levels 20- to 100-fold greater than
plasma.385 It is possible that during vitamin C
deprivation, these organs gain relative priority
over the vascular system and other organs as to
ascorbate concentrations.373 The body stores of
vitamin C then may be more relevant than
plasma levels as it correlates with BP. This
vascular tissue-organ depletion theory is con-
sistent with many of the proposed mechanisms
of vitamin C shown in Table 14.79,353-369,386-392
Vitamin C is not prooxidant and, in fact,
significantly reduces oxidative stress as mea-
sured by the ratio of urinary 8-oxoguanine to
8-oxoadenine.393-395
Summary and Conclusions
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 sug-
gested, but the efficacy of bsupraphysiologicalQ
418
doses of vitamin C and BP effects are yet to
be confirmed.
Vitamin E
The relationship of vitamin E and BP has been
studied in vitro,396 extensively in animals
(SHR),396-401 but limited studies have been
done in human beings.402,403 a-Tocopherol
inhibits thrombin-induced endothelin secre-
tion in vitro at least partially through PKC
inhibition.404 Reduced PKC levels reduce vas-
cular smooth muscle proliferation through
inhibition of activated protein-1 and NF-KB.
In turn, ED is improved, SVR is lowered, and
BP is reduced.
Newaz and Nawal 396 gave c-tocotrienol
15 mg/kg to SHRs and found significant reduc-
tions in lipid peroxides in plasma and in blood
vessel walls, increased SOD activity, increased
total antioxidant status, and lowered BP
Table 15. Vitamin C: Conclusions
1. Blood pressure is inversely correlated with vitamin C
intake and plasma ascorbate levels in humans and
animals in epidemiological, observational, cross-
sectional, and controlled prospective clinical trials.
2. A dose-response relationship between lower BP and
higher plasma ascorbate levels is suggested.
A. Diastolic BP fell about 2.4 mm Hg per plasma
ascorbate quartile in a depletion repletion study.
B. Systolic BP fell 3.6 to 17.8 mm Hg for each 50 lmol/L
increase in plasma ascorbate level.
C. Blood pressure may be inversely correlated to tissue
levels of ascorbate.
D. Doses of 100-1000 mg/d are needed.
3. Systolic BP is reduced proportionately more than DBP,
but both are decreased. Twenty-four–hour ABM
indicates a predominate daytime SBP reduction and
lower HR. Office BP shows a reduction in SBP and DBP
as well.
4. The greater the initial BP, the greater the BP reduction.
5. Blood pressure is reduced in hypertensives,
normotensives, hyperlipidemics, diabetics, and
in patients with a combination of these diseases.
6. Improves ED in HBP, HLP, PAD, DM, CHD, CHF,
smokers, and in conduit arteries, epicardial coronary
arteries, and forearm resistance arteries.
7. Long-term epidemiological studies indicate an inverse
correlation of vitamin C intake and ascorbate levels
with renal vascular resistance of CVD, CHD, and CVAs.
8. The lipid profile seems to be beneficial with small
reductions in TC, TG, and LDL and oxLDL and with
increases in HDL (women).
9. Combinations of vitamin C with other antioxidants such
as vitamin E, b-carotene, or selenium provide
synergistic antihypertensive effects.
MARK C. HOUSTON
( P b .001). In a similar study, Newaz and
Nawal397 gave 34 mg/kg of a-tocopherol to SHRs
and Wistar-Kyoto rats. Lipid peroxide levels
were decreased in plasma and in vascular walls,
plasma SOD activity increased, total antioxidant
status increased, and BP fell ( P b .001). In a
follow-up dose-response study, Newaz et al398
administered a-tocopherol to SHRs in doses of
17, 34, or 170 mg/kg. Nitric oxide synthase
increased significantly ( P b .01) only at the
34 mg/kg dose and BP fell the most also at the
same dose ( P b .001).
Other animal studies have shown beneficial
results of a-tocopherol on hypertension and
stroke in SHRs,399 membrane fluidity and BP in
SHRs and Wistar-Kyoto rats,400 and prostacyclin
production, serum lipids, and BP using a mixture
of a-tocopherol and tocotrienols.401
Human studies of vitamin E in doses of 400 to
1000 IU/d, although limited, have shown bene-
ficial effects on improving insulin sensitivity,402
lowering serum glucose,402 inhibiting TxA2,379
increasing serum glutathione levels,402 increas-
ing intracellular Mg,402 improving arterial com-
pliance (z37% to 44%) (independent of arterial
pressure),405 reducing ED and vascular resis-
tance,405,406 and decreasing oxLDL.406 However,
reductions in BP in hypertensive subjects have
been inconsistent, limited to small numbers of
subjects, or it has been difficult to interpret the
results for a variety of reasons.402,403,407
Barbagallo et al402 evaluated 24 hypertensive
subjects who received vitamin E 600 IU/d for
4 weeks in a double-blind, randomized, placebo-
controlled study. The BP in both treatment and
placebo groups was decreased significantly
( P b .001 for SBP and P b .005 for DBP), but
both groups received furosemide 25 mg/d. The
effects of vitamin E on BP cannot be interpreted in
this study.
Palumbo et al403 administered 300 IU of
vitamin E per day to 142 treated hypertensive
subjects in a randomized, open-labeled trial for
12 weeks. Clinic and 24-hour ABM showed no
change in SBP and a small decrease in 24-hour
ABM, DBP of 1.6 mm Hg (95% CI, 2.8-0.4 mm
Hg; P = .06). However, the mean BP at entry was
147/88 mm Hg in the vitamin E group, indicat-
ing reasonably good BP control. The day and
night changes in mean ABM were not significant.
The antihypertensive treatment clearly restricted
NUTRACEUTICALS AND HYPERTENSION
Fig 6. Vitamin E: mechanism in hypertension and vascular disease.65,402-407
the possibility of actually measuring a BP-
lowering effect of vitamin E.
Iino et al407 performed a double-blind, place-
bo-controlled study on the effects of dl-
a-tocopherol nicotinate in 94 hypertensive
subjects with cerebral atherosclerosis. Subjects
received 3000 mg of the study vitamin for 4 to
6 weeks. In subjects with hypertension, the SBP
declined from 151.0 F 22.1 to 139.2 F 16.8 mm
Hg ( P b .05), but DBP did not change.
If vitamin E has an antihypertensive effect, it is
probably small and may be limited to untreated
hypertensive patients or those with known vas-
cular disease or other concomitant problems such
as diabetes or hyperlipidemia.405-407 However,
vitamin E does improve ED through numerous
mechanisms that could ameliorate vascular health
and reduce vascular damage and TOD that is
either BP-dependent or BP-independent65,404
(Fig 6). Hypertensive patients, compared with
normotensive patients, have significantly lower
plasma and cell content of vitamins E and C with
increased lipid peroxidation.65
Vitamin D
Epidemiological, clinical, and experimental
investigations all demonstrate a relationship
between the plasma levels of 1 1 25 (OH) 2
D3 (1,25-dihydroxycholecalciferol), the active
form of vitamin D and BP,408-414 including
vitamin D–mediated reduction in BP in hyper-
419
tensive 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, metabolism, and excretion have
been shown.408
It has been difficult to dissociate the effects of
Ca from vitamin D on BP in human beings.
Numerous studies have verified the finding of an
inverse relationship between dietary Ca intake
and BP.415 This relationship applies to all ages,
sex, and racial and socioeconomic groups.408
A low serum ionized Ca level is particularly
common in salt-sensitive, low-renin, hyperten-
sive patients who have an increased intracellular
Ca concentration in platelets, lymphocytes, and
renal proximal tubular cells.408,415-417
Vitamin D may have an independent and
direct role in the regulation of BP408-10 and
insulin metabolism.409,410 A study of 34 middle-
aged men demonstrated that serum levels of
1125 (OH2) D3 were inversely correlated with
BP ( P b .02), very LDL triglycerides ( P b .005)
,and triglyceride removal after intravenous fat
tolerance test ( P b .05).409 Serum levels of
25 (OH)2 D3 were correlated with fasting insulin
( P b .05), insulin sensitivity during clamp ( P b
.001), and lipoprotein lipase activity in adipose
tissue ( P b .005) and skeletal muscle ( P b
.03).409 Holdaway et al418 found no difference
in 25 (OH)2 D3 levels in a group of hypertensive
vs normotensive subjects. The Tromso Study
420
analyzed Ca and vitamin intake in 7542 men
and 8053 women and found a significant linear
decrease in SBP and DBP with increasing die-
tary Ca intake in both sexes ( P b .05); how-
ever, vitamin D intake had no significant effect
on BP.419
In the deoxycorticosterone acetate salt model
of hypertension, dietary manipulation of vitamin
D has been shown to reduce BP without a change
in Ca levels, indicating a direct effect on BP
regulation.408,420,421 Vascular tissue contains a
receptor or receptors for both the Ca-regulating
hormones, PTH and 1125 (OH)2 D3.421 MacCar-
thy et al422 demonstrated that 1125 (OH)2 D3
antagonizes the mitogenic effect of epidermal
growth factor on proliferation of VSMCs.
Lind et al,411,412 in double-blind, placebo-
controlled studies, found that BP was lowered
with vitamin D during long-term treatment of
patients with intermittent hypercalcemia. In
another study, Lind et al413 demonstrated that
total and ionized Ca levels were increased, but
DBP was significantly decreased, and the hypo-
tensive effect of vitamin D was inversely related
to the pretreatment serum levels of 1125 (OH)2
D3 and additive to antihypertensive medications.
Pfeifer et al414 showed that short-term supple-
mentation with vitamin D3 and Ca is more
effective in reducing SBP than Ca alone. In a
group of 148 women with low 25 (OH)2 D3
levels, the administration of 1200 mg Ca plus 800
IU of vitamin D3 reduced SBP 9.3% more ( P b .02)
compared with 1200 mg of Ca alone. The HR fell
5.4% ( P = .02), but DBP was not changed.414
Vitamin B6 (Pyridoxine)
Low serum vitamin B6 levels are associated with
hypertension in rats 188,423-427 and human
beings.423,428-434 Vitamin B6 is a readily metabo-
lized and excreted water-soluble vitamin.435 Six
different B 6 vitamins exist, but pyridoxal
5Vphosphate (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.435,436 Numerous PLP-dependent enzymes
that are involved in metabolic pathways that
include carbohydrate metabolism, sphingolipid
biosynthesis and degradation, amino acid metab-
olism, heme biosynthesis, and hormone and
MARK C. HOUSTON
neurotransmitter biosynthesis such as steroid
hormones, thyroid hormone, c amino butyric
acid (GABA), histamine, NE, and serotonin
exist.434,435 The participation of vitamin B6 in
neurotransmitter and hormone biosynthesis and
amino acid reactions with kynureninase, cysta-
thionine synthetase, cystathionase, and mem-
brane L-type Ca channels may account for much
of its antihypertensive effects.435,436 Vitamin B6
(PLP) is involved in the transsulfuration pathway
of homocysteine metabolism to cysteine.435
Animal studies in specific rat strains have
demonstrated an increase in BP, NE, and epi-
nephrine plasma levels, an increase in the NE
cardiac turnover, and a reduction in central
nervous system brain-stem NE, GABA, and
serotonin content that completely reverses after
vitamin B6 repletion.407 Pyridoxine at 10 mg/kg in
B6-deficient hypertensive (B6DHT) rats reduced
BP from 143 to 119 mm Hg within 24 hours
( P b .05).407 In these B6DHT rats, PLP enhanced
binding of CCBs to the vascular membrane,
indicating that PLP corrects membrane abnor-
malities and is an endogenous modulator of
dihydropyridine (DHP)-sensitive Ca chan-
nels.425,437 Low Ca and B6 levels potentiate BP
increases in rats, whereas replacement of both will
reduce BP.188 Vitamin B6 plus tryptophan re-
duced BP more than monotherapy with each in
rats, probably related to effects on brain-stem
serotonin and kynurenine.424 There is a structural
similarity of the B6 vitamins to the DHP-CCBs,
and CCBs are most effective in B6DHT rats.423
Supplemental vitamin B6 in the diet of
prehypertensive, obese, and sucrose-induced
hypertensive Zucker rats and SHRs reduces BP
by increasing the synthesis of cysteine from
methionine.438-440 Cysteine acts directly on
aldehydes and neutralizes their effects. Alde-
hydes bind sulfhydryl groups of membrane
proteins and alter Ca channels (L-type), which
increase cytosolic free Ca, cause vascular
smooth muscle constriction, and elevate BP.440
Aldehydes also induce hyperglycemia and pro-
mote insulin resistance.440 Cysteine is also a
precursor of glutathione, which neutralizes
aldehydes and further improves BP and glucose
metabolism.440 Thus, vitamin B6 both reduces
movement of Ca into cells (cytosolic Ca2+) and
decreases intracellular sarcoplasmic reticulum
release of Ca.
NUTRACEUTICALS AND HYPERTENSION
One human study by Aybak et al434 proved
that high-dose vitamin B6 significantly lowered
BP. This study compared 9 normotensive men
and women with 20 hypertensive subjects, all of
whom had significantly higher BP, plasma NE,
and HR compared with control normotensive
subjects. Subjects received 5 mg/(kgd d) of
vitamin B6 for 4 weeks. The SBP fell from
167 F 13 to 153 F 15 mm Hg, an 8.4%
reduction ( P b .01), and the DBP fell from
108 F 8.2 to 98 F 8.8 mm Hg, a 9.3% reduction
( P b .005). Plasma NE was reduced from 1.80 F
.21 to 1.48 F .32 nmol/L (18% reduction;
P b .005); plasma epinephrine fell from 330 F
64 to 276 F 67 pmol/L (16% reduction; P b .05).
There was no significant change in HR.
The proposed mechanisms of hypertension in
vitamin B6–deficient animals and human beings
include the following435,436:
1. Central nervous system, brain stem, depletion
of neurotransmitters such as NE, serotonin,
and GABA, which leads to an increase in
sympathetic outflow.
2. Increased peripheral SNS activity.
3. Increased VSMC Ca uptake and increased
intracellular Ca release.
4. Increased end-organ responsiveness to
glucocorticoids and mineralocorticoids
(aldosterone).
5. Increased aldehyde levels.
6. Insulin resistance.
In summary, vitamin B6 has multiple antihy-
pertensive effects that resemble those of central a
agonists (ie, clonidine), CCBs (ie, DHP-CCB
such as amlodipine), and diuretics. Finally,
changes in insulin sensitivity and carbohydrate
metabolism may lower BP in selected hyperten-
sive individuals with the metabolic syndrome of
insulin resistance. Chronic intake of vitamin B6
at 200 mg/d is safe and has no adverse effects.
Even doses up to 500 mg/d are probably safe.435
Flavonoids
More than 4000 naturally occurring flavonoids
have been identified in such diverse substances
as fruits, vegetables, red wine, tea, soy, and
licorice.379,441-446 Flavonoids (flavonols, fla-
vones, and isoflavones) are potent free radical
421
scavengers that inhibit lipid peroxidation, pre-
vent atherosclerosis, promote vascular relaxa-
tion, and have antihypertensive properties.379,441
In addition, they reduce stroke446 and provide
cardioprotective effects that reduce CHD mor-
bidity and mortality446 in the Zutphen Elderly
Study,447 Finnish Study,448 and US Health Pro-
fessionals Study.449
Various flavonoids have undergone extensive
scientific studies that demonstrate a wide variety
of protective cardiovascular effects. Soy, which
contains diadzein and genistein, lowers total
cholesterol, LDL-C, and BP, and reduces coro-
nary and generalized thrombosis.220,379,442 Red
wine contains quercetin, which reduces oxida-
tion of LDL (oxLDL) and decreases platelet
aggregation.379,441 Blueberries (vaccinium myr-
tillus) are rich in antioxidants, reduce oxidized
LDL, and are more potent than vitamin C on a
molar basis as an antioxidant.379,443 Licorice root
(glycyrrhiza glabra) is a potent antioxidant, anti-
inflammatory, antiplatelet, and antiviral, but it
may lower K, increase Na retention, and elevate
BP caused by a mineralocorticoid action when
used in high doses.379,444,445
Very few studies have been done in hyperten-
sive human beings to determine the effects of
flavonoids on BP. Hodgson et al450 studied
59 subjects with high normal SBP (SBP,
z125 mm Hg; range, 125-138 mm Hg) in a
randomized, double-blind, placebo-controlled
2-way parallel design for 8 weeks. The treatment
group received one capsule daily containing
55 mg of isoflavonoids from a soy product with
30 mg genistein, 16 mg biochann A, 1 mg
daidzein, and 8 mg formononetin. The clinic
and 24-hour ABM showed no significant change
in BP. This study has many limitations; it was not
a true hypertensive population, so effects on BP
would be minimal at best. It was limited to a soy
product extract with a limited number and
combinations of isoflavonoids and the dose
administered may have been too small.
Genistein and diadzein inhibit TK activity,
which decreases vascular smooth muscle con-
traction, lowers BP, and inhibits oxidation
activity in the blood vessel.220,450 However,
Hodgson et al451 were unable to demonstrate
any reduction in urinary F-2 isoprotanes in
human subjects with high normal BP given a
55 mg daily isoflavanoid supplement for 8 weeks.
422
Urinary F-2 isoprostanes are the best available
marker for in vivo lipid peroxidation.
Asgary et al452 evaluated the flavonoid rich
plant Achillea wilelmssi in a group of 120
hypertensive and hypercholesterolemic men
and women for 6 months. Significant reductions
in TC, LDL, and TG, increased HDL, as well as
significant reductions in SBP and DBP were
found ( P b .05).
Dietary flavonoids may reduce CVAs,446,453
CHD, and MI446 independent of any effect on BP.
Additional studies are needed to determine the
type and amount of dietary flavonoids required
to produce significant effects on BP.
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 Engel-
hard456 evaluated 30 subjects with grade I hyper-
tension, aged 40 to 65 years, taking no
antihypertensive or antilipid medication treated
with a tomato lycopene extract for 8 weeks.
The SBP was reduced from 144 to 135 mm Hg
(9 mm Hg reduction; P b .01) and DBP fell from
91 to 84 mm Hg (7 mm Hg reduction; P b .01). A
similar study of 35 subjects with grade
I hypertension showed similar results on SBP
but not on DBP.455 Serum lipids were significantly
improved in both studies without any change in
serum homocysteine.
Coenzyme Q-10 (Ubiquinone)
Coenzyme Q-10 is a potent lipid-phase antiox-
idant, 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 myo-
cardium from ischemic reperfusion inju-
ry.14,258,361,379,457-465 Coenzyme Q-10 improves
MARK C. HOUSTON
mitochondrial energy production, enhancing
myocardial infusion with improved diastolic
function, left ventricle function, left ventricle
wall tension, and New York Heart Association
(NYHA) class for CHF.258,361
Serum levels of Co-Q-10 decrease with age
and are lower in patients with diseases charac-
terized by oxidative stress such as hypertension,
CHD, hyperlipidemia, DM, and atherosclero-
sis, those who are involved in aerobic training,
patients on total parenteral nutrition, those with
hyperthyroidism, and patients who take statin
drugs.361,457,462 Enzymatic assays showed a
deficiency of Co-Q-10 in 39% of 59 patients
with essential hypertension vs only 6% deficien-
cy in control subjects ( P b .01).460 There is a
high correlation of Co-Q-10 deficiency and
hypertension. Most food contain minimal Co-
Q-10, which is primarily found in meat and
seafood. Supplements are needed to maintain
normal serum levels in many of these disease
states and in some patients taking statin drugs
for hyperlipidemia.361
Numerous animal studies in SHRs, unineph-
rectomized rats treated with saline or deoxycor-
tisone, and dogs with experimentally induced
hypertension have demonstrated significant
reductions in BP after oral administration of
Co-Q-10 at doses of 60 mg/d or higher.466-469
Human studies have also demonstrated signif-
icant and consistent reductions in BP in hyper-
tensive subjects after oral administration of 100
to 225 mg/d of Co-Q-10.258,393,457,459,460,464
Digiesi et al457 studied 26 hypertensive subjects
with an average BP of 164.5/98.1 mm Hg given
Co-Q-10 50 mg oral BID for 10 weeks. The SBP
fell from 164.5 to 146.7 mm Hg, an 11%
reduction ( P b .001). The DBP was reduced
from 98.1 to 86.1 mm Hg, a 12% reduction
( P b .001). The Co-Q-10 serum levels increased
by 0.97 lg/mL ( P b .02), which was highly
correlated with the BP reduction. In addition, the
24-hour ABM showed significant reductions in
SBP and DBP of 18 and 10 mm Hg, respectively
( P b .001). The TC fell 10 mg% ( P b .005), HDL
rose 2 mg% ( P b .01), and SVR fell 29% ( P b
.02). There was no significant change in PRA,
serum K+, serum Na+, urinary K+ or Na+, or urine
aldosterone. Finally, the serum endothelin level,
electrocardiogram, and echocardiogram were
not significantly different.
NUTRACEUTICALS AND HYPERTENSION
Langsjoen et al258 treated 109 hypertensive
subjects taking antihypertensive medications
with 225 mg/d of Co-Q-10 for 4 months and
demonstrated significant reductions in mean SBP
from 159 to 147 mm Hg (a reduction of
12 mm Hg; P b .001) and mean DBP from 94
to 85 mm Hg (a reduction of 9 mm Hg; P b 001).
Serum Co-Q-10 levels were adjusted to an
average of 3.02 lg/mL, but all subjects had
levels therapeutic at greater than 2.0 lg/mL. The
Co-Q-10 dose varied from 75 to 360 mg/d. There
was improvement in diastolic left ventricle
function, left ventricle wall tension, LVH, and
NYHA class ( P b .001), thought to be mediated
secondary to a neurohormonal response with
reduction in serum catecholamines and a fall in
BP. In addition, improved bioenergetics were
noted with improved adrenal function and
vascular endothelial function.470 About 51% of
subjects were able to discontinue between 1 and
3 antihypertensive drugs (37% stopped 1 drug,
11% stopped 2 drugs, 4% stopped 3 drugs) at an
average of 4.4 months after starting Co-Q-10.
No side effects were noted. The reduction in
drug use by category was 16.7% decrease in
digitalis, 40% decrease in diuretics, 59% decrease
in b-blockers, 27.5% decrease in CCBs, 31.7%
decrease in ACEIs, and 35% decrease in other
antihypertensive drugs.258
Yamagami et al471 observed a Co-Q-10 defi-
ciency in 29 subjects with essential hypertension
and found significant improvement in their BP
and correction of the Co-Q-10 deficiency after
oral intake of 1 to 2 mg/(kgd d) of Co-Q-10.
Tsuyusaki et al 472 found that Co-Q-10 at
30 mg/d, when added to a b-blocker, reduced
the negative inotropic effect and lowered BP.
Richardson et al473 demonstrated a significant
reduction in SBP and DBP in 16 subjects with
essential hypertension on 60 mg/d of Co-Q-10
treatment for 12 weeks as well as normalization
of their cardiac output. Hamada et al474 did not
see a significant change in BP in 12 hypertensive
subjects treated with Co-Q-10 at 60 mg/d for
4 weeks, but the negative inotropic effect of a
b-blocker was reduced and the malaise and
fatigue in the patients improved. Yamagami
et al470 showed a significant decrease in SBP
in 20 essential hypertensive subjects with low
Co-Q-10 levels (b0.9 lg/mL) who were random-
ized to receive either placebo or Co-Q-10 at
423
100 mg/d for 12 weeks. The BP decreased signi-
ficantly in the Co-Q-10 group between 8 and 12
weeks. Montaldo et al475 studied 15 hypertensive
subjects treated with 100 mg/d of Co-Q-10 for 12
weeks and noted a significant reduction in BP at
rest and exercise as well as a significant
improvement in myocardial stroke work index.
Digiesi464 in 1992 evaluated 10 subjects with
essential hypertension treated with oral Co-Q-10
50 mg BID for 10 weeks. The SBP fell from
161.5 F 5.1 to 142.2 F 5.3 mm Hg ( P b .001)
and the DBP fell from 98.5 F 1.7 to 83.1 F
2.0 mm Hg ( P b .001). Plasma Co-Q-10 levels
increased from 0.69 F 0.1 to 1.95 F 0.3 lg/mL
( P b .02). In addition, TC decreased from 227 F
24 to 203.7 F 20.6 mg% ( P b .01) and serum
HDL-C increased from 42 F 3.0 to 45.9 F
3.0 mg% ( P b .01). The PRA, urine K+, Na+,
and aldosterone did not change. The SVR de-
creased significantly and correlated directly with
BP reduction.
Digiesi et al460 in 1990 evaluated 18 subjects
with essential hypertension off all antihyperten-
sive drugs treated with Co-Q-10 100 mg PO per
day for 10 weeks vs placebo and then crossed
over to the opposite study group after a 2-week
treatment suspension. Compared with the pla-
cebo subjects, there was a significant reduction
in SBP from 166 F 2.6 to 156 F 2.25 mm Hg and
DBP from 102.9 F 1.2 to 95.2 F 1.04 mm Hg,
both significant at P b .001. The placebo group
had no significant reduction in BP. The antihy-
pertensive effect of Co-Q-10 was observed
during the third and fourth week of treatment,
remained constant for the entire duration of
treatment, and ceased 7 to 10 days after the end
of drug treatment. No adverse effects were noted.
Recently, Singh et al459 evaluated 30 treated
hypertensive subjects with CHD treated with Co-
Q-10 60 mg BID for 8 weeks vs a vitamin
B complex. The Co-Q-10–treated subjects had a
reduction in SBP from 168 F 9.6 to 152 F
8.2 mm Hg (16 mm Hg reduction; P b .05) and
a DBP reduction from 106 F 4.6 to 97 F
4.1 mm Hg (9 mm Hg reduction; P b .05). In
addition, the HR fell from 112 F 7.8 to 85 F
4.8 per minute ( P b .05). Fasting and 2-hour
insulin fell 45% and 35%, respectively ( P b .05),
as fasting glucose decreased 33% ( P b .05).
Serum TG fell 10% and HDL-C increased
significantly ( P b .05), lipid peroxides decreased
424
( P b .05), MDA fell ( P b .05), and olene
conjugates were reduced ( P b .05). Serum
vitamins A, C, and E and b-carotene levels
increased. The only changes in the B-vitamin
complex group were increases in vitamin C and
b-carotene ( P b .05).
Burke et al465 conducted a 12-week, random-
ized, double-blind, placebo-controlled trial with
60 mg of oral Co-Q-10 in 76 subjects with
isolated systolic hypertension. The mean reduc-
tion in SBP in the treated group was 17.8 F
7.3 mm Hg ( P b .01), but DBP did not change.
Only 55% of the subjects were responders
achieving a reduction in SBP z 4 mm Hg, but
in this group, the SBP fell 25.9 F 6.4 mm Hg.
There was a trend between SBP reduction and
increase in Co-Q-10 levels. Adverse effects were
virtually nonexistent.
The mechanisms of action of Co-Q-10 pre-
sumably include a reduction in SVR, decreased
degradation of membrane phospholipids, de-
creased membrane phospholipase A2 activity,
membrane-stabilizing activity, decreased cate-
cholamine and aldosterone levels, improved
insulin sensitivity, decreased oxLDL, antioxidant
effects on endothelium and vascular smooth
muscle with increased NO, decreased VSM
hypertrophy, vasodilation, decreased ED, and
improved mitochondrial energy production with
less vascular ischemia.258,459,460,464
In summary, Co-Q-10 has consistent and
significant antihypertensive effects in patients
with essential hypertension. The major conclu-
sions from in vitro, animal, and human clinical
trials indicate the following:
1. Compared with normotensive patients, essen-
tial hypertensive patients have a high inci-
dence of Co-Q-10 deficiency documented by
serum levels.
2. Doses of 120 to 225 mg/d of Co-Q-10,
depending on the delivery method and
concomitant ingestion with a fatty meal, are
necessary to achieve a therapeutic level of
greater than 2 Ag/mL. This dose is usually 1 to
2 mg/(kgd d) of Co-Q-10. Use of a special
delivery system allows better absorption and
lower oral doses.
3. Patients with the lowest Co-Q-10 serum
levels may have the best antihypertensive
response to supplementation.
MARK C. HOUSTON
4. The average reduction in BP is about
15/10 mm Hg based on reported studies.
5. The antihypertensive effect takes time to
reach its peak level, usually at about 4 weeks,
then BP remains stable. The antihypertensive
effect is gone within 2 weeks after discontin-
uation of Co-Q-10.
6. Approximately 50% of patients taking anti-
hypertensive drugs may be able to stop
between 1 and 3 agents. Both total dose and
frequency of administration may be reduced.
7. Even high doses of Co-Q-10 have no acute or
chronic adverse effects.
Other favorable effects on cardiovascular risk
factors include improvement in the serum lipid
profile and carbohydrate metabolism with re-
duced glucose and improved insulin sensitivity,
reduced oxidative stress, reduced HR, improved
myocardial left ventricle function and oxygen
delivery, and decreased catecholamine levels.
A-Lipoic acid
a-Lipoic acid is a potent and unique thiol
compound-antioxidant that is both water and
lipid soluble.238 a-Lipoic acid helps to recircu-
late tissue and blood levels of vitamins and
antioxidants in both lipid and water compart-
ments 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 a-lipoic acid on the vasculature
and BP.238,476,478 Vasdev et al476 administered
500 mg/(kgd d) in their feed, which was equiv-
alent to 26 mg/kg body weight of a-lipoic acid, to
SHRs for 9 weeks. There was a significant
decrease in SBP ( P b .001) as well as a reduction
in cytosolic and platelet Ca, glucose, insulin
levels, and tissue aldehyde conjugates in the
liver, kidney, and aorta. Most importantly, there
was evidence of structural improvement in the
vasculature with reduced vascular damage, hy-
pertensive vascular smooth muscle hypertrophy,
and atherosclerotic changes. The reduction in
SBP in the a-lipoic acid–treated SHRs was from
a mean of 180 to 140 mm Hg ( P b .001);
whereas the untreated SHRs had an increase in
SBP from a baseline of 180 to 195 mm Hg over
the 9-week study period. The decrease in BP was
gradual and did not show a further decrease after
5 weeks of a-lipoic acid treatment.
NUTRACEUTICALS AND HYPERTENSION
Fig 7. A-Lipoic acid. Mechanism:
vascular biology.476-489
The vasculature of the kidneys in the untreat-
ed SHRs showed hyperplasia of the smooth
muscle, thickening and narrowing of the lumina
of the small arteries and arterioles, vacuoles, and
PAS-positive material in the walls of the arteries.
On the other hand, the a-lipoic acid–treated SHR
kidneys had minimal smooth muscle cell hyper-
plasia, minimal thickening of the wall, and no
narrowing of the lumina in the small arteries and
arterioles. Thus, a-lipoic acid attenuated renal
vascular hyperplasia in SHRs. In this study of
SHRs, a-lipoic acid reduced BP and biochemical
and histologic changes. The dose that would be
425
required for an average 70-kg human patient
would be about 2000 mg/d of a-lipoic acid.
However, it should be emphasized that no dose-
response study in human hypertension has been
done to date.
The mechanisms by which a-lipoic acidreduces
BP and promotes improvement in vascular func-
tion and structure are numerous.476,477,479-489 It is
known that endogenous aldehydes bind sulfhy-
dryl groups (SH) in membrane proteins that
alter membrane Ca channels (especially L-type Ca
channels), which increase cytosolic free Ca,
increase vascular tone, SVR, and BP.476 Thiol
compounds such as a-lipoic acid and N-acetyl
cysteine (NAC) bind these endogenous alde-
hydes, normalize the membrane Ca channels,
and decrease cytosolic free Ca. In addition, a-
lipoic acid raises levels of glutathione and
cysteine, which in turn binds aldehydes, increas-
ing their excretion. It also increases antioxidant
vitamin levels of ascorbic acid and vitamin E,
which improves endothelial function. a-Lipoic
acid acts like a CCB through these indirect
mechanisms (Figs 7 and 8). A detailed summary
of the mechanism of action of a-lipoic acid is
shown in Table 16. Glutathione, which supplies
90% of nonprotein thiols in the body, is depleted
in SHR and human hypertension; thus, a-lipoic
acid, by increasing levels significantly, reducing
aldehydes, and closing L-type Ca channels in

ALA
Blocks
Oxidative Stress Glucose Metabolism AGE’s
Block
ALA Block ↓
Vitamin C
↓
DHLA ↓ Vitamin E
Binds ALDEHYDES ↓ Cysteine
NAC Glutathione
Block Bind
excretion Vit
Binds
B-6
Decrease production L-Type Ca++ Channel Insulin
Increase excretion Sulfhydryl Groups Resistance

Cytosolic Ca++ Methionine

Reduces
← ←

ALA = Alpha Lipoic acid NO

DHLA = Dihydrolipoic acid ↓ ED
Vascular Tone ALA Linoleic Acid
NAC = N-Acetyl Cysteine
←

ED = Endothelial dysfunction NF-KB

ET1 = Endothelin Blood Pressure
TF = Tissue Factor
VCAM-1 = Vascular Cell ↓ ET1
Adhesion Molecule-1
↓ TF
↓ VCAM-1

Fig 8. A-Lipoic acid. Mechanism: Aldehydes, oxidative stress, Ca2+ channels.476-489

426
Table 16. A-Lipoic Acid: Mechanism
of Action476-489
1. Increases levels of glutathione, cysteine, and vitamins
C and E.
2. Binds endogenous aldehydes, reduces production, and
increases excretion.
3. Normalizes membrane calcium channels by providing
sulfhydryl groups (SH), which reduce cytosolic free
calcium, SVR, vascular tone, and BP. Di-hydrolipoic
acid is the redox partner of a-lipoic acid.
4. Improves insulin sensitivity and glucose metabolism
and reduces advanced glycosylation and products
(AGEs) and thus aldehydes.
5. Increases NO levels and stability and duration of action
via increased nitrosothiols such as S-nitrosocysteine
and S-nitroglutathione that carry NO.
6. Reduces cytokine-induced generation of NO (iNOS).
7. Inhibits release and translocation of NF-KB from
cytoplasm into nucleus of cell, which decreases
controlled gene transcription and regulation of
endothelin-I, tissue factor, vascular cell adhesion
molecule-1 (VCAM-1).
8. Improves ED through beneficial effects on NO, AGEs,
vitamins C and E, glutathione, cysteine, endothelin,
tissue factor, VCAM-1, and linoleic and myristic acid.
9. Reduces monocyte binding to endothelium (VCAM-1).
10. Increases LA and reduces myristic acid.
cell membranes, may reduce vascular tone, SVR,
and BP.476-489
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 produc-
tion and increasing excretion to nontoxic com-
pounds.490-494 N-Acetyl cysteine also increases
interleukin 1-B–induced nitrite production by
increasing NOS-messenger RNA transcription
and protein expression, elevating NO levels,
and reducing SVR and BP. These antihyperten-
sive effects of NAC have been shown in SHRs,
but no human hypertensive studies have been
published to date. Similar to ALA, NAC
improves the L-type Ca channel in cell mem-
branes, which decreases cytosolic Ca, SVR, and
BP through aldehyde binding.491-494
N-Acetyl cysteine in doses of 600 mg/d
improved capillary blood flow velocity in smok-
ers through its antioxidant effect by improving
glutathione levels, reducing ROS, increasing NO,
decreasing peroxynitrate, and improving ED.495
Furthermore, NAC lowers homocysteine496-499
MARK C. HOUSTON
and lipoprotein (a)496 and potentiates nitroglyc-
erin-mediated vasodilation500 and reversal of
platelet aggregation.501 All these effects may
benefit the vascular system and impact BP.
N-Acetyl cysteine, like ALA, Mg, vitamin B6,
vitamin C, and possibly vitamin E, has natural
Ca channel blocking activity (Table 17).
Cabassi et al502 have recently shown that NAC
treatment in SHRs improves SBP, HR, aortic
endothelial function, peroxynitrite-induced im-
pairment of endothelial-independent relaxation,
aortic oxidized/reduced glutathione balance, MDA
content, and 3-nitrotyrosine. N-Acetyl cysteine
may have both an antihypertensive and protective
effect against aortic vascular dysfunction.502
L-Arginine
l-Arginine is the primary precursor for the
production of NO,503,504 which has numerous
cardiovascular effects393,504 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, hyper-
lipidemia, and atherosclerosis have elevated
serum levels of asymmetric dimethyl arginine,
which activates NO.393,506 Administration of
l-arginine in human beings at doses of 10 g/d
will increase coronary artery blood flow, reduce
angina, and improve peripheral blood flow and
peripheral vascular disease symptoms.393,507-509
Hypertension induced by sodium chloride
loading in Dahl sensitive rats, 5 1 0 - 5 1 2 in
adrenocorticotrophin-induced hypertension in
Sprague-Dawley rats, 513 and in SHRs can be
prevented and partially reversed by chronic
and acute dietary l-arginine supplementation.
Table 17. Nutrients and Nutraceuticals with
CCB Activity
1. a-Lipoic acid
2. Magnesium (Mg2+)
3. Vitamin B6 (pyridoxine)
4. Vitamin C
5. Vitamin E possibly (zcytosolic Mg2+ with ACa2+)
6. NAC
7. Hawthorne
8. Celery
9. x-3 FAs (EPA + DHA)
10. Calcium
11. Garlic
NUTRACEUTICALS AND HYPERTENSION
l-Arginine reduced BP, SVR, LV mass, and
collagen content, improved coronary hemody-
namics, and restored plasma Nox (nitrite/nitrate)
and citrulline concentrations.513,514
Human studies in hypertensive and normo-
tensive subjects of parenteral and oral ad-
ministrations of l-arginine demonstrate an
antihypertensive effect.505,515-517 The intrave-
nous administration of large doses of l-arginine
acutely reduces BP in normotensive and in salt-
sensitive hypertensive individuals515-517 but not
in cortisol-induced hypertensive human beings.
Siani et al505 evaluated 6 healthy518 normotensive
volunteers in a single-blinded, controlled study
using 3 different isocaloric diets with equal Na
content in each (180 mmol/d) administered in a
crossover design in random sequence, each for a
1 week period. Diet 1 was the control diet
containing 3.5 to 4 g of l-arginine per day. Diet
2 contained natural arginine–enriched food at 10 g
of l-arginine per day. Diet 3 consisted of diet
1 plus an l-arginine supplement of 10 g/d. It
should be noted that the average arginine intake
per day is 5.4 g/100 g of protein, which is found
especially in lentils, hazelnuts, walnuts, and
peanuts.505 The BP decreased significantly in
both diets 2 and 3. In diet 2, the BP fall was
6.2/5.0 mm Hg ( P b .03 for SBP and P b .002 for
DBP). In diet 3, the BP fell 6.2/6.8 mm Hg ( P b .01
for SBP and P b .006 for DBP). In addition, in diet
3, creatinine clearance increased ( P b .07),
glomerular filtration rate increased ( P b .07),
and fasting glucose fell ( P b .008). The reduction
in TC and TG with increased HDL in diet 2 was
thought to be secondary to the natural high
fiber intake.
l-Arginine is not normally the rate-limiting
step in NO synthesis.519 Alternative mechanisms
may exist whereby l-arginine lowers BP through
direct effects of the amino acid on the vasculature
or endothelium, as well as release of hormones,
vasodilating prostaglandins, improved renal NO,
or endothelial NO bioavailability.505
l-Arginine produces a statistically and biolog-
ically significant decrease in BP and improved
metabolic effect in normotensive and hyperten-
sive human beings that is similar in magnitude to
that seen in the DASH-I diet.104,505 This reduc-
tion in BP was seen whether l-arginine was
provided through natural food or as a pharma-
cological supplement when given at approxi-
427
mately a 2-fold dietary increase (doses of
10 g/d)505. Although these doses of l-arginine
appear to be safe, no long-term studies in human
beings have been published at this time.
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 im-
prove 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 about 160 to
900 mg/d of a standardized extract of Hawthorne
have been used to achieve these cardiovascular
effects, which appear to be safe.520,521 Hawthorne
contains oligomeric procyanidins, flavonoids,
hyperoside, quercetin, vitexin, and vitexin rham-
noside, which may also have b-blocking,
Ca-channel–blocking, and diuretic effects.520
The hypolipidemic effects are caused by
b-sitosterol, catechin, chromium, fiber, LA, Mg,
pectin, and ruin, all of which may also reduce BP
as well.520
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 hyper-
tension,525 ischemic heart disease,393,524,526 acute
MI, 393,524 CHF, 393,524,527-529 arrhythmias and
peripheral vascular disease with claudica-
tion,393,523,524,530-532 and dyslipidemia.393,524
Human studies on the effects of l-carnitine are
small and limited.525 Digiesi et al525 compared
3 groups of subjects with essential hypertension.
Group A-1, with 14 subjects, received anti-
hypertensive drugs (ACEI and/or CCB) and
l-carnitine 2 g/d. Group A-2, with 14 subjects,
received only antihypertensive drugs (ACEI or
CCB). Group B, with 9 subjects, was treated with
l-carnitine only at 2 g/d. Groups A-1 and B
subjects received oral l-carnitine, 2 g/d for
428
22 and 10 weeks, respectively. Group A-1
subjects had reductions in extrasystoles, im-
proved electrocardiograms (signs of minor
changes of ventricular repolarization), less as-
thenic symptoms (decrease by 90% vs only a
10% decrease in control subjects), and lower TG
levels ( P b .025), but there was no change in
total cholesterol or HDL-C. The group B subjects
had improvement in left ventricular ejection
fraction from 57.89% to 64.33% ( P b .001),
reduced TC ( P b .02), and increased HDL-C
( P b .05) with no change in TG. The BP
decreased from an SBP of 155 F 4.86 to
150.89 F 5.39 mm Hg (NS) and DBP fell from
97.22 F 1.88 to 94.78 F 2.90 mm Hg (NS).
Carnitine may be useful in the treatment of
essential hypertension, type II DM with hyper-
tension, hyperlipidemia, cardiac arrhythmias,
CHF, and cardiac ischemic syndromes.525,533-540
Cherchi et al533 administered l-carnitine 1 g
PO twice daily to 38 patients with hypertensive or
ischemic heart disease and CHF in a 45-day
placebo-controlled study. Both groups had sig-
nificant improvements compared with baseline
with subjective and objective parameters such as
reductions in HR ( P b .01), SBP ( P b .01), DBP
( P b .05), edema ( P b .01), dyspnea ( P b .01),
daily digitalis consumption ( P b .01), and weight
( P b .01). All patients had a significant diuresis
( P b .01), improved angina, less arrhythmias,
ventricular extrasystoles, echocardiographic
changes, and moved to a lower NYHA category.
However, only the lipid changes and digitalis use
were significantly different between groups
although the carnitine-treated patients trended
toward more improvement in all parameters.
This may have been caused by the limited size
of the trial population. The TC and TG were
significantly reduced only in the carnitine-treated
patients ( P b .05 for TC and P b .001 for TG).
Taurine
Taurine is a sulfonic b-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 myocar-
dium.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
MARK C. HOUSTON
been used to treat hypertension,543 hypercholes-
terolemia, arrhythmias, atherosclerosis, CHF,
and other cardiovascular conditions.541,542,544,545
Animal studies with taurine have shown con-
sistent and significant reductions in BP.546-556
Taurine inhibited the alcohol-induced hyperten-
sion in SHRs by reducing acetylaldehyde and
changing membrane cation handling.546 In the
SHR-high Na model, taurine reduced protein-
uria, lowered BP 20% to 25%,552 and reduced
LVH, urinary epinephrine, and dopamine.547,556
The DOCA-salt rat model had BP reduction
because of decreased SNS activity centrally548,550
caused by an opiate-mediated vasodepressor
response.551,554 Taurine increases renal kallikre-
in555 and has an antiatherosclerotic effect.553
Human studies have noted that essential hy-
pertensive subjects have reduced urinary taurine
as well as other sulfur amino acids.557,558 Taurine
lowers BP543-545,556,559,560 and HR,545 decreases
arrhythmias,545 CHF symptoms,545 and SNS
activity,543,545 increases urinary Na,559,561 and
decreases PRA, aldosterone,561 plasma NE,560 and
plasma and urinary epinephrine.543,562 This di-
uretic effect is seen in normal subjects as well as in
hypertensive and cirrhotics with ascites.559-562 In
doses of 6 g/d for 3 weeks in 22 healthy
normotensive male volunteers, taurine reduced
SNS activity, urinary epinephrine, TC, and LDL
but increased TG, whereas BP and body mass
index did not change significantly.562 Another
study of 31 Japanese men with essential hyper-
tension undergoing an exercise program for
10 weeks showed a 26% increase in taurine levels
and a 287% increase in cysteine levels. The BP
reduction of 14.8/6.6 mm Hg was proportional
to both taurine level elevations and plasma
NE reduction.560 Fujita et al543 reduced BP
9/4.1 mm Hg ( P b .05) in 19 hypertension
subjects given 6 g of taurine for 7 days.
The mechanisms by which taurine exerts its
cardiovascular and antihypertensive effects in-
clude diuresis542,561 and urinary Na loss,561 vaso-
dilation,542 increased atrial natriuretic factor,542
reduced homocysteine,541 improved glucose and
insulin sensitivity,557 increased Na space,549
reduced SNS activity and opiate-mediated vaso-
depressor response,551,554 increased renal kalli-
krein,555 reduced PRA and aldosterone,561 and a
glycine-mediated central nervous system
response with both decreases in BP and HR.563
NUTRACEUTICALS AND HYPERTENSION 429
Concomitant use of enalapril with taurine Table 18. Natural Antihypertensive Compounds
provides additive reductions in BP, LVH, arrhyth- Categorized By Antihypertensive Class
mias,564,565 and platelet aggregation.565 The rec-
ommended dose of taurine is 2 to 3 g/d, at which Diuretics
1. Hawthorne berry 8. Mg2+
no adverse effects are noted, but higher doses may 2. Vitamin B6 (pyridoxine) 9. Ca2+
be needed to reduce BP significantly.543 3. Taurine 10. Protein
4. Celery 11. Fiber
5. GLA 12. Co-Q-10
Celery 6. Vitamin C (ascorbic acid) 13. l-Carnitine
7. K+
Animal studies have demonstrated a significant
b-Blockers
reduction in BP using a component of celery oil, 1. Hawthorne berry
3-N-butyl phthalide.566-568 There was a dose-
response relationship in SBP with a 24 mm Hg fall Central a Agonists (reduce SNS activity)
1. Taurine 7. Vitamin C
(14%; P b .05) in the Sprague-Dawley hyperten- 2. K+ 8. Vitamin B6
sive rat model.568 Significant decreases in plasma 3. Zn 9. Co-Q-10
NE, epinephrine, and dopamine were also highly 4. Na+ restriction 10. Celery
5. Protein 11. GLA/DGLA
dose dependent. Celery, celery extract, and celery 6. Fiber 12. Garlic
oil contain apigenin (which relaxes vascular
smooth muscle), CCB-like substances, and com- Direct vasodilators
1. x-3 FAs 9. Flavonoids
ponents that inhibit tyrosine hydroxylase, which 2. MUFAs (x-9 FAs) 10. Vitamin C
reduces plasma catecholamine levels, and lowers 3. K+ 11. Vitamin E
SVR and BP.567,568 Consuming 4 stalks of celery 4. Mg2+ 12. Co-Q-10
5. Ca2+ 13. l-Arginine
per day, 8 tsp of celery juice 3 times daily, or its 6. Soy 14. Taurine
equivalent in extract form of celery seed (1000 mg 7. Fiber 15. Celery
twice a day) or oil (1/2 to 1 tsp 3 times daily in 8. Garlic 16. ALA
tincture form) seems to provide a similar antihy-
CCBs
pertensive effect in human essential hyper- 1. a-Lipoic acid 7. Hawthorne berry
tension. 520,568-570 In a Chinese study of 2. Vitamin C (ascorbic acid) 8. Celery
16 hypertensive subjects, 14 had significant 3. Vitamin B6 (pyridoxine) 9. x-3 FAs (EPA
4. Magnesium (Mg2+) and DHA)
reductions in BP.568-570 Celery also has diuretic 5. NAC 10. Calcium
effects that may Redfouce BP.568-570 In addition, 6. Vitamin E 11. Garlic
celery has been used to treat CHF, fluid retention,
ACEIs
anxiety, insomnia, gout, and diabetes.568-570 1. Garlic 11. Geletin
2. Seaweed-various 12. Sake
(Wakame, etc) 13. EFAs (x-3 FAs)
Pycnogenol 3. Tuna protein/muscle 14. Chicken egg yolks
4. Sardine protein/muscle 15. Zein
Pycnogenol, a bark extract from the French 5. Hawthorne berry 16. Dried salted fish
maritime pine, at doses of 200 mg/d resulted 6. Bonito fish (dried) 17. Fish sauce
7. Pycnogenol 18. Zn
in a significant reduction in SBP from 139.9 8. Casein 19. Hydrolyzed wheat
to 132.7 mm Hg ( P b .05) in 11 patients with 9. Hydrolyzed whey protein germ isolate
mild hypertension over 8 weeks. Diastolic BP 10. Sour milk
fell from 93.8 to 92.0 mm Hg (NS). Serum ARBs
thromboxane concentrations were significantly 1. Potassium (K+)
reduced ( P b .05).571 2. Fiber
3. Garlic
4. Vitamin C
5. Vitamin B6 (pyridoxine)
Natural Antihypertensive Compounds 6. Co-Q-10
Categorized by Antihypertensive Class 7. Celery
8. GLA and DGLA
As has been discussed previously, many of the
natural compounds in food, certain nutraceutical
supplements, vitamins, antioxidants, and miner-
430
als 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 combina-
tion with other nutrients and nutraceuticals, the
antihypertensive effect is magnified. In addition,
many of these nutrients and nutraceuticals have
varied, additive, or synergistic mechanisms of
action in lowering BP. Table 18 summarizes
these natural compounds into the major antihy-
pertensive drug classes such as diuretics,
b-blockers, central a agonists, CCB, ACEI, and
angiotensin-receptor blockers.
Summary and Conclusions
1. Vascular biology (ED and vascular smooth
muscle dysfunction) plays a primary role in
the initiation and perpetuation of hyperten-
sion, CVD, and TOD.
2. Nutrient-gene interactions are a predomi-
nant factor in promoting beneficial or de-
trimental effects in cardiovascular health
and hypertension.
3. Nutrition (natural whole food, nutraceuti-
cals) can prevent, control, and treat hyper-
tension through numerous vascular biology
mechanisms.
4. Oxidative stress seems to initiate and propa-
gate hypertension and cardiovascular disease.
5. Antioxidants may prevent and treat hypertension.
6. Whole food and phytonutrient concentrates of
fruits, vegetables, and fiber with natural combi-
nations of balanced phytochemicals, nutrients,
antioxidants, vitamins, minerals, and appro-
priate macronutrients and micronutrients are
generally superior to single-component or
isolated artificial or single-component natural
substances for the prevention and treatment
of hypertension and CVD.
! However, there is a role for the selected use
of single and component nutraceuticals,
vitamins, antioxidants, and minerals in the
treatment of hypertension based on scien-
tifically controlled studies as a complement
to optimal nutritional, dietary intake from
food and other lifestyle modifications.
! Exercise, weight reduction, smoking cessa-
tion, alcohol and caffeine restriction, as well
MARK C. HOUSTON
as other changes in lifestyle must be
incorporated.
7. Specific mechanisms of action of nutrition
and nutraceuticals include:
! ACEI activity: garlic, seaweed, tuna, sar-
dine, dry salted fish, zein, fish sauce,
chicken, egg yolks, hydrolyzed whey pro-
tein, Hawthorne, sour milk, gelatin, sake,
bonito, pycnogenol, casein, N-3 FAs, Zn,
wheat germ hydrolysate.
! CCB activity: ALA, vitamin C, vitamin B6,
Mg2+, NAC, vitamin E, Hawthorne, celery,
N-3 FAs, Ca2+, garlic.
! Angiotensin-receptor blocker activity: K+,
fiber, garlic, vitamin C, vitamin B6, Co-Q-
10, celery, GLA and DGLA.
! Diuretic: Hawthorne, vitamin B6, taurine,
celery, GLA, vitamin C, K+, Mg2+, Ca2+,
protein, fiber.
! h-blockers: Hawthorne.
! NO increased: l-arginine, N-3 PUFAs, gar-
lic, vitamin C, vitamin E, ALA, NAC, Mg2+,
K+, MUFAs, Co-Q-10.
! Reduced activity or sensitivity to angioten-
sin-II and NE: K+, fiber, garlic, vitamin C,
vitamin B6, Co-Q-10, taurine, celery, GLA
and DGLA, Zn, protein, Na2+ restriction.
! Gene expression NF-KB: Zn, vitamin E, ALA.
! Advanced glycosylation end products and
receptor-advanced glycosylation end prod-
ucts: N-3 PUFAs, fiber.
! PPAR a ligand: N-3 PUFAs.
! Sterol response element–binding protein-1:
N-3 PUFAs.
! Antioxidants: neutralize ROS; O2:
numerous other effects.
! Insulin sensitivity: fiber, N-3 PUFAs,
vitamin C, vitamin E, vitamin D, vitamin
B6, Co-Q-10, ALA, taurine, K+, Mg2+, Zn,
l-arginine, l-carnitine.
! Increased PGI2, PGE1, PGE3: vitamin C,
niacin, Zn, N-3 FAs, vitamin E, selenium,
Ca2+, Mg2+, GLA and DGLA (N-6 FAs),
l-arginine.
! PKC inhibition: vitamin E.
! Increased cytosolic Mg2+: vitamin E.
! TK inhibition: SO4, flavonoids, genistein,
diadzein.
! zPRA, Aaldo: taurine, GLA, DGLA, vitamin
B6, Co-Q-10.
NUTRACEUTICALS AND HYPERTENSION 431
! Atrial natriuretic factor: taurine. g. No TFAs (0%) (hydrogenated
! Improved arterial compliance: Na+ restric- margarines, vegetable oils)
tion, K+, Mg2+, soy, garlic, vitamin E, ALA. h. Nuts: almonds, walnuts,
! Reduced vascular smooth muscle hypertro- hazelnuts, etc
phy: Na+ restriction, K+, vitamin E, 10. Carbohydrates (40%
Co-Q-10, ALA. total calories)
! Microalbuminuria reduction: Na+ a. Reduce or eliminate refined
restriction. sugars and simple
! Modulates baroreceptor sensitivity: K+. carbohydrates
! Direct vasodilation: K+, Mg2+, Ca2+, fiber, b. Increase complex
garlic, vitamin C, flavonoids, Co-Q-10, carbohydrates and fiber whole
ALA, l-arginine, taurine, celery, MUFAs, grains (oat, barley, wheat),
soy, N-3 FAs, vitamin E. vegetables, beans, legumes
oatmeal or 60 g
Recommendations oatbran (dry) or 40 g
b-glucan or 3g
psyllium 7g
Nutrition Daily Intake
1. DASH I, DASH II-Na+, – Any one of these
and PREMIER diets 11. Garlic 4 cloves/4 g
2. Na restriction 50-100 mmol 12. Mushrooms (shiitake 1-2 servings
3. K 100 mEq and maitake)
4. K/Na ratio N5:1 13. Guava fruit 500-1000 mg
5. Mg 1000 mg 14. Wakame seaweed (dried) 3.0-3.5 g
6. Ca 1000 mg 15. Celery
7. Zn 25-30 mg Celery stalks or 4 stalks
8. Protein: total intake 1.0-1.8 g/kg Celery juice or 8 tsp thrice
(30% total calories) daily
a. Nonanimal sources preferred Celery seed extract or 1000 mg BID
but lean or wild animal protein Celery oil (tincture) O-1 tsp thrice
in moderation is acceptable daily
b. Hydrolyzed whey protein 30 g Any one of these
c. Soy protein (fermented is 30 g 16. Lycopene 10 mg
best) Tomatoes and tomato products,
d. Hydrolyzed wheat germ 2-4 g guava, watermelon, apricots,
isolate pink grapefruit, papaya
e. Sardine muscle concentrate 3 mg Exercise
extract Aerobically 7 d/wk
f. Cold-water fish, fowl poultry 60 min daily
9. Fats: 30% total calories 4200 kJ/wk
a. x-3 FAs PUFAs (DHA, EPA, 2-3 g Resistance training 3x/wk to daily
cold-water fish) Weight Loss
b. x-6 FAs PUFAs (canola oil, 1g To ideal body weight
nuts) Lose 1-2 lb/wk
c. x-9 FAs MUFAs (extra virgin 4 tbsp or 5-10 Body mass index b25
olive oil) (olives) olives Waist circumference
d. Saturated FAs (lean, b1 0 % t o t a l b35 in in women
wild animal meat) (30%) calories b40 inches in men
e. P/S fat ratio N2.0 Total body fat
f. x-3/x-6 PUFAs b16% in men
(ratio 1:1-1:2) b22% in women
432 MARK C. HOUSTON

Increase lean muscle mass ment of High Blood Pressure (JNC-7). JAMA 289:
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