Role of antioxidants in hypertension

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REVIEW ARTICLE JIACM 2011; 12(2): 122-7
Role of Antioxidants in Hypertension
Mujahid Beg*, Vibhor Sharma**, Nishat Akhtar***, Ankush Gupta***, Jasim Mohd.***
Introduction
Hypertension (HT) is a major health problem worldwide.
Individuals with hypertension are at an increased risk for
stroke, heart disease, and kidney failure. Although the
aetiology of essential hypertension has a genetic
component, lifestyle factors such as diet play an important
role. Excess of sugar and salt or deficiencies of antioxidant
vitamins in diet play a vital role in the aetiology of
hypertension.
The relationship between hypertension, oxidative stress
and antioxidants is complex and inadequately
understood. Oxidative stress may play a role in the
pathophysiology of hypertension. Human and animal
studies have demonstrated that HT is accompanied by
increase in oxidative stress. However, the evidence for this
in humans is not definitive1.
Studies demonstrate that hypertension may develop as a
result of increased reactive oxygen species2-8 and that a
variety of antioxidant therapies ameliorate hypertension.
Hypertensive effects of oxidative stress are mostly due to
endothelial dysfunction resulting from disturbances of
vasodilator systems, particularly degradation of nitric
oxide (NO) by oxygen-free radicals9-11.
By altering the balance in the endothelium between
vasoconstrictors such as thromboxane and isoprostanes
and vasodilators such as nitric oxide, reactive oxygen
species contribute to endothelium-dependent
vasoconstriction and increased vascular resistance.
Oxidative stress raises blood pressure by promoting
functional nitric oxide deficiency (through NO inactivation
and tetrahydrobiopterin depletion) and by augmenting
arachidonic acid oxidation and formation of
vasoconstrictive prostaglandin F2α.
Reactive oxygen species (ROS) producing enzymes
involved in increased oxidative stress within vascular
* Professor, Department of Medicine, ** Associate Professor, Department of Obstetrics and Gynaecology,
*** Junior Resident, Department of Medicine, JN Medical College, AMU, Aligarh, Uttar Pradesh.
tissue include NADPH oxidase, xanthine oxidase, and
mitochondrial superoxide producing enzymes.
Superoxide produced by the NADPH oxidase may react
with NO, thereby stimulating the production of the NO/
superoxide reaction product peroxynitrite. Peroxynitrite
in turn has been shown to uncouple eNOS, therefore
switching an anti-atherosclerotic NO producing enzyme
to an enzyme that can accelerate atherosclerosis by
producing superoxide. Increased oxidative stress in the
vasculature is not restricted to the endothelium and also
occurs within the smooth muscle cell layer.
Increased peripheral vascular resistance is an important
contributor to the pathogenesis of hypertension. Elevated
total peripheral vascular resistance is ascribed to
dysregulation of vasomotor function and structural
remodelling of blood vessels.
Many studies have suggested that the intracellular calcium
concentration, which regulates vasomotor function, is
controlled by free radicals and redox signalling, including
NAD(P)H and glutathione (GSH) redox. Key targets that
control intracellular calcium concentration such as ion
channels, Ca2+ release from internal stores and uptake by
the sarcoplasmic reticulum, are regulated by changes in
intracellular redox and oxidants. Reactive oxygen species
increase vascular tone by influencing the regulatory role
of endothelium and by direct effects on the contractility
of vascular smooth muscle. ROS contribute to vascular
remodelling by influencing phenotype modulation of
vascular smooth muscle cells, aberrant growth and death
of vascular cells, cell migration, and extracellular matrix
(ECM) reorganisation. Thus, there are diverse roles of the
vascular redox system in hypertension. The thioredoxin
(TRX) system is active in the vessel wall and functions as
an important endogenous antioxidant. This system
consists of TRX, TRX reductase, and NAD(P)H, and is able
to reduce reactive oxygen species through interactions
with the redox-active centre of TRX. Among the TRX

superfamily is peroxiredoxin (PRX), a family of non-haeme
peroxidases that catalyses the reduction of
hydroperoxides into water and alcohol. Recent evidence
implicates TRX in cardiovascular disease associated with
oxidative stress, such as hypertension. Thioredoxin activity
is influenced by many mechanisms, including
transcription, protein-protein interaction, and post-
translational modification. Regulation of TRX in
hypertensive models seems to be related to oxidative
stress. In addition, oxidative stress in the kidney may be
involved in the pathogenesis of salt retention and
hypertension. Antioxidants can restore endothelial
function and decrease blood pressure as reported in some
studies on hypertension.
Hypertension, on the other hand, may lead to tissue
damage through lipid peroxidation and other oxidative
mechanisms12. In vivo oxidation of low-density
lipoproteins by oxygen-free radicals may increase
hypertension-related atherogenesis, and antioxidants may
be beneficial in this regard. Studies concerning
associations between serum levels of antioxidants and
hypertension have been inconsistent.
Hypertension impairs myocardial microvascular function
and integrity. It is associated with impaired coronary
endothelial function and can impair myocardial perfusion.
One of the mechanisms that might be responsible for HT-
induced myocardial dysfunction is an increase in oxidative
stress. HT has been shown to impair the function of both
the vascular endothelium13-14 and smooth muscle layers.
Increases in arterial blood pressure induce proliferation
of vascular smooth muscle cells and change their
phenotype and conductance of calcium15. The vascular
endothelium functions as a barrier, maintains
homoeostasis, and has anticoagulant and anti-
inflammatory properties. HT is associated with alterations
in mean arterial pressure (MAP), which might reflect
impaired function of the endothelium. It is possible that
antioxidant vitamins might improve some of the
deleterious effects of oxidative stress (e.g., endothelial
function, lipid peroxidation, tissue injury)16, but might not
succeed in reversing the deleterious effect of HT on other
aspects (e.g., vascular remodelling, vascular smooth
muscle cell function, or nervous system activity). In several
studies, antioxidant intervention did reduce blood
pressures in HT17-18. Differences in the effect of antioxidants
on blood pressure may be attributed to different doses,
routes of administration, or timing and type of antioxidant
intervention19-21. Blockade of oxidative stress might have
significant implications in atherosclerosis.
Review of literature
The Dietary Approaches to Stop Hypertension (DASH)
studies showed that diet rich in fruits, vegetables, low fat
dairy products, whole grains, nuts, and deficient in salt and
sugar helps to reduce blood pressure. Supplementation
with antioxidants, including vitamin C, E, or B6, thiols such
as lipoic acid and cysteine, and the quinone enzyme Q10,
have been shown to lower blood pressure in animal
models and humans with essential hypertension. These
antioxidants may achieve their antihypertensive effects
by reducing aldehyde conjugate/AGE formation and
oxidative stress by improving insulin-resistance and
endothelial function, or by normalising calcium channels
and peripheral vascular resistance.
Asplund22 concluded that there was no evidence of an
association between blood pressure (BP) and intakes of
either carotene or Vitamin E. A study by Chen et al23
reported significant associations between hypertension
and serum levels of Vitamins A and E and β-carotene, after
controlling for factors like age, sex, ethnicity, education,
body mass index, alcohol consumption, history of
diabetes, dietary intakes of sodium, potassium, saturated
fat and total energy intake. β-carotene, uric acid, MDA and
homocysteine were significantly associated with
hypertensive status.
Two intervention studies have examined the effect of β-
carotene, in combination with Vitamins C and E, in the
treatment of hypertension, with a beneficial effect on
systolic BP in one, but no effect in the other. The effect of
β-carotene on BP warrants further studies. Uric acid is
widely distributed in the body in relatively high
concentrations and is an efficient scavenger of hydroxyl
radicals, superoxides and singlet oxygen species, and can
chelate transition metals. It contributes up to 60% of the
total antioxidant capacity (TAC) in healthy subjects. Uric
acid levels are frequently elevated in hypertensive
patients. While uric acid is protective because of its
antioxidant properties, it may also be harmful as it may
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have a pathogenic role in hypertension and cardiovascular
disease. In animal models, uric acid has been
demonstrated to stimulate afferent arteriolopathy and
tuberointerstitial disease, leading to hypertension. It also
causes endothelial dysfunction, vascular smooth muscle
proliferation, and impaired nitric oxide production24,
thereby contributing to cardiovascular and renal vascular
disease. Given this complexity of relationship of uric acid
and hypertension, the overall effect of slightly raised uric
acid levels in hypertensive subjects is difficult to decide.
Malondialdehyde is a reliable marker of lipid peroxidation
and perioxidative tissue injury25. It has been shown to be
elevated in animal models of experimentally induced
hypertension, suggesting that it is a consequence rather
than a cause of hypertension. This suggests that active
lipid peroxidation is occurring in essential hypertension,
and this may be related to the development of
atherosclerosis.
In a study by Parslow et al26, decreased plasma level of β-
carotene and elevated level of uric acid was associated
with hypertension. Hypertension was also associated with
higher levels of malondialdehyde. The study by Parslow
et al found no significant association between plasma
levels of Vitamins A and E and hypertension status in
comparison to the findings reported by Chen et al, in
which these measures were strongly associated with
hypertension. The hypertensive state is frequently
associated with elevation of uric acid, as reported by
Parslow et al. Hypertension is associated with decrease in
renal blood flow, which leads to greater reabsorption of
urate. Another mechanism of increased urate may be
through microvascular disease and local tissue ischaemia
produced by hypertension. The study by Parslow et al
showed that hypertension was associated with lower
levels of plasma β-carotene and higher levels of uric acid
but not with levels of plasma Vitamins A and E or total
antioxidant capacity.
These findings are consistent with previous reports of
increased oxidative stress in hypertension, but the direction
of causality cannot be deduced from this study. Whether it
is cause or consequence, reducing oxidative stress is likely
to be beneficial. Longitudinal studies are necessary to
decide causality. The benefits of antioxidants in
hypertension should be examined in well-designed studies.
In a study by Bello Klein et al27, rats were made
hypertensive by the administration of the nitric oxide
synthase inhibitor nitro-L-arginine (LNA). Hearts from
these animals were analysed for lipid peroxidation (LPO),
ψ-glutamylcysteine-synthetase (ψ-GCS), glutathione
disulfide reductase (GR), glutathione peroxidase (GSHPx),
catalase (CAT), superoxide dismutase (SOD), and total
radical trapping potential ( TRAP) activities. LNA treatment
significantly increased the mean arterial blood pressure,
heart rate, LPO and SOD activity. Significant reduction was
found in levels of ψ-GCS, GR, nonselenium GSHPx, catalase
and TRAP. These data suggest that LNA-induced
hypertension is associated with increased myocardial
oxidative stress.
A study was conducted by Niu Tian et al28 to test the
hypothesis that oxidative stress in Dahl salt-sensitive (SS)
rats on a high-sodium intake contributes to the
progression of renal damage, decrease in renal
haemodynamics, and development of hypertension. It
was studied whether antioxidant therapy using vitamins
C and E could help prevent renal damage and reductions
in GFR and renal plasma flow and attenuate the increase
in blood pressure in salt-sensitive rats. The study showed
that in rats with high-sodium diet, vitamin C and E
treatment significantly decreased renal cortical and
medullary O2
– release, mean arterial pressure, urinary
protein excretion, glomerular necrosis, and renal
tubulointerstitial damage. GFR and renal plasma flow
significantly increased in the high-sodium plus vitamins
C and E group compared with the high-sodium diet group
alone. This suggests that increases in reactive oxygen
species are associated with decreases in renal
haemodynamics in salt-sensitive hypertension. For many
years, it has been believed that renal damage in
hypertension is directly caused by exposure of the kidney
to high pressure. However, in the study by Niu Tian et al,
data indicate that the improvement in renal dysfunction
in the high-sodium plus vitamin group could have been
caused by either a decrease in arterial pressure or a
reduction in free radicals in the kidney, or a combination
of the two effects. The decrease in arterial pressure in rats
on high-sodium and vitamins intake was ~ 20 mm Hg
compared with the high-sodium rats. Thus, the mean
arterial pressure of the vitamin-treated rats remained
elevated at 160 mm Hg. However, the renal cortical and

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medullary O2
– release significantly decreased in the high-
sodium plus vitamins C and E group. Because the decrease
in arterial pressure was only moderate in the rats treated
with vitamins and high-sodium diet, it is possible that the
reduction in O2
– release played an important role in the
improvement in renal dysfunction and damage. As
recommended by the American Institute of Nutrition, the
daily amount of vitamin E in humans is 30 IU/d or 0.43 IU/
kg per day. In a study in hypercholesterolaemic patients
by Roberts et al29, a significant decrease in plasma
isoprostane was seen only when vitamin E intake was
increased 25- to 100-fold over the recommended daily
amount. Several clinical trials have been performed to
determine if vitamin treatment can improve
cardiovascular disease. Although variable results have
been found, some studies have shown that treatment of
hypertensive patients with vitamin C lowers blood
pressure30. Most clinical studies on vitamin E used doses
400 IU/d, and no reduction in cardiovascular risk has been
noted; however, when 800 IU/d of vitamin E was used31, 32,
significant decrease in cardiovascular risk occurred. A
second reason why vitamin E was ineffective in some
clinical studies is that vitamin E can become a free radical
in the body, but vitamin C can convert the pro-oxidant
vitamin E radical back to vitamin E.
In a study by Martin Rodriguez-Porcel et al33, pigs were
studied after 12 weeks of renovascular hypertension
without or with daily supplementation of antioxidants
(100 IU/kg vitamin E and 1 g vitamin C), and compared
with normal controls. Myocardial perfusion and
microvascular permeability were measured by electron
beam computed tomography before and after two cardiac
challenges (intravenous adenosine and dobutamine). The
regimen of vitamin C and E preserved endogenous
scavenger enzyme activity, decreasing the abundance of
superoxide anion. The impaired myocardial perfusion
response to adenosine observed in hypertensives was
preserved in rats who received antioxidants. Antioxidant
intervention had little effect on the hypertension-induced
myocardial vascular dysfunction observed in response to
dobutamine. The greater improvement in the responses
to adenosine than to dobutamine challenge in vitamin-
treated HT might at least in part be related to their
different mechanisms of action. This study demonstrates
that the impaired myocardial perfusion and permeability
in early hypertension are significantly improved by long-
term antioxidant intervention. These results support the
involvement of oxidative stress in myocardial vascular
dysfunction in hypertension.
Tubulointerstitial infiltration of lymphocytes and
macrophages is associated with the generation of reactive
oxygen species (ROS) in experimental models of
hypertension. A study by Bernardo Rodriguez-Iturbe et
al34 demonstrated that an antioxidant-enriched diet that
included vitamin E, vitamin C, selenium, and zinc reduces
the renal interstitial inflammation, decreases renal tissue
content of malondialdehyde and improves hypertension.
Reactive oxygen species have been shown to activate
nuclear factor-B, which can in turn promote transcription
of genes encoding proinflammatory cytokines. This
phenomenon can potentially explain the prevention of
the inflammatory infiltration of the kidney in the
antioxidant-treated group. These findings point to
interrelation between oxidative stress and inflammatory
reactivity in the pathogenesis of hypertension. The
presence of oxidative stress and its role in elevation of
arterial pressure has been shown in various other forms
of hypertension including that seen with lead exposure35,
chronic renal insufficiency36, salt sensitivity37, angiotensin
infusion38, pre-eclampsia39, renal artery stenosis40, and
coarctation of the aorta41. Earlier studies have
documented the beneficial effects of vitamin E and
vitamin C in ameliorating hypertension in hypertensive
animals and improving endothelial function in
hypertensive humans. In addition, selenium (the critical
constituent of the antioxidant enzyme glutathione
peroxidase) has been shown to retard progression of renal
disease in diabetic and nondiabetic animals. Finally, zinc
is an important component of cytoplasmic (Cu-Zn SOD)
and extracellular superoxide dismutase, which serves as
the frontline of defense against reactive oxygen species.
Zinc deficiency has been shown to aggravate
hypertension. This explains how amelioration of oxidative
stress with antioxidant therapy improves hypertension.
A study was done by Czernichow et al42, to assess the
effects of supplementation of a combination of
antioxidant vitamins and trace elements, upon the 6.5-
year risk of developing hypertension. Despite an inverse
association between baseline plasma levels of β-carotene

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in men and the risk of developing hypertension, this study
did not demonstrate any beneficial effect of low-dose
antioxidant supplementation upon the risk of developing
hypertension.
A study was performed by Subhash et al43 in south Indian
population to investigate the total antioxidant status (TAS)
and the extent of oxidative DNA damage in lymphocytes
and their relation with essential hypertension. DNA
damage was significantly increased in hypertensive
patients as compared with the control group. There was a
significant decrease in plasma TAS value in essential
hypertensive groups as compared to normotensive
controls. The major increase in lymphocyte DNA damage
was observed in newly diagnosed hypertensive patients
compared with hypertensive patients who were already
on drug therapy. Decreased TAS levels, which reflect
increased oxidative stress, may be the reason of increased
total lymphocyte DNA damage in this study.
A study done by de la Sierra et al44 to assess the correlation
between endothelial dysfunction and the serum levels of
biomarkers of oxidative stress in essential hypertension
showed reduced serum levels of selenium, vitamin C,
erythrocyte glutathione peroxidase in patients compared
to controls. In this study, treatment-naive essential
hypertensives showed a relationship between the
endothelial dysfunction on one hand and serum markers
of inflammation, remodelling, and antioxidants on the
other.
The mechanism underlying blood pressure reduction in
the high fruits and vegetables arm of the Dietary
Approaches to Stop Hypertension (DASH) study is
unknown but may include potassium, magnesium and
fibre. A study was done by Al-Solaiman et al45 to study the
effects of minerals and fibre separately from other
components of DASH on BP in individuals with metabolic
syndrome and pre-hypertension to stage 1 hypertension
(obese hypertensives). This study showed that DASH is
more effective than potassium, magnesium and fibre
supplements for lowering BP in obese hypertensives,
which suggests that high intake of fruits and vegetables
in DASH lowers BP and improves endothelial function by
nutritional factors in addition to potassium, magnesium,
and fibre. Salt induces oxidative stress in salt-sensitive
animals and human beings. It is not clear whether in salt-
sensitive subjects the Low-Sodium Dietary Approaches
to Stop Hypertension (LS-DASH) reduce oxidative stress
more than DASH. A study was done by Al Solaiman et al46
to assess the effects of DASH and LS-DASH on oxidative
stress. This study showed that in salt-sensitive but not salt-
resistant subjects, LS-DASH is associated with lower values
of systolic blood pressure, urine F2-isoprostanes (a marker
of oxidative stress) and aortic augmentation index (a
measure of vascular stiffness). The results suggest that LS-
DASH decreases oxidative stress, improves vascular
function and lowers blood pressure in salt-sensitive but
not salt-resistant volunteers.
Conclusion
Oxidative stress plays an important role in the
pathogenesis of hypertension. A number of sources of
reactive oxygen species have been identified like NADPH
oxidase, endothelial NO synthase, and xanthine oxidase.
Targeted overexpression of antioxidant systems and
interference with expression of oxidant systems has been
successfully used in animal models of hypertension. It is
expected that these strategies will eventually be
translated to human disease. At present, nontoxic
measures like antioxidant vitamins are the only available
treatments for oxidative stress in humans.
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