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Nutrition and hypertension

Article in Nutrition Research February 2002

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 Nutrition Research 22 (2002) 111123
www.elsevier.com/locate/nutres

Nutrition and hypertension

Sudesh Vasdeva,*, Linda Longericha, Pawan Singalb
a
Faculty of Medicine, Health Science Centre, Room H4310, Memorial University of Newfoundland,
St. Johns, New Foundland, A1B 3V6, Canada
b
Institute of Cardiovascular Sciences, University of Manitoba, Faculty of Medicine, Winnipeg, Manitoba, Canada

Received 15 October 2001; accepted 15 October 2001

Abstract
Nutritional supplementation with anti-oxidant vitamins such as Vitamin C and E or with B vitamins
such as Vitamin B6, can lower blood pressure in persons with essential hypertension. These nutritional
supplements may act to prevent one of the underlying causes of essential hypertension, elevated tissue
aldehydes. In essential hypertension, excess endogenous aldehydes bind sulfhydryl groups of mem-
brane proteins, altering membrane Ca2 channels and increasing cytosolic free calcium and blood
pressure. Abnormalities in carbohydrate metabolism may underlie the etiology of the clinical course
of hypertension. Insulin resistance and glucose intolerance is a common feature of hypertension in
human and in animal models. Elevated endogenous aldehydes in hypertension may be due to increased
production of reactive aldehydes such as methylglyoxal, when the glycolytic pathway of glucose
metabolism is impaired. In hypertension there is increased oxidative stress which can lead to a further
increase in reactive aldehydes. The thiol compound, N-acetylcysteine, normalizes elevated blood
pressure by binding excess endogenous aldehydes and normalizing vascular Ca2 channels and
cytosolic free calcium. Vitamin C, vitamin E, vitamin B6 and lipoic acid are nutrients which can
increase endogenous cysteine and glutathione. Dietary supplementation with these nutrients may
improve carbohydrate metabolism, lower blood pressure and normalize associated biochemical and
histopathological changes. 2002 Elsevier Science Inc. All rights reserved.

Keywords: Hypertension; Dietary Supplements

* Corresponding author. Tel.: (709) 777-7260; fax: (709) 777-7010

Email address: svasdev@mun.ca (S. Vasdev).

0271-5317/02/$ see front matter 2002 Elsevier Science Inc. All rights reserved.
PII: S 0 2 7 1 - 5 3 1 7 ( 0 1 ) 0 0 3 7 0 - 0
112 S. Vasdev et al. / Nutrition Research 22 (2002) 111123

1. Introduction

At present, available antihypertensive drugs normalize blood pressure by various means

without removing the cause, which is not known. As a consequence, in most cases, the
hypertension is treated nonspecifically, resulting in a large number of minor side effects and
poor compliance [1].
Two studies in 1997 and 2001, investigating dietary approaches to stop hypertension
(DASH), demonstrated that a diet rich in fruit and vegetables, low-fat dairy, and high-fiber
grain, with modest portions of lean meat and low in salt, significantly reduces blood pressure
in both hypertensive and normotensive people [2,3]. Fruits and vegetables are major sources
of vitamins and antioxidants, as well as other nutrient factors such as fiber, potassium and
magnesium. Although a varied diet may confer benefits greater than those of any single
nutrient, it would be useful to determine whether a particular nutrient plays a major regulatory
role. In this article, we will discuss the role and possible mechanism of action of some dietary
nutrients including Vitamin B6, Vitamin C, Vitamin E and lipoic acid for controlling insulin
resistance, normalizing blood pressure and preventing renal vascular damage.

2. Insulin resistance and hypertension

There is increasing evidence that glucose intolerance and insulin resistance play a key role
in the pathogenesis of essential hypertension in humans. Abnormalities in glucose utilization
are estimated to exist in 25% of the general population and in up to 80% of subjects with
essential hypertension [4 6]. Insulin resistance is characterized by an inadequate glucose
uptake in peripheral tissues at a given concentration of plasma insulin. It involves impair-
ment of the nonoxidative (glycolytic) pathways of intracellular glucose metabolism [4].
Insulin resistance is also a common feature of spontaneously hypertensive rats (SHR), Dahl
salt-sensitive rats, fructose-induced hypertensive rats and ethanol-induced hypertensive rats
[712]. If glucose metabolism via the glycolytic pathway is impaired, as in insulin resistance,
there will be a build up of glyceraldehyde, glyceraldehyde-3-phosphate and dihydroxyac-
etone phosphate with further metabolism to methylglyoxal, a highly reactive ketoaldehyde
[1315]. Methylglyoxal itself also inhibits the glycolytic pathway [16] which leads to insulin
resistance.

2.1. Role of aldehydes in hypertension

Aldehydes react nonenzymatically with sulfhydryl and amino groups of proteins and
inhibit their function. Protein disulfide bonds and sulfhydryl groups have been shown to be
involved in the functioning of L-type Ca2 channels [17,18]. Excess metabolic aldehydes
can lead to the formation of aldehyde protein conjugates [19,20], altering sulfhydryl (SH)
groups of calcium channels and vascular membrane calcium handling. Disruption of the
vascular calcium channels can raise cytosolic free calcium [Ca2]i levels and lead to
increased peripheral vascular resistance and hypertension [21].
Tissue aldehydes are elevated in spontaneously hypertensive rats, a model of insulin
 S. Vasdev et al. / Nutrition Research 22 (2002) 111123 113

resistance and hypertension [22]. Fructose feeding to rats leads to increased tissue levels of
aldehydes with increased blood pressure [23]. Excess dietary fructose in rats produces
conditions which mirror those of insulin resistance hypertension in humans. WKY rats
treated chronically with a diet containing an aldehyde dehydrogenase inhibitor, disulfiram,
leads to an increase in tissue aldehydes and blood pressure [22]. The reactive aldehydes
methylglyoxal and glyceraldehyde given chronically in diet to WKY rats also leads to
hypertension [21,24]. In all these studies, an increase in endogenous aldehydes was accom-
panied by increased cytosolic free calcium and elevated systolic blood pressure.

3. Oxidative stress in hypertension

An imbalance between the production of reactive oxygen species and the antioxidant
defense mechanism leading to oxidative stress has been suggested to contribute to the
etiology of hypertension and the development of its complications [2528]. In essential
hypertension, reactive oxygen species may act through several mechanisms: [1] a direct
action on endothelial cells, resulting in structural and functional damage, [2] degradation of
the potent vasodilator, nitric acid, [3] effect on eicosanoid metabolism in endothelial cells
and [4] oxidative modification of low-density lipoproteins.
In both hypertensive humans and animals, increased oxidative stress leads to increased
lipid peroxidation [25,29 31]. Peroxidation of unsaturated fatty acids such as linolenic acid
results in the formation of aldehydes such as 4-hydroxypentenal, 4-hydroxyhexenal, 4-hy-
droxynonenal and malonaldehyde [3234]. 4-hydroxynonenal is known to inhibit glyceral-
dehyde-3-phophate dehydrogenase, a key enzyme of the glycolytic pathway [35]. However,
aldehydes formed due to oxidative stress do not appear to be the cause of hypertension.
Antihypertensive drugs with no free radical scavenging activity normalize oxidative stress by
lowering blood pressure, suggesting that oxidative stress is a result of elevated blood
pressure but not the cause [31,36]. Hyperglycemia, hyperinsulinemia, increased mobilization
of fatty acids or increased concentration of catecholamines, abnormalities frequently found
in patients with essential hypertension [37], have been reported to be involved in the overpro-
duction of free radicals [38,39]. Altered glucose metabolism leads to formation of excess
aldehydes causing both hypertension and oxidative stress. Increased oxidative stress produces
more aldehydes and a further increase in blood pressure and end-organ damage (Fig. 1).

4. Cysteine

Under normal physiological conditions, tissue levels of aldehydes are maintained at a low
level. This is accomplished through further catabolism or by binding to soluble sulfhydryl
compounds like cysteine. Cysteine reacts with aldehydes forming a hemimercaptal which is
further converted to a thiazolidine-carboxylic acid, which is excreted in bile and urine [40].
In addition to reacting directly with aldehydes, cysteine is also a precursor of glutathione.
Glutathione (-glutamyl-cysteinyl glycine), a tripeptide, represents 90% of the total non-
protein low molecular weight thiols in the body and is present in all cells [41]. It is a storage
114 S. Vasdev et al. / Nutrition Research 22 (2002) 111123

Fig. 1. Role of aldehydes and oxidative stress in the development of hypertension

form of cysteine and is a cofactor in the enzymatic catabolism of methylglyoxal, an aldehyde

produced when glucose metabolism is altered as a result of insulin resistance [15,42].
Cysteine can not be given orally in the diet as it is rapidly oxidized in the air. N-acetyl-
cysteine (NAC) is a commercially available compound which, when given orally, leads to
increased tissue cysteine levels. Hypertensive SHRs have elevated tissue aldehydes and
cytosolic free Ca2 and display hyperplasia of the smooth muscle cell, thickening of the wall
and narrowing of the lumina of the small arteries and arterioles of the kidney. N-acetylcys-
teine when given in the diet to SHRs, normalizes tissue aldehydes, cytosolic free Ca2 and
adverse renal vascular changes and lowers blood pressure (Fig. 3) to levels similar to those
of normotensive Wistar-kyoto (WKY) rats [22]. In isolated rat heart experiments, NAC
treatment increased myocardial glutathione and protected against ischemia and reperfusion
injury, oxidative stress and maintained improved cardiac function [43]. NAC has been shown
to potentiate the antihypertensive effect of angiotensin converting enzyme inhibitors in
hypertensive patients [44]. Acute intravenous administration of thiopronine, an acetylcys-
teine analogue, lowered blood pressure in essential hypertensive subjects but had no effect
on blood pressure in normotensive subjects [45]. NAC administered to patients undergoing
coronary artery bypass, reduced oxidative stress on reperfusion and led to improved cardiac
 S. Vasdev et al. / Nutrition Research 22 (2002) 111123 115

Fig. 2. Antihypertensive mechanism of dietary nutrients

function [43]. In addition to directly binding aldehydes, NAC may also act as an antioxidant
and prevent oxidative stress and further formation of aldehydes due to lipid peroxidation in
hypertension.

5. Vitamin B6

In addition to a dietary source, cysteine is also synthesized metabolically from dietary

methionine [46,47]. The first step in the endogenous synthesis of cysteine involves the
demethylation of methionine to homocysteine. Homocysteine then combines with serine to
yield cystathionine in a reaction catalyzed by cystathionine -synthase. Finally, cystathi-
onine is converted to cysteine and -ketoglutarate by the enzyme cystathionase. Both
cystathionine -synthase and cystathionase are vitamin B6-requiring enzymes. A diet defi-
cient in vitamin B6, when given chronically to rats, leads to a decreased activity of these two
enzymes in the liver [48,49]. Rats given vitamin B6 deficient diet also had lower plasma
cysteine levels and higher plasma homocysteine levels [47]. Dietary supplementation of
vitamin B6 should stimulate the activity if these enzymes and increase the endogenous
synthesis of cysteine from methionine (Fig. 2). In hypertensive animals and humans,
increased production of cysteine would lead to more efficient excretion of excess metobolic
aldehydes, normalizing vascular calcium channels and lowering blood pressure. Supplemen-
tation of Vitamin B6 in the diet of SHRs has been shown to attenuate hypertension (Fig. 3),
cytosolic Ca2 and adverse renal vascular changes by lowering tissue aldehyde conjugates
116 S. Vasdev et al. / Nutrition Research 22 (2002) 111123

Fig. 3. The line graph shows the effect of vitamin B6, vitamin E, vitamin C, N-acetylcysteine, and lipoic acid
supplemented diet on systolic blood pressure in SHR rats. Starting at twelve weeks of age, animals were divided
into five groups of six animals each. Animals in WKY-control group and SHR-control group were given a normal
diet and SHR-Vit B6 group, a diet supplemented with 20mg of vitamin B6; SHR-Vit E group, a diet supplemented
with 3.4mg of vitamin E; SHR-Vit C group, a diet supplemented with 100mg of vitamin C; SHR-NAC group,
a diet supplemented with 1.5 g of NAC and SHR-Lipoic group, a diet supplemented with 50 mg of lipoic acid
per 100g of diet, for the next nine weeks. All animals were on normal drinking water. Values are the mean of 6 animals
in each group. Standard deviation of mean values (not shown) did not vary more than 6 mmHg in each case.

[50]. Oral supplementation of Vitamin B6 has also been shown to lower blood pressure in
hypertensive patients [51].
The antihypertensive effect of Vitamin B6 may also act by lowering production of
aldehydes through improved glucose metabolism. Vitamin B6 supplementation attenuated
hypertension in sucrose-fed rats and Zucker obese rats and normalized elevated plasma
glucose [52]. Similar improvement in glucose tolerance after Vitamin B6 administration has
been reported in gestational diabetes [53,54]. Prospective studies in humans have suggested
that low intake of Vitamin B6 contributes to risk of myocardial infarction and coronary heart
disease, probably due to elevated plasma homocysteine, and its dietary supplementation
above current recommended allowance may prevent this [55,56].

6. Vitamin C

Ascorbic acid (vitamin C) is needed as a cofactor in various enzymatic reactions including

the conversion of cystine to cysteine [57]. It has been shown to increase insulin stimulated
 S. Vasdev et al. / Nutrition Research 22 (2002) 111123 117

glucose metabolism in healthy subjects and type-2 diabetics [58,59]. Dietary supplementa-
tion of ascorbic acid in mice, rats, guinea pigs and humans leads to increased tissue levels
of glutathione, the stable form of cysteine [59 61]. Glutathione is depleted in the tissues of
SHRs and human hypertensives [62,63]. Studies in humans have shown an inverse relation-
ship of vitamin C blood level with blood pressure [64 66]. Increased dietary intake of
vitamin C is also associated with decreased cardiovascular risk [67 69]. Dietary supple-
mentation of vitamin C in spontaneously hypertensive rats lowers blood pressure (Fig. 3),
cytosolic Ca2, plasma insulin, tissue aldehyde conjugates and prevents adverse renal
vascular changes [70 73]. Vitamin C may act to decrease tissue aldehydes and lower blood
pressure by: [1] increasing tissue levels of glutathione and cysteine, [2] improving insulin
stimulated glucose metabolism, and [3] increasing antioxidant activity (Fig. 2).

7. Vitamin E

Vitamin E (-tocopherol), being lipid soluble, is found within the phospholipid bilayer of
cell membranes where it protects against lipid perioxidation by functioning as an electron
donor to free radicals. It has been recognized as one of the major natural antioxidants [74,75].
Studies have shown vitamin E to have several potentially cardioprotective effects [76 78].
By decreasing lipid peroxidation (a source of active aldehydes), it lowers tissue aldehyde
levels and could play a role in reducing elevated blood pressure caused by excess endoge-
nous aldehydes.
Vitamin E supplementation produces a significant improvement in insulin mediated
glucose utilization in healthy people, type-2 diabetics and essential hypertensives [79 80].
This action of vitamin E may be due to decreased oxidative stress and sparing of tissue
glutathione [81,82]. Glutathione has been shown to increase insulin secretion in patients with
impaired glucose tolerance [83]. It has been well documented that vitamin E levels are lower
in essential hypertensive patients [26,84], as well as spontaneously hypertensive rats com-
pared to normotensive [33,85,86]. Low Vitamin E levels may be a predictor of preeclampsia
in pregnant women [87]. Dietary supplementation with Vitamin E significantly lowers
elevated tissue aldehydes, vascular cytosolic free calcium, and blood pressure in spontane-
ously hypertensive rats (Fig. 3) [88,89].
Evidence for the direct effect of vitamin E on cardiovascular health in humans is more
problematic. The US Nurses Health Study and the US Health Professionals Follow-up
Study found a 34% and 39% reduction, respectively, in the risk of having a cardiac event for
those taking vitamin E supplements. The Iowa Womens Health Study found a 47%
reduction in cardiac mortality [90]. However, randomized control trials have not shown
conclusive evidence for primary prevention of hypertension or cardiovascular disease [91].

8. Lipoic acid

Alpha-lipoic acid is a unique short chain fatty acid with two sulphur atoms which are
converted to sulfhydryl (SH) groups in dihydrolipoic acid (DHL), its reduced form. It is
118 S. Vasdev et al. / Nutrition Research 22 (2002) 111123

metabolically active in both the oxidized and reduced form [9294]. Lipoic acid is both water
and fat soluble, which allows it to function in both fatty and aqueous regions of the body.
Lipoic acid exists endogenously in tissues and functions as a cofactor of key mitochon-
drial enzymes controlling glucose oxidation, such as pyruvate dehydrogenase and the
alpha-ketoglutarate dehydrogenase [95]. In insulin resistance, where tissue aldehydes are
elevated [96], lipoic acid increases insulin stimulated glucose metabolism [97,98]. In one
recent study in Type II diabetic patients, receiving as little as 600 mg of lipoic acid twice
daily, showed a significant improvement in glucose disposal after 4 weeks [99]. Treatment
of insulin-resistant obese Zucker rats with lipoic acid increases both oxidative and non-
oxidative glucose metabolism with improvement in insulin resistance [100,101]. Adminis-
tration of lipoic acid to mice also leads to increased tissue levels of the aldehyde binding
compounds, cysteine and glutathione [102].
Dietary lipoic acid supplementation in SHRs lowers the systolic blood pressure (Fig. 3),
cytosolic [Ca2]i, blood glucose and insulin levels, tissue aldehyde conjugates and prevents
adverse renal vascular changes [103]. Alpha-lipoic acid treatment attenuates tissue oxidative
stress and lowers plasma lipids, vascular reactivity, alteration in vascular morphology and
blood pressure in streptozotocin-induced diabetic rats and deoxycorticosterone acetate-salt-
induced hypertensive rats. Supplementation of diet with Vitamin E and lipoic acid protects
the aged rat heart against ischemia-reperfusion injury [104 106]. Lipoic acid may act at four
sites to lower tissue aldehydes and normalize vascular Ca2 channels and blood pressure:
First, lipoic acid, as a component of coenzyme A, stimulates glucose metabolism leading to
a decreased formation of reactive aldehydes; Second, the redox partner dihydrolipoic acid
converts cystine to cysteine; Third, as DHL has two SH groups, it will act similarly to
cysteine and bind excess aldehydes leading to their excretion; Fourth, lipoic acid may act
directly on vascular Ca2 channels to increase free sulfhydryl groups and normalize Ca2
transport (Fig. 2).

9. Nutritional approaches to blood pressure control

There is an increasing body of evidence that coronary artery disease, hypertension,

diabetes mellitus and hyperlipidemia develop due to interaction of genetic and environmental
factors. Diet and lifestyle factors may influence heritability of the variant phenotypes that are
dependent on the nutrient environment for their expression.
In essential hypertension there is a metabolic defect where glucose metabolism is altered
due to insulin resistance, resulting in increased tissue levels of aldehydes and oxygen-free
radicals and hypertension. This metabolic defect can be corrected nutritionally by vitamin E,
vitamin C, vitamin B6, lipoic acid, or a diet rich in protein-containing cysteine. In healthy
people the present recommended daily allowance (RDA) of these nutrients may be sufficient
to maintain normal activities of these metabolic enzymes and normal blood pressure. Excess
intake may not lower blood pressure because these people do not have defective metabolic
enzymes. In essential hypertensives, a higher dietary amount, more than the RDA, will be
needed to stimulate the activity of these metabolic enzymes to achieve normal blood
pressure. These people need extra dietary supplementation of these nutrients which becomes,
 S. Vasdev et al. / Nutrition Research 22 (2002) 111123 119

for them, essential nutrients. The antihypertensive effect documented in the DASH1 and
DASH2 study, which recommends a diet rich in fruits, vegetables, grain products and low-fat
dairy goods, and low in total fat and salt intake for the control of mild hypertension, may be
due to these nutrients.

Acknowledgments

We gratefully acknowledge Ms. Vicki Gill for technical assistance and Ms. Janice Petten
for typing the manuscript. We also thank the Medical Research Council of Canada for
financial support.

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