Review Article | Published:

Review Article

Harmful effects of dietary salt in addition to hypertension

Abstract

In addition to raising the blood pressure dietary salt is responsible for several other harmful effects. The most important are a number which, though independent of the arterial pressure, also harm the cardiovascular system. A high salt intake increases the mass of the left ventricle, thickens and stiffens conduit arteries and thickens and narrows resistance arteries, including the coronary and renal arteries. It also increases the number of strokes, the severity of cardiac failure and the tendency for platelets to aggregate. In renal disease, a high salt intake accelerates the rate of renal functional deterioration. Apart from its effect on the cardiovascular system dietary salt has an effect on calcium and bone metabolism, which underlies the finding that in post-menopausal women salt intake controls bone density of the upper femur and pelvis. Dietary salt controls the incidence of carcinoma of the stomach and there is some evidence which suggests that salt is associated with the severity of asthma in male asthmatic subjects.

Introduction

High blood pressure is the greatest cause of strokes and heart failure and is a major contributor to coronary heart disease. Dietary salt appears to be an important single factor in raising the blood pressure. Throughout evolution the human race only consumed the sodium naturally present in food and the daily intake was about 10 mmol/day.1 It is less than 5000 years ago that salt began to be added to food and the present intake of between 100–400 mmol/day is therefore a considerable, and in evolutionary terms, recent increase.2,3

A dispute which lasted about 100 years over the evidence that suggested that hypertension is in part due to the present high intake of salt is now resolved. There is a consensus that dietary sodium plays a significant role in determining the blood pressure of populations, the number of individuals who have a raised blood pressure, and its severity, and that it is responsible for much of the rise in pressure that occurs with age.4 The previous debate, however, obscured the considerable evidence that in addition to raising the blood pressure dietary salt has other harmful effects, several of which in the cardiovascular system are independent, though additive, to the effect of the hypertension, and some of which appear to be as important as the rise in arterial pressure.

Cardiovascular effects

Left ventricular mass

In humans there is a relation between left ventricular mass and cardiovascular mortality and morbidity independent of the blood pressure.5,6,7 In normotensive subjects left ventricular mass and diastolic filling have been found to be positively correlated with urinary sodium excretion8,9 (Figure 1) and in two other normotensive groups followed up for 3 to 8 years the initial left ventricular mass and wall thickness were significantly related to the subsequent development of hypertension.5 Normotensive rats given 1% saline for several weeks develop an increase in heart weight due to an increase in left ventricular mass without an increase in blood pressure.10,11 In both normotensive humans and the rat therefore, left ventricular mass is positively related to the salt intake which, in normal circumstances is equivalent to the dietary salt intake. Left ventricular mass is independent of the blood pressure, and in normal humans an increase in left ventricular mass predicts the onset of hypertension.

Figure 1
figure1

Correlation between salt intake and left ventricular mass in subjects with systolic blood pressure >121 mm Hg. (Adapted from Kupari P, Koskinen P, Virolainor J. Circulation 1994; 89: 1041–1050.)

The relation of left ventricular mass to salt intake in essential hypertension is well documented in that in such patients 24-h sodium excretion is an independent determinant for relative wall thickness, and is a more powerful determinant than the blood pressure.9,12,13,14 These findings have been confirmed using ambulatory blood pressure monitoring.8 In patients with hypertension associated with type I diabetes multiple regression analysis has identified dietary sodium intake as an independent predictor of left ventricular mass, there was no significant association between left ventricular mass and the blood pressure.15 A high intake of salt increases cardiac mass in both the spontaneous hypertensive rat (SHR) and its control, the Wistar-Kyoto (WKY) rat, though the blood pressure in the WKY rat does not rise.16 In rats with experimental reno-vascular hypertension those on a high intake of sodium have an increase in left ventricular mass which is more consistent than the associated change in blood pressure.17 Though the rise in arterial pressure induced by a high salt diet in the Dahl salt-sensitive rat is prevented by the chronic intracerebroventricular administration of Fab fragments to block brain ouabain this does not prevent the increase in the weight of the left ventricle.18

The increase in left ventricular mass, both in the normal rat on an increased salt intake and in the hypertensive rat is associated with an increase in myocardial angiotensin-converting enzyme (ACE) mRNA,19 non-collagenous protein and total collagen content. Angiotensin II increases cardiac protein.20 There is also a marked increase in intramyocardial interstitial fibrosis both in the left ventricle and intramyocardial arteries and arterioles.11,21 In addition there is over-expression of TGF-β, mRNA which parallels the degree of fibrosis.21 In the stroke-prone hypertensive rat a high salt diet has been shown to increase the cardiac expression of the endothelin−1 gene transcript in the absence of a change in blood pressure.22

The increase in left ventricular mass associated with essential hypertension can be reduced by lowering the intake of salt.8,23,24 The Treatment of Mild Hypertension Study Research Group25 showed a significant correlation between the reductions in salt intake and the left ventricular mass. In the whole study group lowering salt intake was the only factor which was significantly correlated with a reduction in left ventricular mass. Similarly in the two-kidney one-clip hypertensive rat a low sodium diet can reverse the myocardial hypertrophy and certain enzyme changes, in the absence of a significant change in blood pressure.26,27 In the stroke-prone spontaneously hypertensive rat a 1% saline intake is associated with severe hypertension and cardiac hypertrophy (heart weight to body weight ratio). This is prevented by the administration of a diuretic which causes a small fall in blood pressure from about 300 to 250 mm Hg but prevents the development of cardiac hypertrophy and practically prevents myocardiac interstitial fibrosis and perivascular fibrosis.28

Conclusion

There is a close link between urinary sodium excretion and left ventricular mass in both man and the rat which is independent of hypertension. In hypertensive patients a reduction in salt intake reduces left ventricular mass independent of a change in blood pressure.

Vessels

An increase in sodium intake, in both humans and experimental animals, increases the stiffness of conduit arteries and the activity of resistance arteries, and both become hypertrophied.29,30 Stiffness of conduit arteries, measured as an increase in pulse wave velocity31 or pulse pressure,32 is a strong independent predictor of cardiovascular risk. Tobian was the first to show that in various forms of experimental hypertension in the rat a high salt intake induces structural alterations in cerebral and renal vessels independent of the blood pressure.33,34 Levy et al35 found that the administration for 12 weeks of a diuretic to a group of SHR stroke-prone rats on a high sodium intake diminished the increase in carotid artery thickness and collagen content though the blood pressure of the diuretic group was significantly greater than in the control group. Recent studies in humans have shown that a moderate reduction in salt intake causes a reduction in the stiffness and thickness of the arterial wall, independent of the blood pressure.36

In one early study in individuals in a rural community in China, pulse wave velocity in the lower aorta, the arms and the legs was, after adjustment for blood pressure, consistently lower than in a comparable group in an urban community on a higher salt intake.37 Similarly, the pulse wave velocity of a group of normotensive subjects who lowered their salt intake for a mean of about 2 years was significantly lower than that of a control group, independent of the blood pressure.36 The increase in large artery thickness in essential hypertension appears to be due at least in part to angiotensin II in that it is lowered by ACE inhibitors and is independent of any associated change in blood pressure.38 The influence of dietary salt intake and angiotensin II on large artery stiffness in essential hypertension appear to be additive. For instance, neither a 2% NaCl diet or intravenous angiotensin (50 ng/kg/min) for 12 weeks has an effect on the blood pressure or the wall/lumen ratio of small resistance vessels in the Sprague Dawley rat but, when combined, the combination alters both.39

The structural changes in intramyocardial coronary arteries induced by a high salt diet are accompanied by a number of metabolic alterations including an increased generation of reactive oxygen species40 which, among other effects, oxidise nitric oxide thus reducing its dilator effect41,42 and the arteriolar response to acetylcholine.40

As a rise in salt intake is usually accompanied by a small rise in plasma sodium and plasma sodium tends to be raised in essential hypertension43 it is possible that the effect of a small change in sodium concentration on in vitro cultures of endothelial cells may also be relevant to a consideration of the effect of dietary salt on vessels in vivo. For instance increasing the sodium concentration of the culture fluid of cultured myocardial myocytes and vascular smooth muscle by 6 mM/l for 5 days causes hypertrophy.44 Subsequently the investigators responsible for this finding also demonstrated that raising the sodium concentration of the fluid bathing cultured human umbilical vein endothelial cells by 6 mM/l (from 142 to 148 mmol/l) for 5 days raises their content of cellular protein and total RNA. When exposed to a sodium concentration of 152 mmol/l (ie, an increase of 10 mM/l) there is first, after 2 h incubation, a transient increase in c fos proto-oncogenic mRNA expression. After 3 days there is a general increase in mRNA expression of several factors which are related to hypertrophy.45

Conclusion

Dietary salt intake controls the stiffness of the larger conduit arteries, the reactivity of the smaller resistance vessels and the wall thickness of both. A raised intake induces an increase in collagen deposition and an increased generation of reactive oxygen species within the arterial walls. A reduction in salt intake reverses these changes. Small variations in the concentration of plasma sodium which, in vitro, can induce hypertrophying effects on cultured vascular endothelium may contribute to these changes.

Cardiac failure

Cardiac failure in association with essential hypertension is the end product of several harmful consequences of dietary salt.46 Primarily there is systolic contractile dysfunction due to the salt induced hypertension.47 Some older patients may develop diastolic dysfunction due to impaired ventricular filling, this usually precedes systolic dysfunction and is a consequence of the collagen deposition and fibrosis of the ventricle which are closely related to salt intake. Furthermore the salt-induced increase in the size of the muscle mass, due to the hypertrophy and deposition of collagen and fibrous tissue, and the salt-induced thickening of the coronary arteries, impair coronary perfusion, which can be detected as an inadequate reserve of coronary blood flow.48,49 Myocardial function is further impaired by the increase in cardiac output which results in part from the salt-induced rise in right auricular pressure. The gain in weight associated with the salt and water retention that accompanies cardiac failure also increases cardiac work. Reducing salt intake in patients with overt heart failure is commonly used and leads to an improvement of symptoms similar to that which occurs with diuretics. Nevertheless there has, as yet, been no controlled trials of salt restriction in heart failure.

Stroke

The higher the salt intake, the greater the incidence of strokes.50,51 Multivariate analyses calculated from the urinary electrolyte data obtained from the Intersalt study (from persons aged 20 to 40 years) and from the age and sex-specific stroke mortality data from 25 countries worldwide51 showed no significant relationship between either the systolic or the diastolic pressure and stroke mortality but there was a significant relationship between stroke mortality and sodium excretion in men, and the Na/K ratio in women.51 These findings are similar to those calculated for 12 European countries (Figure 2) in which, whereas sodium excretion was not significantly related to systolic pressure, it was related to stroke mortality.50

Figure 2
figure2

Correlation between urinary salt excretion and death from strokes in 12 European countries. (Adapted from Perry IJ and Beevers DG. J Hum Hypertens 1992; 6: 23–25.)

In the rat strokes are related to salt intake independent of blood pressure.33 The separate effect of salt intake, as opposed to blood pressure, in causing strokes in rats has been beautifully delineated by Tobian et al.34 The blood pressure of normal rats on a normal intake of salt was raised by the administration of DOCA. The animals were then divided into two groups, one of which was placed on a high sodium intake and the other on a low intake. The blood pressure remained raised in both groups but the group on the high salt intake had a greater number of strokes and a high death rate. Conversely, in the stroke-prone SHR, the administration of a diuretic can, without changing the arterial pressure, reduce the incidence of cerebrovascular accidents.35

The mechanism responsible for the connection between salt intake and strokes is not clear but may, in part, be related to conduit artery thickness and stiffness, and platelet reactivity.

Conclusion

Stroke mortality has a strong relationship to dietary sodium intake which is independent of the blood pressure.

Platelets

In one study in normal men platelet aggregation induced by adenosine 5′-diphosphate was significantly greater when they were on a high salt intake.52 Similarly in normal women a change in salt intake from 10 to 200 mmol/day was associated with a significant increase in platelet aggregation.53 In two groups of men with and without a family history of hypertension a high salt intake increased the blood pressure of those with a family history but platelet aggregation increased in both groups, though it rose more in those with a family history.54

The effect of salt intake on adrenaline-induced platelet aggregation and α-2 adrenergic receptors on platelet membrane fraction has been studied in patients with essential hypertension. The response was linked to the associated changes in blood pressure. In those in whom there was a rise in blood pressure, platelet aggregation also rose as did the number of α-2 adrenergic receptors.55

Conclusion

In normal men and women, with and without a family history of hypertension and in patients with essential hypertension, salt intake influences platelet aggregation. These dietary salt-induced changes in platelet reactivity may be a link between salt intake, thrombotic strokes and myocardial infarction.

Renal function

Variable increases in salt intake from 1 to 8% for 7 days to 16 weeks increase the blood pressure and the size and weight of the kidneys in the Dahl salt-sensitive and -resistant rat,56 and the SHR and its control the WKY rat.11 The effect is greatest in the Dahl salt-sensitive and the SHR rats. The kidneys become hypertrophied and develop glomerular and interstitial fibrosis accompanied by a significant increase in collagen in both the SHR and the WKY rat. In the SHR rats there is also an increase in urinary protein excretion.57,58 The increase in glomerular and intertubular interstitial fibrosis, and of TGF-β in the SHR and WKY rat, is greater in the SHR but not the change in collagen deposition, though the rise in blood pressure in the WKY rat is significantly less than in the SHR. In the uninephrectomised SHR salt restriction inhibits compensatory kidney growth.59

In patients with hypertension an increase in salt intake often increases glomerular filtration rate, vascular resistance, calculated intraglomerular capillary pressure and protein excretion.60 In normal humans the effect of a raised salt intake varies from no detectable effect or a decrease in renal vascular resistance, a few have a similar response to that which occurs in those hypertensive patients who have an increase in glomerular filtration.60,61,62,63

Proteinuria and renal function

In human renal disease the reduction in glomerular filtration rate is significantly related to the histological changes observed in the tubules and the intestitium. It is not related to the historical changes that occur in the glomeruli.64,65 It now appears that the interstitial changes are the consequence of increased quantities of filtered proteins overloading the reabsorptive capacity of the proximal tubules.66 The excess filtered protein reabsorbed by the proximal tubules is degraded by lyosomes. The intracellular products of this degradation, and a local intrarenal increase in angiotensin II (see below), up-regulate genes within the proximal tubule cells which are responsible for an excess production of vasoactive and inflammatory substances. When these reach the interstitial space they give rise to focal infiltrates of inflammatory cells with an increased deposition of collagen, matrix and fibrous tissue.67

In renal disease the increase in filtered protein is due in part to an increase in glomerular permeability. There is, in addition, both in renal disease and in hereditary hypertension, an increase in glomerular capillary pressure caused by a relative rise in tone of the renal efferent arteriole.61 This, in turn, appears to be due to a rise in the intrarenal concentration of angiotensin II68 for in the sub- totally nephrectomised rats and the SHR an increase in gene expression of components of the renin- angiotensin system has been detected in the glomeruli.69 Angiotensin II is known to affect the tone of the efferent arteriole more than that of the afferent arteriole.70 In addition the intrarenal increase in angiotensin II increases the expression of heme exogenase71 and NAD(P)H oxidase which increases the production of oxygen radicals. This gives rise to oxidative stress including the consequence of oxidising nitric oxide to nitrite and nitrate72,73 and to other harmful effects which contribute to progressive renal injury.72 These findings are supported, in part, by the observation that the administration of an ACE inhibitor reduces glomerular capillary pressure and proteinuria. The apparent discrepancy between the observation that in renal disease and in hypertension the intrarenal concentration of angiotensin II may be raised, while plasma angiotensin II is usually low, is due to the kidney's intrinsic ability to produce angiotensin II.68,74 Overall the evidence suggests that, in relation to dietary salt, the angiotensin II level is inappropriately high and that this increase is responsible, in part, for many of the damaging effects. This appears to be similar to the changes which occur in the heart.75,76

The effect of dietary salt restriction on proteinuria and renal function

Patients with progressive renal disease on a diet containing 100 mmol of sodium/day have a lower protein excretion and a slower fall in glomerular filtration rate than those who eat a diet containing 200 mmol sodium/day.77 The prevalence of sclerosis, increase in glomerular volume and proteinuria in diabetic rats, or rats subjected to right nephrectomy and partial infarction of the remaining kidney, are either prevented or reduced by a low sodium intake.78,79,80

The antiproteinuric effect of ACE inhibitors or calcium antagonists

In various renal disorders in humans, induced nephropathies in animals and in essential hypertension the administration of ACE inhibitors reduces proteinuria and improves prognosis.66,81 This effect is independent of any associated change in blood pressure or the extent of pre-existing renal impairment. The conclusion that this beneficial effect is indeed due to the induced fall in proteinuria is supported by two studies in experimental nephropathies in animals in which, when ACE inhibitors failed to reduce proteinuria, the kidneys were not protected from injury.66,82

In essential hypertension83,84 and most forms of human renal disease,66 including diabetic nephropathy, proteinuria appears to determine the pro- gnosis. Nevertheless, induced reductions in proteinuria with an ACE inhibitor or a calcium antagonist, which diminish the rate of decline in renal function, are reversed or prevented by a high salt intake.76,85,86 In 12 patients with proteinuria varying from 3.2 to 10.5 g/24 h Heeg et al76 studied the effect of increasing salt intake from 50 to 200 mmol/24 h on the antiproteinuric effect of 10 mg of lisinopril. On a sodium intake of 50 mmol/day, proteinuria fell by 50% whereas on a salt intake of 200 mmol/day the antiproteinuric effect of the ACE inhibitor was abolished (Figure 3). In a group of patients with non-diabetic renal disease the best antiproteinuric effect, accompanying the administration of an ACE inhibitor, was observed on those days when the daily sodium intake was below 100 mmol/day.75 The blunting of the antiproteinuric effect of ACE inhibition is reversed by the administration of a diuretic such as hydrochlorothiazide.87 The blocking effect of a high salt intake on the antiproteinuric effect of an ACE inhibitor has also been demonstrated in diabetic hypertensive rats.

Figure 3
figure3

The effect of a rise in urinary sodium excretion on the proteinuria of nine patients who were on lisinopril whose mean proteinuria before the administration of lisinopril was 6.4 g/day; the lisinopril was administered throughout the three consecutive periods of observation. The change in urinary sodium excretion was not accompanied by a significant change in blood pressure.73

Conclusion

In patients and rats with hereditary hypertension or various forms of renal disease dietary salt intake controls intraglomerular capillary pressure and urinary protein excretion, and thus the rate of renal functional deterioration, and it opposes the beneficial antiproteinuric effect of ACE inhibitors and calcium antagonists.

Non-cardiovascular effects

Bone density and renal stones

Urinary sodium excretion and therefore sodium intake controls the urinary output of calcium.88,89 A high dietary salt intake therefore leads to a raised urinary calcium which in the long term may lead to calcium mobilisation from bone.88 In 410 healthy men and 476 healthy women aged 20–79 years Itoh and Suyama found that the higher the sodium intake the greater the loss of urinary calcium and the excretion of hydroxyproline,89 an increase in dietary sodium of 100 mmol/day was associated with an increase in calcium excretion of 0.6–1 mmol. In elderly healthy normal humans an increase in salt intake for 2 to 10 days increases the urinary excretion of calcium, hydroxyproline, cyclic AMP and osteocalcin.90,91,92 An increase in dietary salt and the resultant increase in calcium excretion also stimulate an increase in 1,25(OH)2D3 which appears to be mediated by a rise in parathyroid hormone. The increase in 1,25(OH)2D3 indicates a compensatory response to calcium depletion, while increases in urinary hydroxyproline92 and osteocalcin92,93 are indicators, respectively, of an increase in bone resorption and bone formation. A rise in urinary cyclic aderosine monophosphate (AMP) occurs when there is a rise in plasma parathyroid hormone (PTH).90,92 A rise in salt intake from 70 to 170 mmol/day in elderly women increases their calcium loss.92 Conversely a modest reduction in salt intake reduces urinary calcium excretion.90,94 The finding that in the elderly urinary sodium excretion controls the urinary excretion of calcium and some aspects of bone metabolism suggests that dietary sodium intake may contribute to the reduction in bone density that occurs in the elderly.

The effect of salt intake on the bones, however, is likely to be relevant throughout the life of the individual. A study in 380 girls early in puberty, which confirmed the close association between urinary sodium and calcium excretion, has shown that urinary calcium has a negative effect on total body calcium and total body bone density. It follows, therefore, that the attainment in youth of a reasonable peak bone mass, which has a significant bearing on the incidence of osteoporosis after the menopause, is imperilled by a high sodium intake during puberty.95 In post-menopausal women, Zarkadas et al96 calculated, from the effect of a few days rise in sodium intake, that an increased intake of 50 mmol/day for 10 years would deplete the calcium stores by about 7.5% which is in line with Devine et al’s97 finding in 124 post-menopausal women, studied for 2 years, that urinary sodium excretion is negatively related to bone density at the intertrochanteric and total hip sites. Multiple regressions also showed that both dietary calcium and urinary sodium excretion are significant determinants of the reduction in bone mass which occurred over the 2 years.97 The data suggested that if the daily excretion of sodium were halved it would have an equivalent effect on reducing bone loss to that of increasing calcium intake by 891 mg/day. No bone loss occurred at the hips when calcium intake was above 1768 mg/day or the urinary sodium excretion was below 92 mmol/day.

There is one retrospective study in men and women using 24-h diet recalls, for a 2-year period between 1973 and 1975, and a follow-up mineral density measurement between 1988 and 1991. No effect of sodium intake on bone mineral density was apparent except for a small significant protective effect of a lower sodium intake on the distal radius of men.98 Nordin and Polley,99 however, did find a negative association between forearm mineral density and 24-h sodium excretion in post-menopausal women. A subsequent 9-month period of sodium restriction (by only 30 mmol/day) in a sub-sample failed to reveal any change in bone mineral density. A high sodium intake is also implicated in the pathogenesis and treatment of hypercalciuria in both children and adults100,101,102 and of calcium depletion in corticosteroid treated patients.103 Normal rats given salt supplements also have an increase in urinary calcium excretion, and after a year their bones contain less calcium than their controls.104,105

It is possible that the relation between urinary sodium excretion to bone density in patients with essential hypertension may be more significant than in normotensive controls. For a given salt excretion patients with essential hypertension excrete greater quantities of calcium, hydroxyproline and cyclic AMP than normotensive controls.91 They also have a tendency for a reduced serum ionised calcium, a raised plasma parathyroid hormone and 1,25 dihydroxyvitamin D and an increased calcium absorption. When given a high salt diet the children of hypertensive parents have a greater urinary calcium excretion than children from normotensive parents.106 Over a mean follow-up of 3.5 years in 3676 white women aged 66 to 91 years the rate of bone loss in the femoral neck, adjusted for age, initial bone density, weight, smoking and regular use of hormone replacement therapy, the rate of bone resorption increased with the blood pressure measured at base line.107 The SHR and Milan hypertensive rats are also more likely to develop bone demineralisation than their normotensive controls.108,109 Thiazide diuretics which cause a reduction in calcium excretion when given to men and women with and without hypertension reduce the number of hip fractures.110,111

Inasmuch as kidney stones are known to be associated with a raised urinary excretion of calcium it is probable that the salt-induced increase in urinary calcium excretion in SHR and essential hypertension contributes to their greater incidence of renal stones.112,113,114

Conclusion

In normal humans salt intake influences urinary calcium excretion and bone turnover. In essential hypertension and hypertensive strains of rat urinary calcium excretion is raised, there is an increase in bone turnover and the bones of the SHR and the Milan hypertensive rat tend to be demineralised. In post-menopausal women urinary sodium excretion controls calcium excretion positively and bone density negatively. It is probable that the increase in renal stones in essential hypertension and the SHR is due to the salt induced rise in urinary calcium excretion.

Carcinoma of the stomach

Of all the factors that relate to cancer of the stomach, the second most common cancer in the world, the relationship to salt is the strongest.115 Randomly selected 24-h urine collections from 39 populations sampled from 24 countries were obtained from the Intersalt study. Median sodium excretion levels were standardised for age and sex between the ages of 20 and 49 years and averaged per country. Ecological correlation-regression analyses of the sodium excretion levels in relation to national stomach cancer mortality rates were highly significant in men and women (Figure 4).

Figure 4
figure4

The relation of urinary salt excretion to cancer of the stomach. (Adapted from Joossens JB, Hill MJ, Elliott P. Int J Epidemiol 1996; 25: 494–504.)

A high salt diet in both humans and experimental animals is known to cause gastritis and when co-administered with known gastric carcinogens promotes their carcinogenic effect.116,117 One such promoter appears to be Helicobacter pylori, which has been shown to be associated with progression of gastritis to gastric cancer.116 Furthermore a high salt diet increases Helicobacter pylori colonisation.116 Prospective studies have shown a positive association between Helicobacter pylori and gastric cancer amounting to a two-to three-fold increase in risk.118

Conclusion

Carcinoma of the stomach is strongly related to dietary sodium intake.

Asthma

Regional data from England and Wales have shown that there is a strong correlation between the purchase of table salt and asthma in men and children.119 There are two interventional randomised double-blind, placebo controlled, crossover trials in men with mild to moderate asthma, of the effect of altering the intake of sodium for several weeks. There were 27 patients in the first trial and 36 in the second. The clinical severity of the asthma was assessed in one trial while, in another, the airway's response to histamine was measured.120,121 Both these small trials showed that an increase in dietary sodium, 80 mmol/day in one and 204 mmol/day in the other, increased both the severity of the asthma and bronchial reactivity. There is another randomised, crossover trial in 17 male asthmatics. There were three levels of sodium intake, each for 2 weeks. The largest difference in intake was 118 mmol/day. The only observation recorded was peak expiratory flow which was measured by the patients themselves in their own homes. No effect on peak expiratory flow was detected.122

An observational study on 138 men with initial to moderate asthma showed that bronchial reactivity was strongly related to 24-h urinary sodium excretion, allowing for the effect of age, atopy and cigarettes.123 Three other observational studies on relatively large groups of normal men and boys did not reveal a relation between urinary sodium excretion and bronchial reactivity to methacholine.124,125,126,127

Conclusion

The level of salt intake may be injurious to male patients with asthma. There is no evidence that salt intake effects airway responsiveness in normal subjects.

References

  1. 1

    Eaton SB, Konner M . Paleolithic nutrition N Eng J Med 1985 312: 283–289

  2. 2

    Multhauf R . Neptune's Gift John's Hopkins University Press: Baltimore 1978

  3. 3

    Adshead SAM . Salt and Civilization Macmillan Academic and Professional Ltd: London 1992

  4. 4

    Tuomilehto J et al. Urinary sodium excretion and cardiovascular mortality in Finland: a prospective study Lancet 2001 357: 848–851

  5. 5

    Langenfeld MR, Schmieder RE . Salt and left ventricular hypertrophy: what are the links? J Hum Hypertens 1995 9: 909–916

  6. 6

    Perry IJ . Dietary salt intake and cerebrovascular damage Nutr Metab Cardiovasc Dis 2000 10: 229–235

  7. 7

    Schmieder RE, Messerli FH . Hypertension and the heart J Hum Hypertens 2000 14: 597–604

  8. 8

    Schmieder RE, Beil AH . Salt intake and cardiac hypertrophy In: Laragh JH, Brenner BM (eds) Hypertension: Pathophysiology, Diagnosis and Management Raven Press: New York 1995 pp 1327–1333

  9. 9

    Du Cailar G, Ribstein J, Daures JP, Mimran A . Sodium and left ventricular mass in untreated hypertensive and normotensive subjects Am J Physiol 1992 263: H177–H181

  10. 10

    Fields NG, Yuan B, Leenen FHH . NaCl-induced cardiac hypertrophy: cardiac sympathetic activity versus volume load Circ Res 1991 68: 745–755

  11. 11

    Kihara M et al. Biochemical aspects of salt-induced pressure-independent left ventricular hypertrophy in rats Heart & Vessels 1985 1: 212–215

  12. 12

    Daniels SD, Meyer RA, Loggie MH . Determinants of cardiac involvement in children and adolescents with essential hypertension Circulation 1990 82: 1243–1248

  13. 13

    Schmieder RE, Messerli FH, Garavaglia GG, Nunez BD . Dietary salt intake. A determinant of cardiac involvement in essential hypertension Circulation 1988 78: 951–956

  14. 14

    Schmieder RE et al. Sodium intake modulates left ventricular hypertrophy in essential hypertension J Hypertens 1988 6: S148–S150

  15. 15

    Gerdts E, Myking OL, Lund-Johansen P, Omvik P . Factors influencing LVM in hypertensive type-1 diabeticpatients Blood Press 1997 6: 197–202

  16. 16

    Frolich ED, Chien Y, Sesoko S . in Pegram BL Relationship between dietary sodium intake, hemodynamics and cardiac mass in SHR & WKY rats Am J Physiol 1993 264: R30–R34

  17. 17

    de Simone G et al. Influence of sodium intake on in vivo left ventricular anatomy in experimental renovascular hypertension Am J Physiol 1993 264: H2103–H2110

  18. 18

    Huang BS, Leenen FH . Both brain angiotensin II and ‘ouabain’ contribute to sympathoexcitation hypertension in Dahl S rats on high salt intake Hypertension 1998 32: 1028–1033

  19. 19

    Kreutz R et al. Induction of cardiac angiotensin I-converting enzyme with dietary NaCl-loading in genetically hypertensive and normotensive rats J Mol Med 1995 73: 243–248

  20. 20

    Geenen DL, Malhotra A, Scheuer J . Angiotensin II increases cardiac protein synthesis in adult rat heart Am J Physiol 1993 265: H238–H243

  21. 21

    Yu HCM et al. Salt induces myocardial and renal fibrosis in normotensive and hypertensive rats Circulation 1998 98: 2621–2628

  22. 22

    Feron O, Salomone S, Godfraind T . Influence of salt loading on the cardiac and renal preproendothelin-1 mRNA expression in stroke-prone spontaneously hypertensive rats Biochem Biophys Res Commun 1995 209: 161–166

  23. 23

    Liebson PR et al. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass inpatients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS) Circulation 1995 91: 698–706

  24. 24

    Ferrara LA, de Simone G, Pasanisi F, Mancini M . Left ventricular mass reduction during salt depletion in arterial hypertension Hypertension 1984 6: 755–759

  25. 25

    Drayer JIM, Gardin JM, Weber MA . Echocardiographic left ventricular hypertrophy in hypertension Chest 1983 84: 217–221

  26. 26

    Lindpaintner K, Sen S . Role of sodium in hypertensive cardiac hypertrophy Circ Res 1985 57: 610–617

  27. 27

    Shen S, Young DR . Role of sodium in modulation of myocardial hypertrophy in renal hypertensive rats Hypertension 1986 8: 918–924

  28. 28

    Contard F et al. Diuretic effects on cardiac hypertrophy in the stroke prone spontaneously hypertensive rat Cardiovasc Res 1993 27: 429–434

  29. 29

    Safar ME, Thuilliez C, Richard V, Benetos A . Pressure-independent contribution of sodium to large artery structure and function in hypertension Cardiovasc Res 2000 46: 269–276

  30. 30

    Simon G, Illyes G . Structural vascular changes in hypertension: role of angiotensinll, dietary sodium supplementation, and sympathetic stimulation, alone and in combination in rats Hypertension 2001 37: 255–260

  31. 31

    Blacher J et al. Arotic pulse wave velocity as a marker of cardiovascular risk in hypertensivepatients Hypertension 1999 33: 1111–1117

  32. 32

    Anttikainen RL, Jousilahti P, Vanhanen H, Tuomilehto J . Excess mortality associated with increased pulse pressure among middle aged men and women is explained by high systolic pressure J Hypertens 2000 18: 417–424

  33. 33

    Tobian L . Salt and hypertension. Lessons from animal models that relate to human hypertension Hypertension 1991 17: 52–58

  34. 34

    Tobian L, Hanlon S . High sodium chloride diets injure arteries and raise mortality without changing blood pressure Hypertension 1990 15: 900–903

  35. 35

    Levy BI, Poitevin P, Duriez M . Sodium, survival and the mechanical properties of the carotid artery in stroke-prone hypertensive rats J Hypertens 1997 15: 251–258

  36. 36

    Avolio AP et al. Improved arterial distensibility in normotensive subjects on a low salt diet Arteriosclerosis 1986 6: 166–169

  37. 37

    Avolio AP, Deng FQ, Li WQ . Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China Circulation 1985 71: 202–210

  38. 38

    Kool MJ, Lusterman FA, Breed JG . The influence of perindopril and the diuretic combination amiloride+hydrochlorothiazide on the vessel wall properties of large arteries in hypertensivepatients J Hypertens 1995 13: 839–848

  39. 39

    Simon G, Illyes G, Csiky B . Structural vascular changes in hypertension: role of angiotensin II, dietary sodium supplementation, blood pressure, and time Hypertension 1998 32: 654–660

  40. 40

    Lenda DM, Sauls BA, Boegehold MA . Reactive oxygen species may contribute to reduced endothelium-dependent dilation in rats fed high salt Am J Physiol 2000 279: H7–H14

  41. 41

    Boegehold MA . Effect of dietary salt on arteriolar nitric oxide in striated muscle of normotensive rats Am J Physiol 1993 264: H1810–H1816

  42. 42

    Boegehold MA . Flow-dependent arteriolar dilation in normotensive rats fed low- or high-salt diets Am J Physiol 1995 269: H1407–H1414

  43. 43

    Komiya I et al. An abnormal sodium metabolism in Japanesepatients with essential hypertension, judged by serum sodium distribution, renal function and the renin-aldosterone system J Hypertens 1997 15: 65–72

  44. 44

    Gu JW et al. Sodium induces hypertrophy of cultured myocardial myoblasts and vascular smooth muscle cells Hypertension 1998 31: 1083–1087

  45. 45

    Gu JW, Sartin A, Elam J, Adair TH . Dietary salt induces gene expression of hypertrophy-related factors in cultured human endothelial cells Am J Hypertens 2000 12: F015 (Abstract)

  46. 46

    Frolich ED . Risk mechanisms in hypertensive heart disease Hypertension 1999 34: 782–789

  47. 47

    Frolich ED, Tarazi RC, Dustan HP . Clinical-physiological correlations in the development of hypertensive heart disease Circulation 1971 44: 446–455

  48. 48

    Marcus ML et al. Decreased coronary reserve: a mechanism for angina pectoris inpatients with aortic stenosis and normal coronary arteries N Engl J Med 1982 307: 1362–1367

  49. 49

    Houghton JL et al. Relations among impaired coronary flow reserve, left ventricular hypertrophy and thallium perfusion defects in hypertensivepatients without obstructive coronary artery disease J Am Coll Cardiol 1990 15: 43–51

  50. 50

    Perry IJ, Beevers DG . Salt intake and stroke: a possible direct effect J Hum Hypertens 1992 6: 23–25

  51. 51

    Xie JX, Sasaki S, Joossens JV, Kesteloot H . The relationship between urinary cations obtained from the INTERSALT study and cerebrovascular mortality J Hum Hypertens 1992 6: 17–21

  52. 52

    Gow IF et al. The sensitivity of human blood platelets to the aggregating agent ADP during different dietary sodium intakes in healthy men Eur J Clin Pharmacol 1992 43: 635–638

  53. 53

    Gow IF et al. High sodium intake increases platelet aggregation in normal females J Hypertens Suppl 1987 5: S243–S246

  54. 54

    Nara Y et al. Dietary effect on platelet aggregation in men with and without a family history of essential hypertension Hypertension 1984 6: 339–343

  55. 55

    Ashida T et al. Effect of dietary sodium on platelet alpha 2-adrenergic receptors in essential hypertension Hypertension 1985 7: 972–978

  56. 56

    McCormick CP, Rauch AL, Buckalew VM . Differential effect of dietary salt on renal growth in Dahl salt-sensitive and salt-resistant rats Hypertension 1989 13: 122–127

  57. 57

    Blizard DA et al. The effect of a high salt diet and gender on blood pressure, urinary protein excretion and renal pathology in SHR rats Clin Exp Hypertens A 1991 13: 687–697

  58. 58

    Vaskonen T et al. Cardiovascular effects of chronic inhibition of nitric oxide synthesis and dietary salt in spontaneously hypertensive rats Hypertension Res 1997 20: 183–192

  59. 59

    Benstein JA, Feiner HD, Parker M, Dworkin LD . Superiority of salt restriction over diuretics in reducing renal hypertrophy and injury in uninephrectomized SHR Am J Physiol 1990 258: F1675–F1681

  60. 60

    Campese VM, Parise M, Karubian F, Bigazzi R . Abnormal renal hemodynamics in black salt-sensitivepatients with hypertension Hypertension 1991 18: 805–812

  61. 61

    Bigazzi R et al. Microalbuminuria in salt-sensitivepatients Hypertension 1994 23: 195–199

  62. 62

    Mallamaci F, Leonardis D, Bellizzi V, Zoccali C . Does high salt intake cause hyperfiltration inpatients with essential hypertension J Hum Hypertens 1996 10: 157–161

  63. 63

    Weir MR, Dengel DR, Behrens MT, Goldberg AP . Salt induced increases in systolic blood pressure affect renal hemodynamics and proteinuria Hypertension 1995 25: 1339–1344

  64. 64

    Risdon RA, Sloper JC, de Wardener HE . Relationship between renal function and histological changes found on renal biopsy specimens frompatients with persistent glomerular nephritis Lancet 1968 2: 363–366

  65. 65

    Bohle A et al. The consequences of tubulo-interstitial changes for renal function in glomerulopathies. A morphometric and cytological analysis Pathol Res Pract 1990 186: 135–144

  66. 66

    Remuzzi G, Tullio B . Mechanisms of disease: pathophysiology of progressive nephropathies N Engl J Med 1998 339: 1448–1456

  67. 67

    Ruggenenti P, Remuzzi G . The role of protein traffic in the progression of renal diseases Annu Rev Med 2000 51: 315–327

  68. 68

    Taal MW, Brenner BM . Renoprotective benefits of RAS inhibition: from ACE1 to angiotensin II antagonists Kidney Int 2000 57: 1803–1817

  69. 69

    Obata JE et al. Increased expression of components of the renin-angiotensin system in glomeruli of genetically hypertensive rats J Hypertens 2000 18: 1247–1256

  70. 70

    Hall JE, Guyton AC, Branda MW . Control of sodium excretion and arterial pressure by intrarenal mechanisms and the renal-angiotensin system. In: Laragh JH, Brenner BM. (eds). Hypertension: Pathophysiology, Diagnosis and Management Raven Press Ltd: New York 1995

  71. 71

    Haugen EN, Croatt AJ, Nath KA . Angiotensin II induces renal oxidant stress in vivo and in vitro Kidney Int 2000 58: 144–152

  72. 72

    Haugen E, Nath KA . The involvement of oxidative stress in the progression of renal injury Blood Purif 1999 17: 58–65

  73. 73

    Lincoln J, Hoyle CHV, Burnstock G . Nitric Oxide in Health and Disease Cambridge University Press: Cambridge 1997

  74. 74

    Navar LG, Imig JD, Zou L, Wang CT . Intrarenal production of angiotensin II Semin Nephrol 1997 17: 412–422

  75. 75

    Gansevoort RT, de Zeeuw D, de Jong PE . Long-term benefits of the antiproteinuric effect of angiotensin-converting enzyme inhibition of nondiabetic renal disease Am J Kidney Dis 1993 22: 202–206

  76. 76

    Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D . Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril Kidney Int 1989 36: 272–279

  77. 77

    Cianciaruso B et al. Salt intake and renal outcome inpatients with progressive renal disease Miner Electrolyte Metab 1998 24: 296–301

  78. 78

    Waldron ATJ, Casley D, Jerums G, Cooper ME . Salt restriction reduces hyperfiltration, renal enlargement, and albuminuria in experimental diabetes Diabetes 1997 46: 19–24

  79. 79

    Dworkin LD, Bernstein JA, Tolbert E, Feiner HD . Salt restriction inhibits renal growth and stabilizes injury in rats with established renal disease J Am Soc Nephrol 1996 7: 437–442

  80. 80

    Allen TJ et al. Salt restriction reduces hyperfiltration, renal enlargement, and albuminuria in experimental diabetes Diabetes 1997 46: 19–24

  81. 81

    Peters H, Border WA, Noble NA . Targeting TGF-beta overexpression in renal disease: maximizing the antifibrotic action of angiotensin II blockade Kidney Int 1998 54: 1570–1580

  82. 82

    Marinides GN, Groggel GC, Cohen AH . Failure of angiotensin converting enzyme inhibition to affect the course of chronic puromycin aminonucleoside nephropathy Am J Pathol 1987 129: 394–401

  83. 83

    Bianchi S, Bigazzi R, Campese VM . Microalbuminuria in essential hypertension: significance, pathophysiology and therapeutic implications Am J Kid Dis 1999 34: 973–995

  84. 84

    Bigazzi R, Bianchi S, Baldari D, Campese VM . Microalbuminuria predicts cardiovascular events and renal insufficiency inpatients with essential hypertension predicts J Hypertens 1998 16: 1325–1333

  85. 85

    Bakris GL, Smith A . Effects of sodium intake on albumin excretion inpatients with diabetic nephropathy treated with long-acting calcium antagonists Ann Intern Med 1996 125: 201–204

  86. 86

    van der Klerj FG et al. Angiotensin converting enzyme insertion/deletion polymorphism and short-term renal response to ACE inhibition: role of sodium status Kidney Int 1997 63: S23–S26

  87. 87

    Buter H et al. The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide Nephrol Dial Transplant 1998 13: 1682–1685

  88. 88

    Massey LK, Whiting SJ . Dietary salt, urinary calcium and bone loss J Bone Min Ref 1996 11: 731–736

  89. 89

    Itoh R, Suyama Y . Sodium excretion in relation to calcium and hydroxyproline excretion in healthy Japanese population Am J Clin Nutr 1996 63: 735–740

  90. 90

    Goulding A, Everitt HE, Cooney JM, Spears GFS . Sodium and osteoporosis In: Truswell AS, Walqvist ML (eds) Recent Advances in Clinical Nutrition John Libbey: London 1986 pp 99–108

  91. 91

    MacGregor GA, Cappuccio FP . The kidney and essential hypertension: a link to osteoporosis J Hypertens 1993 11: 781–785

  92. 92

    McParland BE, Goulding A, Campbell AJ . Dietary salt affects biochemical markers of resorption and formation of bone in elderly women Br Med J 1989 299: 834–835

  93. 93

    Lian JB, Gundberg CM . Osteocalcin. Biochemical considerations and clinical applications Clin Orthop 1988 226: 267–269

  94. 94

    Saggar-Malik AK, Markandu ND, MacGregor GA, Cappucio FP . Case report. Moderate salt restriction for the management of hypertension and hypercalcurea J Hum Hypertens 1996 10: 811–813

  95. 95

    Matkovic V et al. Urinary calcium, sodium, and bone mass of young females Am J Clin Nutr 1995 62: 417–425

  96. 96

    Zarkadas M et al. Sodium chloride supplementation and urinary calcium excretion in postmenopausal women Am J Clin Nutr 1989 50: 1088–1094

  97. 97

    Devine A et al. A longitudinal study of the effect of sodium and calcium intakes on regional bone density in postmenopausal women Am J Clin Nutr 1995 62: 740–745

  98. 98

    Greendale GA et al. Dietary sodium and bone mineral density: results of a 16 year follow-up study J Am Geriatr Soc 1994 42: 1050–1055

  99. 99

    Nordin BEC, Polley KJ . Metabolic consequences of the menopause: a cross sectional, longitudinal and intervention study on 557 normal postmenopausal women Calcif Tissue Int 1987 41: S1–S59

  100. 100

    Golabek B, Slownik M, Grabowski M . Importance of dietary sodium in the hypercalciuria syndrome and nephrolithiasis Polski Merkuriusz Lekarski 2000 8: 174–177

  101. 101

    Jungers P, Daudon M, Hennequin C, Lacour B . Correlation between protein and sodium intake and calciuria in calcium lithiasis Nephrologie 1993 14: 287–290

  102. 102

    Muldowney FP, Freaney R, Moloney MF . Importance of dietary sodium in the hypercalciuria syndrome Kidney Int 1982 22: 292–296

  103. 103

    Adams JS, Wahl TO, Lukert BP . Effects of hydrochloro-thiazide and dietary sodium restriction on calcium metabolism in corticosteroid treatedpatients Metab Clin Exper 1981 303: 217–221

  104. 104

    Goulding A, Campbell DR . Effects of oral loads of sodium chloride on bone composition in growing rats consuming ample dietary calcium Miner Electrolyte Metab 1984 10: 58–62

  105. 105

    Chan EL, Swaminathan R . Calcium metabolism and bone calcium content in normal and oophorectomized rats consuming various levels of saline for 12 months J Nutrit 1998 128: 633–639

  106. 106

    Yamakawa H et al. Disturbed calcium metabolism in offspring of hypertensive parents Hypertension 1992 19: 528–534

  107. 107

    Cappuccio FP, Meilahn E, Zmuda JM, Cauley JA . High blood pressure and bone-mineral loss in elderly white women: a prospective study. Study of Osteoporotic Fractures Research Group Lancet 1999 354: 971–975

  108. 108

    Cirillio M et al. On the pathogenetic mechanism of hypercalciuria in genetically hypertensive rats of the Milan strain Am J Hypertens 1989 2: 741–746

  109. 109

    Izawa Y, Sagara K, Kadata T, Makita T . Bone disorders in spontaneously hypertensive rats Calcif Tissue Int 1985 37: 605–607

  110. 110

    Wasnich R, Davis J, Ross P, Vogel J . Effect of thiazide on rates of bone mineral loss: a longitudinal study Br Med J 1990 301: 1303–1305

  111. 111

    LeCroix AZ et al. Thiazide diuretic agents and the incidence of hip fracture N Engl J Med 1990 322: 286–290

  112. 112

    Cappuccio FP, Strazzullo P, Mancini M . Kidney stones and hypertension: population based study of an independent clinical association Br Med J 1990 300: 1234–1236

  113. 113

    Cirillo M, Laurenzi M . Elevated blood pressure and positive history of kidney stones: results from a population-based study J Hypertens 1988 6: 485–486

  114. 114

    Wexler BC, McMuirtry JP . Kidney and bladder calculi in spontaneously hypertensive rats Br J Exp Pathol 1981 62: 369–374

  115. 115

    Joossens JV et al. Dietary salt, nitrate and stomach cancer mortality in 24 countries. European Cancer Prevention (ECP) and the INTERSALT Cooperative Research Group Int J Epidemiol 1996 25: 494–504

  116. 116

    Fox JG et al. High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice Cancer Res 1999 59: 4823–4828

  117. 117

    Watanabe H et al. Effects of sodium chloride and ethanol on stomach tumorigenesis in ACI rats treated with N-methanol-N-nitro-N-nitrosoguanidine: a quant-itative morphometric approach Jpn J Cancer Res 1992 83: 588–593

  118. 118

    Palli D . Epidemiology of gastric cancer: an evaluation of available evidence J Gastroenterol 2000 35: 84–89

  119. 119

    Burney P . A diet rich in sodium may potentiate asthma. Epidemiological evidence for a new hypothesis Chest 1987 91: 143S–148S

  120. 120

    Burney PGJ et al. Response to inhaled histamine and 24 hour sodium excretion Br Med J 1986 292: 1483–1486

  121. 121

    Burney PG et al. Effect of changing dietary sodium on the airway response to histamine Thorax 1989 44: 36–41

  122. 122

    Lieberman D, Heimer D . Effect of dietary sodium on the severity of bronchial asthma Thorax 1992 47: 360–362

  123. 123

    Carey OJ, Locke C, Cookson JB . Effect of alterations of dietary sodium on the severity of asthma in men Thorax 1993 48: 714–718

  124. 124

    Britton J et al. Dietary sodium intake and the risk of airway hyperreactivity in a random adult population Thorax 1994 49: 875–880

  125. 125

    Devereux G et al. Effect of dietary sodium on airways responsiveness and its importance in the epidemiology of asthma: an evaluation in three areas of northern England Thorax 1995 50: 941–947

  126. 126

    Pistelli R et al. Respiratory symptoms and bronchial responsiveness are related to dietary salt intake and urinary potassium excretion in male children Eur Respir J 1993 6: 517–522

  127. 127

    Sparrow D, O'Connor GT, Rosner B, Weiss ST . Methacholine airway responsiveness and 24-hour urine excretion of sodium and potassium. The Normative Aging Study Am Rev Respir Dis 1991 144: 722–725

Download references

Author information

Correspondence to H E de Wardener.

Rights and permissions

Reprints and Permissions

About this article

Keywords

  • dietary salt
  • left ventricular mass
  • conduit and resistance arteries
  • strokes
  • renal function
  • bone mass

Further reading