Salt Intake and Blood Pressure

When salt is ingested it is readily absorbed in the small intestine in association with other molecules such as glucose. The intestinal secretions also contain sodium at concentrations similar to those found in the plasma but the colon has a highly effective active transport system for absorbing practically all the sodium in the colonic contents; only about 1 mmol of sodium is normally excreted in the feces except in cases of severe diarrhea Once the sodium is absorbed the body ensures that the tonicity of the body fluids is finely maintained; so water is retained by the kidney and the blood volume tends to expand until the hormonal responses, e.g., from the atrial naturetic hormone (released in response to changes in atrial pressure) and in the renin-angiotensin system, lead to a fall in the kidney and sweat glands' reabsorption of sodium and therefore a greater sodium urinary excretion and loss in sweat. There are also adjustments in vasomotor tone and the neuronal responses as well as changes in the exchange of sodium and potassium across cellular membranes. The blood pressure then rises, as the kidney reflex demands a higher blood pressure in order to limit the body's extracellular volume expansion.

The degree to which the blood pressure rises in response to dietary salt depends on a range of interacting genetic factors and other environmental influences including the intake of potassium, magnesium, and calcium. The suppressive effects of these minerals in part explain the blood pressure-lowering effects of a diet rich in fruit and vegetables. Fat intakes have been shown to amplify resting blood pressures whereas moderately intense exercise is followed by a lower blood pressure. As fat intakes rise and physical activity falls in many modern societies the body weight and body fat of children and adults increase. The greater storage of fat leads to changes in a range of hormonal secretions from the fat cells including angiotensinogen, a precursor of the renin-angiotensin axis affecting the kidney's excretion of sodium. Adiponectin secretion from expanding adipocytes falls thereby making the blood vessels much more sensitive to plaque formation, medial hypertrophy, and fibrosis. Salt-induced increases in blood pressure also involve an array of other hormonal responses including the potent vasocontrictor endothelin-1 and the vasodilator bradykinin, these being potentially involved in the blood pressure-independent effects of higher salt intake on arterial thickening, cardiac ventricular hypertrophy, and the synthesis of elastin and collagen in the artery. This makes them progressively thicker and less pliable.

Given this complex of interacting factors it is not surprising that the selective effect of salt intake on blood pressure has been hard to define. The role of salt in inducing high blood pressure is based on extensive animal experiments at the cellular and physiological level, on clinical studies and dietary intervention trials, as well as on major population analyses of blood pressure in relation to salt intake. Meta-analyses of longer term intervention trials to investigate the effect of salt reduction on hypertension also demonstrate that a modest reduction in salt intake has a significant effect on blood pressure in normotensive individuals and an even greater effect in those with pre-existing hypertension.

The response of neurohumoral mechanisms to salt loading varies in different individuals and for many years investigators sought to define what they termed 'salt-sensitive' individuals. There are rare genetic mutations associated with extreme salt sensitivity but within the general population there appears to be a more or less continuous variation in responsiveness consistent with multiple gene-environmental interactions. So perhaps it is not surprising that no clear cut-off points have been agreed for defining 'salt-sensitivity.' Patients with advanced renal failure do have an increased response of their blood pressure to salt loading but this is due to a loss of functioning nephrons.

Rural-urban differences in salt intake and blood pressure Migrant studies are useful in assessing the impact of environmental changes on blood pressure in different ethnic groups. Shaper's original study on Samburu men recruited from Kenyan villages to military camps was associated with a 12-mmHg increase in systolic blood pressure within weeks and similar findings were obtained in Ugandan villagers who had migrated to an urban environment. Table 5 shows some of the differences between individuals living in

Table 5 Migration studies that assessed rural-urban differences in Uganda, Africa

Villager

Migrant

Systolic blood pressure/age slopea

0.15

0.64

Urinary sodium (mmolr1)3

82.4

108.6

Urinary potassium (mmolr1)3

67.4

38.4

aPoulter, NR etat. (1990) The Kenyan Luo migration study: Observations on the initiation of a rise in blood pressure. Br. Med. J. 300: 967-972.

aPoulter, NR etat. (1990) The Kenyan Luo migration study: Observations on the initiation of a rise in blood pressure. Br. Med. J. 300: 967-972.

their original Ugandan environment and those who had migrated to a more complex urban environment. The Ugandan analyses evaluated the rate of rise in blood pressure with age in the two communities and showed marked differences.

Beaglehole also found that the blood pressure of Polynesian children migrating to New Zealand rose simultaneously with dietary changes and this increase was not explained simply by an increase in body weight. More recent studies, e.g., in Mexico (Table 6), show the effect of migration on both sexes. Blood pressure rises in association with increases in urinary sodium but pottasium excretion also rises and the men show a decrease in BMI.

Conversely, Japanese people migrating to the US showed marked reductions in the prevalence of hypertension and stroke mortality consistent with the known markedly lower salt intake in association with other environmental changes in the US.

In all these analyses, several dietary changes as well as altered salt intake have occurred, e.g., in potassium and calcium intakes together with weight

Table 6 The urinary 24-h output of electrolytes and the associated blood pressure (BP) differences in rural and urban Mexico

Men

Women

Rural (n = 24)

Urban (n = 19)

Rural (n = 54)

Urban (n = 58)

Sodium

103.3

133.1

93.3

114.7

(mmolday-1)

Potassium

41.6

56.7

36.9

50.4

(mmolday-1)

Sodium/potassium

2.64

2.51

2.67

2.44

ratio

NaCl (g day-1)

5.99

7.72

5.41

6.65

Systolic BP

110.4

114.3

104.4

113.8

(mmHg)

Diastolic BP

73.3

75.6

67.0

72.8

(mmHg)

BMI

25.5

25.1

24.1

26.6

BP, blood pressure; BMI, body mass index. From Sanchez-Castillo et al. (1996) Salt intake and blood pressure in rural and metropolitan Mexico. Archives of Medical Research 27: 559-566.

BP, blood pressure; BMI, body mass index. From Sanchez-Castillo et al. (1996) Salt intake and blood pressure in rural and metropolitan Mexico. Archives of Medical Research 27: 559-566.

gain, altered intensities of physical activity, and doubtless psychosocial stress from entering an unfamiliar environment. Experimental, epidemiological, and clinical evidence suggests that dietary deficiencies of potassium or calcium potentiate the sodium induction of high blood pressure. Potassium loading prevents or ameliorates the development of sodium chloride-induced hypertension in several animal models and epidemiologically the ratio of urinary sodium to potassium (Na:K) is a stronger correlate of blood pressure than either sodium or potassium alone. Results of clinical trials also suggest that an increased potassium intake decreases blood pressure in patients with hypertension and the antihyperten-sive effect of potassium is more pronounced in persons consuming a high sodium chloride intake. With acculturation, primitive societies tend to increase their sodium intake and reduce the potassium content of their diet; therefore, the combination of a high potassium with a high salt diet is somewhat unusual. High potassium intakes were found, however, in the Aomori prefecture of Japan where there was a lower blood pressure and a reduced mortality from strokes despite high-salt intake.

There is also an inverse association within and among populations between dietary calcium and blood pressure. A low calcium intake may amplify the effect of a high sodium chloride intake on blood pressure, and calcium supplementation blunts this effect. High dietary calcium also preferentially lowers blood pressure or attenuates the development of hypertension in sodium chloride-sensitive experimental models.

Given all these dietary effects discerning the impact of salt intake changes as such is not easy. The migrant studies are crude compared with analyses of controlled dietary changes in the sodium intakes of volunteers. More robust analyses can also be obtained from the relationship between sodium intakes and blood pressure across a whole spectrum of different societies where account is taken of the possible effects of sodium intakes at different ages, of other dietary and environmental effects, as well as of differences in body size. The ability to reduce blood pressure by selectively limiting dietary sodium intake has also been assessed in a series of meticulous meta-analyses.

Genetic influences Primary hypertension has a well-known familial aggregation and has been calculated to be about 40% genetically determined. Children with a family history of hypertension are 30% more likely to remain in the upper quartile of systolic blood pressure than their peers. Young adults from families with hypertension have a greater rate of sodium excretion after a salt load than adults from normotensive families. Studies of twins also provide convincing evidence for a hereditary component to salt responsiveness. However, the effect of family history decreases with age as other environmental factors, e.g., weight gain, modify the risk. Studies have suggested that polymorphisms in certain genes, such as the angiotensinogen gene, might be implicated in the blood pressure response to a high-salt intake and genes whose products function prominently in the renin-angiotensin-aldoster-one system are potential candidate genes contributing to essential hypertension. However, two meta-analyses assessed the relation of both insertion/ deletion (I/D) polymorphisms of the angiotensin-con-verting enzyme (ACE) gene and the M235T angioten-sinogen gene with primary hypertension and cardiovascular diseases and found no association with hypertension in ACE I/D gene polymorphism. Individuals homozygous for the deletion allele seem to have a higher risk of macrovascular and microvascular complications and the T allele encoding angiotensinogen may be a marker for hypertension, at least in white subjects, but great caution is needed before inferring that a single set of genes has a substantial impact on the development of higher blood pressures in response to increases in salt intake as so many neurohormonal mechanisms are involved.

Age-related changes in blood pressure In most populations, blood pressure increases with age but there are a few small groups who have not been exposed to modern environmental conditions and they do not show a rise in blood pressure with age. The Kuna indigenous population living on islands in the Panamanian Caribbean was among the first communities described showing almost no age-related rise in blood pressure or hypertension. Other populations in Africa, the Americas, Asia, and the Pacific region have the same characteristics. In many of these communities, the primary evidence that the protective factor is environmental rather than genetic was the blood pressure rise following migration to an urban environment. Among the many lines of evidence suggesting a role for salt intake in the pathogenesis of hypertension, particularly compelling has been the identification of these isolated communities where salt intake is low, hypertension is rare, and blood pressure does not rise with age. Salt intake in such communities generally provided less than 40 mmol of sodium per day, and typically much less. The age-related rise is rare at mean sodium excretion rates of <100 mmol per day but clearly there are many other dietary and environmental differences.

TO X

o T5

Range of blood pressure in a population (increases with sodium intake)

Range of individual average 24 h sodium intakes, e.g., for a Western population

100 200 300

Sodium intake (mmol/24 h)

90th Centile

Range of blood pressure in a population (increases with sodium intake)

Range of individual average 24 h sodium intakes, e.g., for a Western population

100 200 300

Sodium intake (mmol/24 h)

Figure 1 The relationships between sodium intake and blood pressure in the INTERSALT study. Adapted from: Frost CD, Law MR, Wald NJ (1991) Analysis of observational data within populations. BMJ 302: 815-818.

Intersalt studies A major transnational study of over 10 000 men and women described the association between urinary excretion of sodium chloride (as a measure of salt intake) and blood pressure. After adjustments for body weight, alcohol intake, sex, and age, a higher sodium intake of 100mmolday-1 was linked with a systolic blood pressure rise of 3-6mmHg in adults aged 40 years but one of 10mmHg when aged 70 years. Updated results suggest that the association between sodium excretion and blood pressure is stronger when not adjusted for body weight, but the relationship is present whether or not the adjustment is made.

Figure 1 summarizes the relationships between sodium intake and blood pressure in the INTERSALT study. Different populations may show different responses depending on the host of other environmental factors that may be involved. The figure also illustrates the fact that individuals within any population may show very different effects and that appreciable changes in salt intake may be needed before a clear change in blood pressure is evident. Part of the problem in displaying the relationship arises from the difficulty in establishing what the prevailing blood pressure of individuals is given the remarkable variation in blood pressure during the day and night; difficulty also arises because it takes many complete 24-h urinary collections to obtain a reasonable estimate of the customary sodium intakes. The age-related incline also implies longer term amplification of the pathophysiological changes in hormonal controls and in blood vessel reactivity and plasticity; thus, as the blood pressure increases the tendency to further increase is enhanced in an accelerating process. This emphasizes the potential importance of early interventions when the blood pressure is tending to rise. It also implies that interventions to alter the diet of the young may be particularly valuable. This is borne out by the observation in the Netherlands that newborn babies fed a reduced salt content in their formula milk for the first 6 months of life had very much lower blood pressures when reassessed at the age of 15 years.

Table 7 shows the estimated changes with age in blood pressures as the salt intake is increased by

Table 7 Predicted change in systolic and diastolic blood pressure (mmHg) for each 100mmolper 24 h change in sodium intake for various centiles of blood pressure distribution

Age (years) Centile

Table 7 Predicted change in systolic and diastolic blood pressure (mmHg) for each 100mmolper 24 h change in sodium intake for various centiles of blood pressure distribution

Age (years) Centile

5th

20th

50th

80th

90th

Systolic

15-19

3

4

5

6

7

20-29

2

4

5

6

8

30-39

2

4

6

7

9

40-49

2

4

7

9

11

50-59

4

6

9

12

15

60-69

6

8

10

13

15

Diastolic

15-19

1

1

2

2

3

20-29

1

2

3

3

4

30-39

1

2

3

4

5

40-49

2

3

4

4

5

50-59

2

3

5

6

7

60-69

2

3

4

6

7

From Law et al. (1991) By how much does dietary salt reduction lower blood pressure? III. Analysis of data from trials of salt reduction. British Medical Journal 302: 819-824.

From Law et al. (1991) By how much does dietary salt reduction lower blood pressure? III. Analysis of data from trials of salt reduction. British Medical Journal 302: 819-824.

100mmol sodium per day. Epidemiologists concerned with the subtle but substantial population effects are mostly of the opinion that salt is an important causal factor in determining the steady increase in average blood pressure and the prevalence of hypertension in Western societies.

Adults with episodic high blood pressure, e.g., as a response to mental stress, have a greater tendency to develop persisting hypertension. The higher the blood pressure level becomes, the greater the further increase in blood pressure. Thus, the age-dependent increase in blood pressure may be a particularly important factor to measure in both individuals and the community.

On a population basis it has been estimated that in affluent societies, where average population blood pressures are high, a reduction of 2 mmHg in diastolic blood pressure would result in a 15% reduction in the risks of stroke and transient ischemic attacks and a 6% reduction in risk of coronary heart disease. There may also be a reduction independent of the effects on blood pressure on other conditions such as left ventricular hypertrophy.

A higher frequency of salt responsiveness has been observed in adults with hypertension. Estimates of the prevalence of this sensitivity have ranged from 29 to 60% in hypertensive populations and 15-46% in normotensive populations, although the larger studies have indicated that over 50% of a hypertensive population and approximately 25% of a nor-motensive population are clearly salt responsive. Longer term, e.g., 27-year-long, studies have shown that those with initially normal blood pressure but a marked responsiveness to salt had an increased risk of cardiological events and death as had those with pre-existing hypertension. In the absence of a consensus on defining either the genetic polymorphisms relating to hypertension or the parameters of salt sensitivity the greatest benefits are likely to be achieved by taking a population approach to reducing salt intake.

The most recent meta-analysis, which related to studies with modest salt reductions and a duration of at least 4 weeks, showed that there were 17 trials in hypertensives and 11 trials in normotensives for analysis. The combined and pooled estimates found significant reductions in blood pressure of 4.96/2.73 mmHg in hypertensives and 2.03/0.97 mmHg in normotensives, which on a population-wide basis are significant effects.

Recently, new diagnostic thresholds to define hypertension were made available in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High

Blood Pressure. A new category designated 'prehy-pertension' is defined as systolic blood pressure values between 120 and 139 mmHg and diastolic blood pressure values of 80 to 89 mmHg. Individuals within this group require health-promoting life-style modifications to prevent cardiovascular disease since they are at increased risk for progression to hypertension. The thresholds for stage 1 hypertension are blood pressure values of 140-159 mmHg (systolic) and 90-99 mmHg (diastolic) with stage 2 hypertension being defined when blood pressure values are >160 mmHg (systolic) and >100 mmHg (diastolic) values, respectively. Both categories require life style modifications as well as drug therapy. Individuals with diabetes, who are recognized as being at greater cardiovascular risk, should keep their blood pressure below 130/80 mmHg.

Salt reduction in pre-existing hypertension Salt deprivation became the major means of treating hypertension in the early part of the twentieth century. The low-salt diets were notoriously unpalatable so patients reduced their food intake and the consequent weight loss helped to reduce the blood pressure further. A large number of trials of salt restriction have been conducted since then on both hypertensive and normotensive subjects and the overall analyses show that the greater the initial blood pressure, the more marked the fall in blood pressure, particularly if the sodium intake reduction persists. These data have been interpreted to suggest that the effect of a universal moderate reduction in dietary salt would substantially reduce a population's mortality from stroke and ischemic heart disease with an impact far greater than that achieved by drug treatment of those with high blood pressure. Thus, the World Health Organization (WHO) and most national dietary guidelines now call for a lowering of salt intake to 5-6gday-1 on average or less.

More recently, two controlled intervention trials, the Dietary Approaches to Stop Hypertension (DASH) and the follow-up DASH sodium trial, compared three different types of eating patterns: (1) the 'control diet'; (2) extra fruit and vegetables; and (3) the 'DASH or combination diet,' which was lower in saturated fat, total fat, and cholesterol as well as having higher intakes of fruits, vegetables, and low-fat dairy products. All three eating plans used 3gday-1 sodium. The results of the clinical trials found that the combination diet or 'DASH diet' decreased systolic blood pressure (SBP) by 11.4 mmHg below the control diet and decreased diastolic blood pressure (DBP) by 5.5 mmHg in adults with hypertension. In adults without hypertension the decreases were 3.5mmHg (SBP) and 2.1 mmHg (DBP).

When the selective effects of salt were examined without weight changes then reducing the salt intake from 9 to 3 g significantly reduced blood pressure by 6.7/3.5 mmHg on the controlled diet and on the higher potassium DASH diet by 3.0/1.6 mmHg. Thus, the combined effects of the DASH diet and low-salt intake on blood pressure were greater than either of the interventions alone. With this combination, mean SBP was 11.5 mmHg lower in participants with pre-existing hypertension, and 7.1 mmHg lower in participants without hypertension. The effects were observed in both sexes and across racial groups. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure in the USA and the Scientific Advisory Committee on Nutrition from the Food Standards Agency, Department of Health in the UK have acknowledged that the clear and distinct effect of salt on blood pressure shown in the trial indicates that lowering salt intake as part of a healthy whole diet strategy would be most effective as a population-based approach to lowering blood pressures.

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