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The Influence of Dietary Sodium on Blood Pressure

Departments of Medicine and Radiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts

Address reprint requests to: Norman K. Hollenberg, M.D., Ph.D., Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail: djpagecapo{at}rics.bwh.harvard.edu

	ABSTRACT

TOP FOOTNOTES ABSTRACT Introduction Observational Studies Intervention Studies... Categorical Determinants of Salt... Essential Hypertension Subtypes... Other Dietary Constituents and... Conclusions References

 
The goal of this essay is to examine the evidence relating salt intake to blood pressure in humans. Despite studies involving many thousands of subjects and patients performed in many hundreds of centers the issue remains controversial—indeed far more controversial than seems appropriate. There is little disagreement that in some animal models and in some patients with hypertension salt intake can exert a rather substantial influence. There is more controversy on the responsible mechanisms. The greatest controversy, by far, involves whether or not policy should involve a mandatory reduction in salt intake in all members of the community. The available evidence shows that the influence of salt intake is too inconsistent and generally too small to mandate policy decisions at the community level. At the level of the individual patient and that patient’s physician, it is important to recognize that salt intake can make a substantial contribution to hypertension. That contribution is more likely if the patient is old rather than young, obese rather than lean, black rather than white, has diabetes mellitus with hypertension, or has evidence of renal injury. Unfortunately, tools for assessing the sodium and chloride intake in the individual and for assessing its contribution to BP in the individual are inadequate. On the bright side, prognosis is improved substantially by the array of antihypertensive drugs available today.

Key words: sodium, chloride, bicarbonate, potassium, epidemiology, clinical trials, mechanisms

	Introduction

TOP FOOTNOTES ABSTRACT Introduction Observational Studies Intervention Studies... Categorical Determinants of Salt... Essential Hypertension Subtypes... Other Dietary Constituents and... Conclusions References

 
The word "controversial", as commonly used, has a range of meanings. At one extreme the statement is dispassionate, indicating essentially that a consensus of informed opinion has not yet been achieved. At the other extreme, the term reflects passionate advocacy and equally impassioned denial: The debate has an emotional content. The subject of sodium intake and its relationship to blood pressure often comes much closer to the latter, passionate state than the former.

This passionate controversy does not reflect the absence of information. A review of the recent literature uncovers a very large series of epidemiological studies [1–5] some of which are truly substantial, ranging from 7,354 [3] to 17,030 [4] subjects studied. In these five reports, data from over 52,000 subjects are described. The epidemiological studies vary in their design: Seventeen are cross sectional cohort studies, and ten are prospective cohort studies. Four of these papers use the Intersalt Database, which employed twenty-four urine sodium excretion measurements as the estimate of dietary intake [1]. Conversely, most other studies relied exclusively on dietary assessment instruments to estimate sodium intake. Analyses in various papers reflect fairly compelling evidence of an interaction with other dietary factors such as alcohol, potassium, the accompanying anion, fat, saturated or polyunsaturated, calcium, and dietary fiber. A detailed analysis of the contribution of these additional factors goes beyond the scope of this essay.

Not all of the observational studies found an association between sodium intake and blood pressure. Moreover, when an association was found, it generally was not very strong: After correction for potential confounding variables, especially body mass index and age, there was an influence in which 100 mmol rise in sodium intake—a truly substantial amount—led to a rather modest rise in systolic blood pressure in the range of 1–3 mmHg and diastolic blood pressure of 0–2 mmHg.

In addition, there has been a large series of intervention studies, in which salt was either withheld or supplemented, which in turn led to the publication of a series of meta-analyses. The results of these studies were rather more consistent and showed a larger effect than did the observational studies: The response to a reduction in sodium of approximately 100 mmol/day led to a reduction in systolic blood pressure of 4–5 mmHg, and a fall in diastolic blood pressure of 1–3 mmHg.

The DASH Study has led to five papers dealing with various aspects of diet and blood pressure. They documented that a reduction of sodium intake of about half led to a blood pressure fall, but less than the blood pressure fall associated with the increased fruit and vegetable intake, along with low-fat dairy products in the DASH diet [6–8]. There were eight studies on the effect of sodium loading, with mixed results. There were, in addition, several studies on the interaction between potassium intake and sodium intake where both were controlled, and studies on the influence not only on the cation, sodium, and potassium but also the accompanying anion. Sodium bicarbonate or citrate was much less effective than sodium chloride in raising blood pressure, and potassium bicarbonate had effects on blood pressure response that exceeded substantially the effects of potassium chloride. The accompanying anion clearly matters.

Another approach has involved examining subjects in isolated communities generally living a hunter-gatherer existence, in whom blood pressure rose little or not at all with age, and hypertension was distinctly uncommon. In their review, James and Baker cited thirty-nine such populations in Africa, the Americas, Asia, and the Pacific region [9]. The primary evidence that the responsible factor was environmental rather than genetic was the finding that blood pressure rose following migration to an urban environment. Among the lines of evidence suggesting a role for salt intake in the pathogenesis of hypertension, particularly compelling has been the evidence from these isolated communities where salt intake is low, hypertension is uncommon, and blood pressure does not rise with age. By 1976, Page was led to conclude that all isolated low blood pressure populations have a low-salt intake as part of their biology and probably as a major causal mechanism, and supported that conclusion by citing nine earlier studies [10]. Salt intake in such "protected" communities generally provided less than 40 mEq of sodium per day and often much less. Among the communities cited by James and Baker was the Kuna Indian tribe that resides in Panama [11]. We have recently shown that the Kuna have acculturated in situ, enjoying a very high-salt intake while still living in their original indigenous island homes: Despite the high-salt intake, blood pressure remains low, does not rise with age, and hypertension is very uncommon [12]. As fascinating as the literature reviewed by Page was [10], in fact definitive evidence that it was the change in salt intake that was the environmental factor responsible for the rise in blood pressure on migration was never obtained. Migration to an urban environment, of course, involves far more change than just a change in salt intake.

Thus, despite the accumulation of an enormous database, the issue of salt intake and its relation to blood pressure remains controversial. Perhaps it is not surprising that salt use is controversial. Salt intake has its roots deep in our history and culture. Widely separated early complex societies in Babylon, Egypt, and China described its use [13,14]. Sanskrit and daughter languages do not share a common root for the word and Indo-Europeans when first migrating did not know its use some three thousand years ago. Homer, the first European poet, called it "divine" [14]. In the Bible, Job asked "can that which is unsavory be eaten without salt". Modern scholars place that statement over twenty-four hundred years ago [15]. Mathew called the best and most admirable element of mankind the "salt of the earth". The strikingly positive words "salary, salubrious, and salutary" all owe their origins to the same root. On the other hand, in Genesis, Lot’s wife became a pillar of salt. The Romans knew the value of healthy skepticism and often took conclusions "cum grano salis". Thus, mixed attitudes to salt use are part of a tradition that is well over two thousand years old.

	Observational Studies

TOP FOOTNOTES ABSTRACT Introduction Observational Studies Intervention Studies... Categorical Determinants of Salt... Essential Hypertension Subtypes... Other Dietary Constituents and... Conclusions References

 
Perhaps the most widely cited study is the one that was performed by the Intersalt Cooperative Research Group. This study was performed in 52 centers from 32 countries [1]. Each center was asked to recruit 200 men and women ranging in age from 20 to 59 years. The assessment of sodium intake was made through the measurement of sodium excretion in a single 24-hr urine collection. After a number of adjustments, including adjustments for age and sex, body mass intake, alcohol intake, and adjustment for variance in each center’s data, positive, a statistically significant relation between median sodium excretion and median systolic blood pressure was found.

The influence of salt intake was not large. A change in sodium intake of 100 mmol/day was associated with a change of 2.2 mmHg in systolic blood pressure and 0.1 mmHg for diastolic blood pressure after the adjustments described above.

Much of this statistical effect reflected four centers with very low sodium intake and very low systolic blood pressure. Although much has been made of the fact that removal of those four centers abolished the statistical significance, that complaint does not make a great deal of sense to this reviewer. The reality is that correlation statistics depend on a spread in the x-axis, and there was much less variation in sodium intake or excretion in the remaining 48 centers.

In a similar study performed in 7,354 Scots selected from 22 districts in Scotland, a single 24-hr urine collection was again used to estimate sodium and potassium excretion [3]. The subjects ranged from 40 to 59 years of age. In this study, performed in a much more homogeneous community, no association was found between sodium excretion and blood pressure level.

Unfortunately, both of these studies restricted entry to individuals who were 59 years of age or younger. Evidence of sensitivity of blood pressure to sodium intake increases with increasing age, reviewed below, limits the interpretation of these two studies. Moreover, the study design, in which only a single 24-hr urine sample was obtained in each study does not allow us to examine the validity of that measure.

In two other very large studies, sodium intake was estimated from questionnaires based on 24-hr dietary recall. In 8,058 Belgians ranging in age from 25 to 74 years, a positive association was found between sodium intake, assessed in this way, and blood pressure [2]. In a similar study performed in the USA in 17,030 participants who were over 20 years of age, but without an upper limit of age, the relation between sodium intake and blood pressure did not achieve statistical significance in a univariate analysis [4]. In a multivariate analysis, however, which adjusted intake for body size rather than caloric intake, a significant positive correlation was found between sodium intake and blood pressure. Of some interest is the fact that the findings reported in NHANES-III [4] did not appear to confirm earlier reports from NHANES-I [5], but a different approach to analysis was employed.

These observational studies suggest, but do not prove, a relationship between sodium intake and blood pressure in the community. The effect was not large. To some extent limitations of the methods are responsible. A single 24-hr recall is not a very powerful tool for dissecting details of diet, and anyone who has tried to collect a 24-hr urine knows the limitations of a single collection. There was probably too little variation in salt intake in single communities for the assessment. Although the range was quite wide in most populations, there is no doubt that the bulk of the population occupied a rather narrow part of the range. The possibility exists that there is a threshold level and a crucial range of salt intake. For example, a 60 to 70 mmol/day intake might be necessary with the amount taken exceeding that level mattering little or not at all. The timeframe for the development of hypertension may be crucial. Current salt intake may in some way be less important than overall past intake. If our ability to assess salt intake yesterday is limited, how much more limited is our ability to assess it over years? It does not seem likely that increasing the number of subjects beyond the 52,000 in these 5 studies will provide more persuasive information.

	Intervention Studies Manipulating Salt Intake: Surfeit and Deficit

TOP FOOTNOTES ABSTRACT Introduction Observational Studies Intervention Studies... Categorical Determinants of Salt... Essential Hypertension Subtypes... Other Dietary Constituents and... Conclusions References

 
If passive observation has proven to be an inadequate approach, perhaps one can anticipate greater resolving power in studies in which salt intake is either reduced sharply or increased sharply. Indeed, that has been the case.

One of the most widely cited studies was performed by Fujita, et al. on a metabolic ward [16]. The study was small, involving only 20 patients with hypertension. They were admitted to a metabolic ward for a 3-week study in which sodium intake was limited to very low levels, then increased to levels of 250 mmol/day, and then reduced once again. One group of 10 participants was labeled "salt sensitive" in that their blood pressure rose with a high-salt intake, fell with sodium restriction, and the changes were substantial. In the other 10 participants, blood pressure on average did not change with a change in salt intake. Although the study did not identify the responsible pathophysiological mechanism, they did show that the salt sensitive showed more positive sodium balance and a larger weight gain on the transition from a low-salt to a high-salt diet, leading them to argue that the salt sensitivity reflected an inability to handle a salt load. Unfortunately, the sensitivity of blood pressure to the change in salt intake was not bimodally distributed. Rather, there was a continuum, and the decision to divide the participants into two groups of ten was arbitrary. The fact that the blood pressure response to a salt load is a continuum has been confirmed in much more substantial studies [17,18], and represents an important limitation in this field. The selection of a cutpoint has always been and remains arbitrary.

Probably because of its therapeutic implications, the influence of restriction of salt intake on blood pressure has been the subject of an enormous series of studies. An examination of published meta-analyses is instructive. Law, et al. examined seventy-eight trials of dietary salt restriction [19] and came to the conclusion that in subjects 50 to 59 years of age, a reduction of daily sodium intake of 100 mmol would lower systolic blood pressure by 14 mm Hg in hypertensive subjects if the reduction of salt intake was sustained for five weeks or more. Diastolic blood pressure would be lowered by about half as much. These effects are very large and clearly, if correct, would merit consideration for policy decisions. Unfortunately, of the seventy-eight trials that they examined only ten involved randomized controlled trials. Comparison of the results from the adequately controlled trials in the meta-analysis with poorly controlled studies suggested that most of the fall in blood pressure was attributable to the poor quality of the study. Cutler, et al. [20] adopted a more rigorous approach, and included only properly controlled randomized trials. By 1996 Midgley, et al. increased the number to 56 trials examined [21]. In 1998 Graudal, et al. had increased the number in the meta-analysis to 58 trials [22]. There seems to be a de-acceleration in the rate of growth in this area!

In 58 controlled, randomized trials in which the effect of a reduction in salt intake on blood pressure in subjects with hypertension was assessed, it was possible to induce a substantial reduction in salt intake as assessed by sodium excretion. A reduction in sodium excretion from typical levels of 170–200 mmol/day to 118 mmol/day reduced systolic blood pressure by an average of 3.9 mm Hg and diastolic blood pressure by 1.9 mm Hg [22]. The effect was smaller in 58 trials performed on the influence of salt intake in blood pressure in normotensive individuals. The results in the larger meta-analysis differed little from the earliest report [20], in which hypertensives showed a drop of 4.9–2.6 mm Hg with a smaller response in normotensive volunteers. Cutler, et al. also noted evidence of a relation between "dose" (reduction of sodium intake achieved) and response [20].

Despite the similarities of the findings, the two groups of authors were led to draw somewhat different conclusions, especially about policy recommendations. Cutler, et al. concluded that the findings were very consistent with the results of observational studies and had important implications for preventative strategies in blood pressure control [20]. The follow-up meta-analysis, although confirming the direction and magnitude of the response, suggested that a reduction in sodium intake might be employed as a supplement in treatment rather than an organizing principle [21,22]. This will be discussed further below.

If a reduction in sodium intake reduced blood pressure, one might anticipate that an increase in sodium intake will lead to an increase in blood pressure. There are many fewer studies in this direction, but the results overall are internally consistent [23,24].

Murray, et al. studied 8 healthy men who ingested a daily sodium intake ranging from 10 mEq to 1500 mEq/day, a heroic level of intake [23]. This was achieved by ingesting very large volumes of a salt-rich bouillon. Blood pressure was not increased until an 800 mEq/day sodium intake was achieved, and an additional rise in BP occurred with an increase to 1500 mEq/day. In a very similar study, Roos, et al. studied 8 normal participants over a range of sodium intakes from 20 mEq/day to 1128 mEq/day [24]. Although renal hemodynamics and plasma levels of renin and aldosterone showed dramatic shifts with changes in sodium intake, there was no consistent effect on blood pressure of a very high salt intake in this group of healthy subjects.

In this area animal studies have been much more compelling than studies in humans, at least in part because they can be carried out for months or years or many generations. Although there is an enormous literature, two studies stand out in particular. Over forty years ago, Dahl and coworkers developed a model in rats [25]. Inbreeding led to a strain of rats whose blood pressure was exquisitely sensitive to an increase in salt intake. This was accomplished by breeding rats which showed the largest blood pressure response to a high-salt intake. In an identical fashion, a group of rats in which blood pressure was resistant to salt intake were bred based on the same principle. There were two remarkable features. First was the magnitude of the influence. In sensitive rats, a high-salt diet could lead to a sustained systolic blood pressure exceeding 200 mm Hg in a few weeks and an early demise in a few months. The second surprise was how few generations were required for these models to emerge. Unambiguous and consistent salt sensitivity was induced within three generations.

The most convincing demonstration of salt sensitivity in an animal species close to humans was that obtained by Denton, et al. [26]. In this experiment, a one-year control period permitted a careful assessment of blood pressures in chimpanzees which were eating their usual, natural low-sodium, high-potassium fruit and vegetable diet. This control period was followed by a 20-month interval where salt intake was increased up to 15 grams per day gradually, added to the natural diet. The animals finally reverted to their habitual low-salt diet in a third-phase period. The study was designed to make it likely that the one variable that was changed was salt intake. The effect of salt was large with a systolic blood pressure rise of 26 mm Hg. Perhaps not surprisingly, the chimpanzees varied in their sensitivity to salt: As much as 70% were "salt sensitive". Such experiments, of course, are impossible in humans, but the fact that the influence of salt extends over many species makes it likely that humans participate in the same process.

	Categorical Determinants of Salt Sensitivity

TOP FOOTNOTES ABSTRACT Introduction Observational Studies Intervention Studies... Categorical Determinants of Salt... Essential Hypertension Subtypes... Other Dietary Constituents and... Conclusions References

 
Age has proven to be a major determinant of the sensitivity of blood pressure to changes in salt intake [1,18,27–30]. As pointed out above, some of the variation in the conclusions drawn from observational studies may very well reflect entry criteria. Several major studies restricted entry to subjects who are less than 60 years of age, a decision that could have influenced the outcome. In a recent study, systolic blood pressure and diastolic blood pressure were analyzed separately [18]: The influence of age was almost totally confined to systolic blood pressure. This finding has important implications for the interpretation of studies, which use mean arterial pressure as the blood pressure index.

Race and ethnicity have also been suggested to predispose to the sensitivity of blood pressure to salt intake. African Americans not only have a higher prevalence of hypertension and more frequent severe hypertension, they also have a greater blood pressure sensitivity to salt intake than do Caucasians [28,31–33]. Although it is tempting to attribute the salt sensitivity of African Americans to genetic factors, there is actually more genetic heterogeneity in Africa than between Africa and the rest of the world [28], so that environmental factors are more likely to make a contribution. The possibility that a specific influence of angiotensinogen gene polymorphisms plays a role is considered below.

Although obesity has been thought to contribute to salt sensitivity, in fact, the relation between body mass index and sensitivity of blood pressure to salt intake has been rather more inconsistent [18,27,32,34]. Perhaps the most compelling evidence suggesting that obesity, indeed, contributes to sensitivity of blood pressure to salt intake comes from the landmark study of Rocchini, et al. [35]. They examined the blood pressure responses to changes in salt intake in 60 obese adolescents who ranged in age from 10 to 16 years and 18 age-matched participants who were not obese. In a shift from a high salt intake (250 mmol/day) to a low salt intake (30 mmol/day), the obese showed a much larger change in blood pressure than did the non-obese. Among the predictors of salt sensitivity of blood pressure to salt intake, the percentage of body weight that was made up of fat made a substantial contribution. Fasting plasma insulin level and plasma aldosterone concentration on a low-salt diet also predicted strongly this sensitivity of blood pressure to salt intake. Following a 20-week weight loss program, some of the adolescents lost weight and others did not. With this weight loss, often rather modest, the adolescents showed a reduced sensitivity of blood pressure to salt intake and a reduction in plasma insulin concentration, aldosterone, and norepinephrine level. The 15 adolescents who did not lose weight failed to lose their sensitivity of blood pressure to salt intake.

	Essential Hypertension Subtypes and Salt Sensitivity

TOP FOOTNOTES ABSTRACT Introduction Observational Studies Intervention Studies... Categorical Determinants of Salt... Essential Hypertension Subtypes... Other Dietary Constituents and... Conclusions References

 
Few involved in studying the pathogenesis of hypertension believe that the very large group of patients identified today as having "essential hypertension" represents a single process with a single pathogenesis. Advances in our understanding of hypertension had a characteristic sequence: A specific mechanism was identified in a subset of patients, which became a form of "secondary hypertension". Chronic renal failure, recognized by Bright at Guys Hospital early in the nineteenth century, remains the most common secondary cause today. Blood pressure tends to be sensitive to salt intake in such patients. This century has seen the identification of Cushing’s syndrome, pheochromocytoma, primary aldosteronism, coarctation of the aorta, and renovascular hypertension. The identifiable causes to date are dominated by the kidney and the adrenal. The central logic in each case has involved removing from a large group of patients with a similar phenotype elevated blood pressure, subgroups of patients with an identified pathogenesis. In each case, blood pressure in these subjects was sensitive to salt intake.

Hurwitz found that nonmodulation and low-renin hypertension are two dominant mechanisms leading to salt sensitivity of hypertension [18]. Nonmodulation, involving anomalous angiotensin-dependent control of the renal circulation and the adrenal, leads to a disorder in sodium handling and sensitivity of the blood pressure to salt intake [36]. Nonmodulation has been tied to angiotensinogen gene polymorphisms both in normotensive individuals and in patients with essential hypertension [37,38].

Among diagnostic categories, low-renin essential hypertension was found to be the most common cause of salt sensitivity of blood pressure [18]. Among 274 patients with essential hypertension who were categorized, 170 or 39% proved to be low-renin essential hypertensives. In these individuals, systolic blood pressure rose by an average of 16.6 mm Hg on a shift from a low to a high salt diet. The next most frequent category was the nonmodulator designation, reflecting 24% of the patients. In this group, systolic blood pressure rose by 14.9 mm Hg on a shift from a low to a high-salt diet. Diastolic blood pressure rose more in nonmodulators (11.8 mm Hg) than it did in low-renin hypertensives (10.3 mm Hg). Both responses were about double the change in diastolic blood pressure in the remainder (6.9 mm Hg).

It has long been recognized that familial factors contribute to the sensitivity of blood pressure to salt intake [39]. Two recent studies have linked polymorphisms of the angiotensinogen gene to sensitivity of blood pressure to salt intake [40,41]. These observations have not been confirmed by two studies with equal power [42,43]. Hurwitz’s observations could account for differences in the relation between the angiotensinogen gene polymorphism and salt sensitivity [18].

	Other Dietary Constituents and Blood Pressure Salt Sensitivity

TOP FOOTNOTES ABSTRACT Introduction Observational Studies Intervention Studies... Categorical Determinants of Salt... Essential Hypertension Subtypes... Other Dietary Constituents and... Conclusions References

 
As pointed out earlier, analyses in various studies reflect rather compelling evidence of an interaction with other dietary factors. These factors include alcohol intake, potassium and magnesium, fat whether saturated or polyunsaturated, calcium, dietary fiber, and the accompanying anion. Although a detailed analysis of the contribution of these additional factors goes beyond the scope of this essay, the contribution of the accompanying anion merits attention.

In 1987, Kurtz, et al. described detailed balance studies in patients whose blood pressure was clearly sensitive to intake of sodium chloride. The surprise in that study was that in every case replacement of sodium chloride with equimolal sodium bicarbonate (administered as sodium citrate) did not replicate the blood pressure influence of sodium chloride. When bicarbonate was the anion sodium was much less likely to influence blood pressure [44].

Curtis Morris and colleagues have made a compelling argument that these findings reflect the fact that our biological processes were designed to handle a substantial intake of potassium and bicarbonate and substantially less sodium and chloride [45]. Chloride intake is minimal on a fruit and vegetable diet and rises sharply with ingestion of meat. In black subjects supplemental potassium bicarbonate blunted the pressor response to salt loading [46]. In other patients, largely Caucasian, who had essential hypertension supplementing dietary potassium intake with potassium bicarbonate for eight weeks induced a significant attenuation of hypertension, whereas similarly supplemented potassium chloride did not [47]. In rats the two potassium salts, potassium chloride and potassium bicarbonate, have opposite effects on blood pressure [48]. Of all of the food components that might interact with sodium and potassium intake, the chloride and bicarbonate story today seems to be the most compelling.

	Conclusions

TOP FOOTNOTES ABSTRACT Introduction Observational Studies Intervention Studies... Categorical Determinants of Salt... Essential Hypertension Subtypes... Other Dietary Constituents and... Conclusions References

 
This essay opens with a statement that the area is controversial. Wherein lies the controversy? There is little disagreement that in some animal models and in some humans, a large change in salt intake can lead to a substantial change in blood pressure. There is more disagreement as to the mechanisms involved, but that is disagreement and not controversy. The issues become controversial when they reach the level of policy and recommendations. For some experts, the data are sufficient that they feel passionate about the need to deal with sodium as a toxin and recommend a sharp reduction in salt intake for the community as a whole. For other experts, generally viewing the same data, such recommendations seem to go beyond the available data. The effects on average are too small and too inconsistent to demand that society as a whole changes its ways.

If the available data are insufficient to make recommendations for society as a whole, what about the individual patient and the individual physician? In some patients, the effects of salt intake are very substantial, and attention should be paid to salt intake as part of their management. In some cases, this represents abuse of salt intake with the ingestion of very large amounts. In many others, it is a special susceptibility. They tend to be older rather than younger, black rather than white, obese rather than lean, often have evidence of renal injury, and often have diabetes mellitus. Unfortunately, our tools for identifying salt sensitivity of blood pressure are inadequate. Indeed, our tools for assessing salt intake in the individual patient are not very good.

Fortunately, drugs available for the management of hypertension have improved to the point that these issues are much less important than they were sixty years ago.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT Introduction Observational Studies Intervention Studies... Categorical Determinants of Salt... Essential Hypertension Subtypes... Other Dietary Constituents and... Conclusions References

 
Sources of Support: National Institutes of Health grants T32HL-07609, NCRR GCRC M01 RR026376, P01AC00059916, 1P50ML53000, and 1R01DK54668.

Received January 9, 2006.

	References

TOP FOOTNOTES ABSTRACT Introduction Observational Studies Intervention Studies... Categorical Determinants of Salt... Essential Hypertension Subtypes... Other Dietary Constituents and... Conclusions References

 

1. Intersalt Cooperative Research Group: Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Br Med J297 :319 –328,1988 .[Medline]
2. Kesteloot H, Joosens JV: Relationship of dietary sodium potassium, calcium, and magnesium with blood pressure. Belgian interuniversity Research on Nutrition and Health. Hypertension12 :594 –499,1988 .[Abstract/Free Full Text]
3. Smith WCS, Crombie IK, Tavendale RT, Gulland SK, Tunstall-Pedoe HD: Urinary electrolyte excretion, alcohol consumption, and blood pressure in the Scottish heart health study. Br Med J297 :329 –330,1988 .[Medline]
4. Haijar IM, Grim CE, Gerge V, Kotchen TA: Impact of diet on blood pressure and age-related changes in blood pressure in the U.S. population. Arch Intern Med161 :589 –593,2001 .[Abstract/Free Full Text]
5. McCarron DA, Morris CD, Henry HJ, and Stanton JL: Blood pressure and nutrient intake in the United States. Science24 :1392 –1398,1984 .
6. Sacks FM, Svetkey LP, Volmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Mller III ER, Simons-Morton DG, Karanja N, Lin PH: Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (DASH) diet. N Engl J Med344 :3 –10,2001 .[Abstract/Free Full Text]
7. Vollmer WM, Sacks FM, Ard J, Appel LJ, Bray GA, Simons-Morton DG, Conlin PR, Svetkey SP, Erlinger TP, Moore TJ, Karanja N: Effects of diet and sodium intake on blood pressure subgroup analysis of the DASH sodium trial. Ann Intern Med135 :1019 –1028,2001 .[Abstract/Free Full Text]
8. Conlin PR, Chow D, Miller III ER, Svetkey LP, Lin PH, Harsha DW, Moore TJ, Sacks FM, Appel LJ: The effect of dietary patterns on blood pressure control in hypertensive patients: results in the dietary approaches to stop hypertension (DASH) trial. Am J Hyperten13 :949 –955,2000 .[Medline]
9. James GD, Baker PT: Human population biology and blood pressure: evolutional and ecological considerations and interpretations of population studies. In JH Laragh and BM Brenner (eds): "Hypertension, Pathophysiology, Diagnosis, and Management," 2nd ed. New York: Raven Press, pp115 –125,1995 .
10. Page LB: Epidemiologic evidence on the etiology of human hypertension and its possible prevention. Am Heart J91 :527 –534,1976 .[Medline]
11. Kean BH: The blood pressure of the Kuna Indians. Am J Trp Med Hyg24 :341 –343,1944 .
12. Hollenberg NK, Martinez G, McCullough M, Meinking T, Passan D, Preston M, Rivera A, Taplin D, Vicaria-Clement M: Aging, acculturation, salt intake, and hypertension in the Kuna of Panama. Hypertension29 :171 –176,1997 .[Abstract/Free Full Text]
13. Meneely GR: Salt. Am J Med16 :1 –3,1954 .[Medline]
14. Kaunitz H: Causes and consequences of salt consumption. Nature178 :1141 –1144,1956 .[Medline]
15. Gersh H: "The Sacred Book of the Jews." New York: Stein and Day,1968 .
16. Fujita T, Henry WL, Bartter FC, Lake CR, Delea CS: Factors influencing blood pressure in salt-sensitive patients with hypertension. Am J Med69 :334 –344,1980 .[Medline]
17. Weinberger MH Cardiovascular and humoral response to extremes of sodium intake in normal black and white men. Circulation60 :697 –706,1979 .[Free Full Text]
18. Hurwitz S, Fisher NL, Ferri C, Hopkins PN, Williams GH, Hollenberg NK: Controlled analysis of blood pressure sensitivity to sodium intake: interactions with hypertension type. J Hypertens21 :951 –959,2003 .[Medline]
19. Law MR, Frost CD, Wald NJ: By how much does dietary salt reduction lower blood pressure? Meta-analysis of data from trials of salt reduction. Br Med J302 :819 –824,1991 .[Medline]
20. Cutler JA, Follmann D, Elliott P, Suh I: An overview of randomized trials of sodium reduction and blood pressure. Hypertension17[Suppl I] :I27 –I33,1991 .[Medline]
21. Midgley JP, Matthew AG, Greenwood CMT, Logan AG: Effect of reduced dietary sodium on blood pressure. JAMA275 :1590 –1597,1996 .[Abstract]
22. Graudal NA, Galloe AM, Garred P: Effects of sodium restriction on blood pressure, renin, aldosterone, catecholamines, cholesterols, and triglycerides: A meta analysis. JAMA279 :1383 –1391,1998 .[Abstract/Free Full Text]
23. Murray RH, Luft FC, Bloch R, Weyman AE: Blood pressure responses to extremes of sodium intake in normal man (40364). Proc Soc Exp Biol Med159 :432 –436,1978 .[Medline]
24. Roos JC, Koomans HA, Dorhout Mees EJ, Delawi IMK: Renal sodium handling in normal humans subjected to low, normal, and extremely high sodium supplies. Am J Physiol (Renal Fluid Electrolyte Physiology 18)249 :F941 –F947,1985 .
25. Dahl LK, Heine M, Tassinari L: Effects of chronic excess salt ingestion. Evidence that genetic factors play an important role in susceptibility to experimental hypertension. J Exp Med115 :1173 –1190,1962 .
26. Denton D, Weisinger R, Mundy NI, Wickings EJ, Dixson A, Moisson P, Pingard AM, Shade R, Carey D, Ardaillou R, et al.: The effect of increased salt intake on blood pressure of chimpanzees. Nat Med1 :1009 –1016,1995 .[Medline]
27. Overlack A, Ruppert M, Kulloch R, Kraft K, Stumps KO: Age is a major determinant of the divergent blood pressure responses to varying salt intake in essential hypertension. Am J Hypertens8 :829 –836,1995 .[Medline]
28. Weder AB: Pathogenesis of hypertension: Genetic and environmental factors. In Hollenberg NK (ed): "Hypertension: Mechanisms & Therapy," 3rd ed. Philadelphia: Current Medicine,2001 .
29. Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS: Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension8 :127 –134,1986 .
30. Miller JZ, Weinberger MH, Daugherty SA, Fineberg NS, Christian JC, Grim CE: Heterogeneity of blood pressure response to dietary sodium restriction in normotensive adults. J Chronic Dis40 :245 –250,1987 .[Medline]
31. He FJ, Markandu ND, Sagnella GA, MacGregor GA: Importance of the renin system in determining blood pressure fall with salt restriction in black and white hypertensives. Hypertension32 :820 –824,1998 .[Abstract/Free Full Text]
32. Weinberger MH: Salt sensitivity of blood pressure in humans. Hypertension27 :481 –490,1996 .[Abstract/Free Full Text]
33. Luft FC, Miller JZ, Grim CE, Fineberg NS, Christian JC, Daugherty SA, Weinberger MH: Salt sensitivity and resistance of blood pressure. Age and race as factors in physiological response. Hypertension17 :1102 –1108,1991 .
34. Galletti F, Ferrara I, Stinga F, Iaccone R, Noviello F, Strazzullo P: Evaluation of a rapid protocol for the assessment of salt sensitivity against the blood pressure response to dietary sodium chloride restriction. Am J Hypertens10 :462 –466,1997 .[Medline]
35. Rocchini AP, Key J, Bondine D, Chico R, Moorehead C, Katch V, Martin M: The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med321 :580 –585,1989 .[Abstract]
36. Hollenberg NK, Moore TJ, Shoback D, Redgrave J, Rabinowe SL, Williams GH: Abnormal renal sodium handling in essential hypertension: Relation to failure of renal and adrenal modulation of responses to angiotensin II. Am J Med81 :412 –418,1986 .[Medline]
37. Hopkins PN, Lifton RP, Hollenberg NK, Jeunemaitre X, Hallouin MC, Skuppin J, et al.: Blunted renal vascular response to angiotensin II is associated with a common variant of the angiotensinogen gene and obesity. J Hypertens14 :199 –207,1996 .[Medline]
38. Hopkins PN, Hunt SC, Jeunemaitre X, Smith B, Solorio D, Fisher ND, et al.: Angiotensinogen genotype affects renal and adrenal responses to angiotensin II in essential hypertension. Circulation105 :1921 –1927,2002 .[Abstract/Free Full Text]
39. Luft FC, Miller JZ, Cohen SJ, Fineberg NS, Weinberger MH: Heritable aspects of salt sensitivity. Am J Cardiol61 :1H –6H,1988 .[Medline]
40. Johnson AG, Nguyen TV, Davis D: Blood pressure is linked to salt intake and modulated by the angiotensiogen gene in normotensive and hypertensive elderly subjects. J Hypertens19 :1053 –1060,2001 .[Medline]
41. Hunt SC, Geleinjnse JM, Su LL, Witteman JC, Williams RR, Grobbee DE: Enhanced blood pressure response to mild sodium reduction in subjects with the 235T variant of the angiotensinogen gene. Am J Hypertens12 :460 –466,1999 .[Medline]
42. Giner V, Poch E, Bragulat E, Oriola J, Gonzalez D, Coca A, et al.: Renin-angiotensin system genetic polymorphisms and salt sensitivity in essential hypertension. Hypertension35 :512 –517,2000 .[Abstract/Free Full Text]
43. Schorr U, Blaschke K, Beige J, Distler A, Sharma AM: Angiotensinogen M245T variant and salt sensitivity in young normotensive Caucasians. J Hypertens4 :475 –479,1999 .
44. Kurtz TW, Al-Bander HA, Morris RC Jr: "Salt-sensitive" essential hypertension in men. Is the sodium ion alone important? N Engl J Med317 :1043 –1048,1987 .
45. Morris RC Jr, Schmidlin O, Tanaka M, Forman A, Frassetto L, Sebastian A: Differing effects of supplemental KCl and KHCO3: Pathophysiological and clinical implications. Sem Nephrol19 :487 –493,1999 .[Medline]
46. Morris RC Jr, Sebastian A, Forman A, et al.: Normotensive salt sensitivity: Effects of race and dietary potassium. Hypertension33 :18 –23,1999 .[Abstract/Free Full Text]
47. Overlack A, Maus B, Ruppert M, et al.: Potassium citrate vs potassium chloride in essential hypertension: Effect on hemodynamic, hormonal, and metabolic parameters (Kaliumicitrate versus Kaliumchloride bei essentieller hypertension). Dtsch Med Wschr120 :631 –635,1995 .[Medline]
48. Tanaka M, Schmidlin O, Yi S-L, et al.: Genetically determined chloride-sensitive hypertension and stroke. Proc Natl Acad Sci USA94 :14748 –14752,1997 .[Abstract/Free Full Text]

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