A Comprehensive Review of the Salt and Blood Pressure Relationship Martin Muntzel
and Tilman
Driieke
D
espite intensive research, the relationship between dietary salt intake and blood pressure has remained imperfectly defined. While blood pressure responses following diminished salt intake have been investigated in numerous intervention trials, the outcomes are complex and not well understood. For example, Miller et al instructed a large group of normotensive individuals to reduce sodium intakes from 157 mmol/day to 68 mmol/day for a 1
From Institut National de la Sante et de la Recherche Medicale (INSERM) Unite 90, Hopital Necker, Paris, France. This work was supported in part by La Fondation pour la Recherche Medicale, Paris; Le Comite des Salines, Paris; and US Public Health Service National Institute of Diabetes and Digestive and Kidney Diseases Clinical Nutrition Research Unit P30 - DK40566, Oregon Health Sciences University, Portland, Oregon. Publication costs were defrayed by educational grants from the European Committee for the Study of Salt, Vienna and Paris; and the Salt Institute, Washington, DC. Address correspondence and reprint requests to Martin Muntzel, PhD, Department of Psychology and the Cardiovascular Center, University of Iowa, Iowa City, IA 52242.
homeostasis; potential mechanisms of salt-induced hypertension; the epidemiology of salt intake and blood pressure; the effects of salt restriction and supplementation on blood pressure regulation; the potential roles of sodium and chloride ions, as well as interactions with dietary potassium, calcium, and magnesium; current theories of salt sensitivity; the clinical risks of dietary salt depletion; and the dietary sources of salt. Am J Hypertens 1992;5:1S - 42S
KEY WORDS: Dietary sodium chloride, blood pressure, hypertension, salt sensitivity.
period of 12 weeks. The blood pressure responses following this reduction are illustrated in Figure 1. Although the population mean decreased significantly by 1 mm Hg, the responses were heterogeneous and raised the possibility that some individuals responded to sodium restriction with a decrease in blood pressure, others with no change, and still others with a blood pressure elevation. Obviously, the relation between salt intake and blood pressure is not simple and many questions need to be addressed. These questions, outlined below, make up a large part of the salt and blood pressure literature and provide an organizational framework for this review.
The Physiology of Salt Metabolism and Blood Pressure Control The cardiovascular response to salt restriction is determined by numerous physiologic mechanisms which simultaneously regulate blood pressure and sodium balance. An understanding of these systems provides a logical basis for more specific questions and for the design of appropriate studies. Thus, this section
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Salt has played an important role in the human diet since earliest times. However, increases in the availability and consumption of dietary salt have raised concerns that excessive intakes may cause hypertension. Although recent research has linked salt intake to variations in blood pressure, definitive conclusions have been lacking. Uncertainties in this area are due to the complex effects of salt on the cardiovascular system and on blood pressure regulation. Nevertheless, many of these complexities are now well understood and have been summarized in this review. Among the topics we examine are the effects of salt on fluid and electrolyte
Normotensive
Adults
rately defined by a curvilinear relationship. Other important questions concern the time length of salt restriction, a possible sensitive period to low salt during the life span, and whether salt loading, as opposed to salt deprivation, influences blood pressure.
FIGURE 1. Change in mean arterial blood pressure following dietary salt restriction in normotensive adults. The change is determined by subtracting initial blood pressure from that obtained during diet. From Miller J.Z. et al. 1
provides a review of the principles of cardiovascular physiology that interface with sodium homeostasis. Epidemiology of Salt Intake and Blood Pressure Associations between salt intake and blood pressure in large populations can be examined in epidemiologic studies. An advantage of epidemiology is that it demonstrates diet-blood pressure relationships in free-living populations consuming relatively fixed salt intakes for long periods of time. Hence, epidemiologic results indicate whether the hypothesized relation between salt and blood pressure exists in day-to-day conditions, and not only in the short-term clinical settings implemented during intervention trials. The epidemiology of salt and blood pressure can be examined through comparisons of salt intake and blood pressure across cultures, within cultures, and in migrating populations. Intervention Trials Intervention trials test whether correlations identified by epidemiologic results are direct, and not merely caused by confounding variables, or by false relationships created by chance variation in the data. In addition, by altering salt intake and holding other variables constant, intervention trials answer precise questions concerning the relation between salt and blood pressure. This type of experiment can determine whether greater reductions in salt intake stimulate greater diminutions in blood pressure. Related to this question is the problem of whether the blood pressure response to salt deprivation is linear or is more accu-
Salt Restriction as an Adjunct to Medication Dietary salt restriction may improve the capacities of many antihypertensive medications to lower blood pressure and to increase withdrawal from medication in a portion of the patient population. However, one must avoid generalizations as blood pressure responses to salt restriction combined with drug therapy seem to vary depending on the class of medication. Salt Sensitivity Dietary salt restriction generates a variable blood pressure response, including increases in some individuals and decreases in others. From a clinical point of view, an interesting possibility would be to identify subjects who consistently respond with blood pressure reductions. The search for genetic or physiologic markers of salt sensitivity has suggested some interesting directions, but it has not provided a simple answer as to why some persons are salt-sensitive and others are not. Nevertheless, salt-sensitive individuals have been characterized as being older, obese, and having higher initial blood pressures. In addition, persons of black ancestral origin have a higher degree of salt sensitivity. Other markers associated with greater sensitivity include low circulating renin levels, disturbances in calcium metabolism, excess secretion of the putative natriuretic hormone, deficits in sympathetic nervous system regulation, and an increased tendency for renal sodium retention. Finally, researchers are seeking possible genetic markers to predict the presence of salt sensitivity more accurately. Health Risks Associated with Low Salt Intakes Given the possibility that salt sensitivity may be identified with physiologic and genetic markers, these individuals may be singled out for low-salt therapy as a means to control blood pressure. However, some studies suggest that this dietary maneuver may result in health risks that may outweigh the benefits of blood pressure reduction.
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Blood Pressure Effects of Dietary Sodium and Chloride Loading Recent work has focused on the role of sodium and chloride ions in the control of arterial pressure. These studies have revealed numerous physiologic actions of the cationic and anionic components of sodium chloride as well as modest blood pressure effects. Nevertheless, it appears that only NaCl, and not other sodium or chloride salts, has a significant impact on the development of hypertension.
Problems of Adherence to Low-Salt Diets Low dietary salt therapy for hypertension control not only may involve important health risks, but may be difficult to maintain in a large number of individuals. Studies targeting the feasibility of long-term salt restriction have demonstrated the importance of individualized attention for dietary counseling, follow-up, and feedback. Furthermore, widespread salt restriction in industrialized countries may be difficult to achieve and maintain, especially in the younger sector which is more dependent on convenience and processed foods.
D I E T A R Y SALT INTAKE: B L O O D PRESSURE AND ELECTROLYTE H O M E O S T A S I S The molecule NaCl, commonly known as salt, participates in virtually every level of bodily function, from blood pressure control to the regulation of the cell membrane potential. Because of the great physiologic importance of salt, its regulation has been assigned to several interacting feedback mechanisms, all designed to guard a certain set-point of body salt. This redundancy of control works so well that astonishingly large variations in salt intake generate very small alterations in body sodium balance. In this section, the discussion of salt regulation will be limited to the mechanisms responsible for maintaining blood pressure and total body sodium balance during changes in dietary salt intake. Although these two functions are inextricably bound in their physiology, they will first be explained separately and then they will be united in the conclusion to provide an appreciation of the complexities of this interaction. 2
Dietary Salt and Blood Pressure Homeostasis Sodium chloride is the major ionic component that determines blood and extracellular osmolality, and as such it exerts direct control on extracellular and blood volumes. Therefore, reduced dietary salt intake may produce a contraction of blood volume resulting in decreased cardiac filling pressure, reduced cardiac preload and output, and an eventual fall in blood pressure. The autoregulation of blood flow in local tissues potentiates hypotensive responses. According to this mechanism, decreases in blood pressure result in decreased blood flow and, consequently, diminished oxygen supply to the tissues. For reasons not completely established, re-
Renin-Angiotensin-Aldosterone System Renin, a 40,000dalton protein with enzymatic properties, is released by the kidneys in response to reductions in body sodium and arterial blood pressure. Renin initiates a series of events in the blood stream leading to the eventual synthesis and proliferation of angiotensin II, the active protein in the renin pathway. Angiotensin II directly stimulates vascular smooth muscle contraction, increases peripheral arterial resistance, and under certain conditions elevates blood pressure. In addition, angiotensin II stimulates peripheral sympathetic nervous system activity, thereby aiding necessary increases in arterial resistance. Sympathetic Nervous System Reductions in dietary salt intake are perceived by the central nervous system directly by a diminution in sodium balance and indirectly by the consequent decline in blood pressure. These peripheral changes stimulate increases in sympathetic vasoconstrictor activity and elevations in circulating catecholamines, both contributing to elevations in cardiac output and peripheral resistance. Furthermore, elevated sympathetic renal efferent nerve activity initiates mechanisms responsible for renal sodium retention. These combined effects provide conditions favorable for blood pressure increase. 3
Antidiuretic Hormone (ADH) Antidiuretic hormone is released from the posterior hypothalamus in response to numerous stimuli including increased plasma osmolality, contraction of blood volume, and decreased blood pressure. After release into the circulation, ADH directly reduces renal water excretion, thereby preserving total body water content. In addition to regulating plasma osmolality, ADH has potent vasoconstrictor properties of its own, and can potentiate vascular smooth muscle constriction to other vasoactive agents, such as catecholamines and angiotensin II. The vasoactive properties of ADH appear to be important only under conditions of hypovolemic stress. Atrial Natriuretic Factor (ANF) Atrial natriuretic factor represents another volume and blood pressure regulatory hormone sensitive to changes in dietary salt intake. Cardiac atrial cells release ANF following volume expansion and the consequent atrial stretching. In the circulation, ANF is cleaved to an active fragment with vasorelaxing properties in the kidney and other vascular beds. Reduced salt intake will normally reduce blood volume and therefore reduce ANF release. Because ANF
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Blood Pressure Interactions with Other Dietary Ions Recent interventions have pointed to the importance of other dietary ions in the regulation of arterial pressure. Two of the more important factors, potassium and calcium, not only exhibit blood pressure effects of their own, but also modify the pressure responses to alterations in dietary salt. More complete knowledge of these complex interactions will be necessary for a full understanding of the influence of diet on the development of hypertension.
duced blood flows cause arteries to dilate in most tissues, tending to reestablish flows to normal. Because arterial blood pressure must be maintained within a narrow range to deliver a constant supply of oxygen to all tissues, a number of compensatory mechanisms are activated to avoid dangerously large decrements in pressure when dietary salt intake is altered.
induces vascular relaxation, reduced circulating levels of this hormone should promote the opposite effect, ie, elevated arterial pressure.
Dietary Salt and Electrolyte Homeostasis Changes in salt intake activate blood pressure control systems as well as other homeostatic mechanisms responsible for basal body NaCl balance. In blood pressure control, these mechanisms provide one of the finest examples of redundancy in biological systems. Consequently, serum sodium and total body sodium are maintained in the face of large variations in salt intake. The systems maintaining salt balance exist at all levels of biological control including behavior modification, alterations in hormone secretion, changes in sympathetic nervous system activity, and adjustments in renal function. Behavioral Mechanisms During volume depletion or periods of elevated blood osmolality, central control mechanisms and hormonal systems activate thirst mechanisms, thereby increasing fluid intakes. In the case of salt depletion, other, less well-defined mechanisms stimulate an elevation in salt appetite, producing salt-seeking behaviors that lead to increased ingestion of NaCl. Renin-Angiotensin-Aldosterone System Renin is released from the kidneys not only in response to low blood pressure, but also when NaCl deficits are perceived in the kidneys. As described earlier, renin induces the production of angiotensin II, which stimulates sodium conservation in the proximal convoluted tubules. Complementary to this mechanism, angiotensin II activates the synthesis and secretion of aldosterone, a steroid hormone responsible for further sodium retention in distal parts of the renal tubule. Sympathetic Nervous System Activity Sodium depletion stimulates sympathetic nervous system activity and sodium excess inhibits it. During salt depletion, sympathetic activation at the level of the efferent renal sympathetic nerves will activate sodium retention through three mechanisms: 1) an increase in renal afferent arteriole resistance producing a reduced glomerular filtration rate, 2) an increase in renal tubular reabsorption, and 3) an activation of the renin-angiotensin system.
Natriuretic Hormone Natriuretic hormone is thought to be released from the central nervous system in response to blood volume expansion by a stimulus probably similar to that for ANF. Once in the circulation, it is believed to inhibit the Na,K-ATPase pump in the renal tubules, thereby increasing renal excretion of sodium. The opposite physiologic condition, that is, reduced salt intake and the associated contraction of blood volume, should diminish natriuretic hormone levels, leading to increased renal retention of sodium. As yet, however, there is little direct evidence for the existence of the natriuretic hormone. Interactions Between Blood Pressure and Electrolyte Balance As mentioned earlier, blood pressure control and salt regulation cannot readily be separated. The renin-angiotensin system, sympathetic nervous system, and ANF all regulate salt balance and blood pressure more or less simultaneously; the functions are not distinct. This interdependence is further illustrated by the well-known pressure-natriuresis relationship. Stated simply, increases in blood pressure lead to increased renal sodium excretion, whereas decreases in pressure reduce sodium excretion. This relationship can be demonstrated in isolated kidney preparations and is basic to renal function. The dependence of blood pressure on blood volume is another example of the interdependence between salt and blood pressure. Thus, changes in urinary salt excretion may stimulate change in blood volume which, through alterations in cardiac output, may alter blood pressure. Section Summary The above description is only an overview of the exceedingly complex physiology of salt and blood pressure homeostasis. In fact, more important than a complete understanding of the physiology is a realization of this complexity, which may explain the heterogeneous blood pressure response to salt depletion. Figure 1 shows responses to salt depletion that appear to be specific for each person, attributed to the unique physiologic and genetic makeup of each subject. This natural biological variation explains a large part of the difficult and conflicting literature describing the relation between salt and blood pressure.
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Summary of Blood Pressure Mechanisms Dietary salt intake strongly influences blood volume and pressure. The importance of this influence is illustrated by multiple compensatory mechanisms that ensure stable blood pressure during variations in salt intake. Accordingly, dietary salt reduction elevates both renin-angiotensin and peripheral sympathetic nervous system activity, counteracting the tendency towards diminished blood volume and pressure. Low salt-generated increases in ADH and decreases in ANF further aid in re-elevating blood pressure to the normal range.
Atrial Natriuretic Factor Recent evidence suggests that ANF plays a direct role in sodium homeostasis. During sodium depletion, for example, contraction of the vascular space will decrease intra-atrial pressure, reducing the stimulus for ANF release. Because ANF reduces renal vascular resistance and increases glomerular filtration leading to enhanced sodium excretion, a diminution of ANF will result in the opposite effect, that is, a decrease in urinary sodium loss.
MECHANISMS OF SALT-GENERATED B L O O D PRESSURE ELEVATIONS
standing of the epidemiologic and intervention data that follow.
While it is well-accepted that NaCl elevates blood pressure in sensitive individuals, the mechanisms of this response have not been elucidated. Progress in this area has been slow because of physiologic and genetic variations in blood pressure responsiveness to salt intake. As suggested by current data, the subset of "responders," those subjects who respond to NaCl deprivation with a decrease in blood pressure, is probably not a homogeneous group. Of the entire group of responders in one study, some were characterized by a decrease in cardiac output while others exhibited a decrement in peripheral resistance. This is not surprising considering the diversity of pressure responses observed for nearly all cardiovascular stimuli. Consequently, blood pressure response to dietary salt manipulation must be examined on an individual basis; the direction of the response will vary according to the subject, and the mechanisms responsible for that response will again be specific to that individual's particular physiology.
Elevated Blood Volume and Cardiac Output Using experimental evidence and elegant computer modeling, Guyton et al developed a cybernetic framework proposing a critical role of the kidneys in salt-induced hypertension. According to this scheme, renal NaCl excretory defects combined with large sodium intakes exceed excretory capacity, leading to sodium and water retention and blood volume expansion. Augmented venous return increases cardiac preload, reflexively enhancing cardiac output and elevating arterial blood pressure. Under normal conditions, this elevated cardiac output is accompanied by increased peripheral vascular resistance to maintain pressure in balance with physiologic need, a process called long-term autoregulation. By elevating arterial pressure and boosting renal sodium and water excretion, these effects progressively diminish blood volume until blood pressure returns to normal. However, in hypertensive-prone kidneys, a sustained tendency to retain sodium and water leads to sustained long-term autoregulation, eventually generating permanent elevations in peripheral vascular resistance, along with renal vascular lesions, and ultimately hypertension. Consistent with this hypothesis, diminished capacities for sodium and water excretion have been observed in models of hypertension. One group suggested that this defect depends on diminished renal response to ANF. In agreement with the hypothesis of Guyton et al, rats made hypertensive with excess dietary NaCl often display transient elevations in cardiac output followed by sustained increases in vascular resistance. However, these elevations have only been observed in partial nephrectomy models and have been difficult to induce in intact animals, and may be explained by mechanisms other than NaCl-induced volume expansion. This pattern of physiologic events has also been reported in humans. However, there is little evidence that total body sodium, exchangeable sodium, plasma volume, or cardiac output are predictably disturbed in hypertension. In addition, researchers have had difficulty finding a quantitative relation between sodium retention and blood pressure change during salt loading.
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Central Role of the Kidneys in the Development of Hypertension Dietary salt can influence blood pressure only through an alteration of renal function. This theoretical framework arose from a series of transplantation studies which pointed to a critical role of the kidneys in the development and maintenance of hypertension. When kidneys from hypertensive rats were transplanted to their normotensive counterparts, these animals developed chronic high blood pressure. However, hypertensive rats receiving kidneys from normotensive animals showed no change in blood pressure. The subsequent hypothesis, known as the pressure-natriuresis relationship, indicated a pivotal role of the kidneys in long-term control of blood pressure. According to this cybernetic hypothesis, an influence that stimulates an elevation in blood pressure (eg, a rise in cardiac output or peripheral resistance) will generate increases in urinary sodium and water excretion, eventually effecting blood volume losses until blood pressure returns to normal. For salt loading to result in permanent changes in arterial pressure, renal function must be altered. Thus, all the theories proposed to explain the blood pressure effects of salt loading include an alteration of renal sodium handling as part of the mechanism. Comprising the leading hypotheses are salt-induced changes in blood volume and cardiac output, enhanced secretion of the putative natriuretic hormone, derangement of the sympathetic nervous system, and alterations of calcium metabolism. Because analysis of the strength of each hypothesis is beyond the scope of this article, each is discussed only to the extent required for a clear under6
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The Natriuretic Hormone Hypothesis Excess dietary salt intake may elevate blood pressure through a hormonal mediator. The most commonly postulated mediator is an inhibitor of Na,K-ATPase known as the natriuretic hormone. This hormone may function in parallel with the pressure-natriuresis mechanism to rid the body of excess sodium when intake is elevated. As described by Guyton et al, increased dietary sodium elevates intravascular volume and occasionally in13,14
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Elevated Sympathetic Nervous System (SNS) Activity Excess salt intake may elevate blood pressure through stimulation of peripheral SNS activity. Enhanced sympathetic outflow activates peripheral vasoconstriction and increases renal sodium retention through renal sympathetic nerve activity. Sodium chloride may boost sympathetic activity at the nerve endings or by elevating circulating natriuretic hormone levels. Excess salt may additionally enhance peripheral sympathetic activity through central effects. Consistent with this possibility, lesions in sympathetic control centers of 18,19
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experimental animals prevent the expression of salt-induced hypertension. Similarly, salt-induced blood pressure elevations alter transmitter activity in the anterior hypothalamus of the spontaneously hypertensive rat (SHR). This brain area plays an important role in the regulation of peripheral sympathetic outflow. Two hypotheses emerging from these data suggest altered central sympathetic activity, with subsequent disinhibition of peripheral outflow and vasoconstriction. The first, primarily a receptor mechanism, proposes salt-induced diminished affinity of central a ' P f ° their agonists, with a disrupted central sympathetic control leading to an eventual stimulation of peripheral activity. According to the second hypothesis, excess dietary salt may alter sodium channel activity in the anterior hypothalamus, leading to reduced central NE activity followed by elevated peripheral activity and the generation of chronic hypertension. Thus, excess dietary sodium may stimulate sympathetic vasoconstriction through alteration of peripheral and central regulation sites. Salt-associated elevations in sympathetic activity enhance vasoconstriction and potentiate renal sodium retention, the latter elevating blood pressure through volume expansion. Clearly, the physiology is complex: salt may increase blood pressure through one or both of these mechanisms. 20
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Alteration of Calcium and Potassium Metabolism Dietary sodium loading may generate calcium and potassium deficiencies leading to altered hormone balances, vascular smooth muscle contraction, and elevated blood pressure. Excess dietary salt enhances urinary calcium excretion in humans and experimental animals. " " If this condition is prolonged, the calcium deficit generates defects in cellular calcium pump activity, increased intracellular calcium, and vascular constriction. Further, calcium deficiency may engender metabolic adjustments including increases in circulating parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (l,25(OH)D ) levels. Both of these hormonal factors may increase cellular calcium influx in vascular smooth muscle cells and stimulate blood pressure rises. ' Salt loading also increases urinary potassium loss. This dietary maneuver is even associated with occasional decreases in plasma potassium concentration. It has been hypothesized that high sodium-induced potassium deficiency may lead to increased vasoconstriction and enhanced cardiac contractility. Potassium depletion may potentiate vasoconstriction, in part through inhibition of the Na,K-ATPase in vascular cells. Combined, these physiological alterations stimulate increases in arterial pressure. 23
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creases serum sodium concentration. By whatever receptor mechanism, these alterations are perceived by the brain, triggering a hypothetical release of natriuretic hormone. In the kidneys, this hormone reduces tubular reabsorption of sodium by inhibiting Na,K-ATPase, leading to natriuresis and diuresis. Chronic natriuretic hormone release may elevate arterial pressure. This rise is thought to be generated by wide-spread inhibition of Na,K-ATPase in vascular smooth muscle, depolarizing the cell membrane, and eventually increasing calcium influx. The resulting reduction in the sodium gradient across the cell membrane diminishes calcium efflux via the N a / C a exchange pump. Reduced efflux and increased influx elevates cytosolic calcium, promoting vascular smooth muscle contraction and elevated blood pressure. These identical cellular events operating at sympathetic nerve endings potentiate norepinephrine (NE) release and inhibit re-uptake, leaving more NE at the neuromuscular cleft. An elevation of sympathetic activity through this mechanism promotes the tendency for blood pressure elevation. Despite intense investigation, the nature, anatomical source, and mode of action of the natriuretic hormone have not been elucidated, primarily because of the complexity of this system. Natriuretic hormone may be composed of a series of compounds making up a regulatory system. Supporting the natriuretic hormone hypothesis, increased intracellular sodium has been reported in hypertensive humans compared with their normotensive counterparts. ' In addition, Goto et a l isolated compounds from human urine which inhibited Na,K pump activity and elevated cytosolic free calcium in isolated cells. Other researchers have demonstrated that dietary salt loading not only elicits increases in blood pressure in salt-sensitive patients, but also elevates lymphocyte calcium concentrations. These events were not correlated in patients not sensitive to dietary salt. In contrast, altered N a / K transport in hypertension has not been clearly demonstrated. Furthermore, the existence of the natriuretic hormone remains hypothetical, and therefore its role in the development of hypertension remains only speculative.
EPIDEMIOLOGY OF DIETARY SALT INTAKE AND HYPERTENSION
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Between-Population Studies Early cross-cultural epi demiology of salt and hypertension was dominated by the work of D a h l and Gleibermann. Dahl examined sodium intake and blood pressure in five world-wide populations from which he showed a near-linear, posi tive relationship. Although provocative, these findings were limited by small sample size and the nonuniform, prospective study design. Gleibermann reexamined this association using published data from a much larger cross-section of the world's population. Her findings (the results shown in Figure 2 apply to males only) again revealed a positive linear relationship between salt in take and blood pressure across 27 populations. From a medical standpoint, the lack of hypertension in nonindustrialized low-salt consuming populations was of primary interest. In these populations, over 20 of which have been described, sodium intake was invari ably less than 30 mmol/day, and blood pressure re mained constant or even diminished slightly through out life. A commonly cited report by Page et a l described six separate, relatively primitive populations in the Solomon Islands. Unique among them were the Lau, who prepared most of their meals in salty coastal waters, resulting in higher salt intakes (150 to 230 mmol/day) than the other groups (20 to 130 mmol/ day). The Lau exhibited the highest blood pressures (Fig ure 3), consistent with the hypothesis that higher salt intake may increase blood pressure. The lack of statistical analysis weakened this conclu sion. Furthermore, other explanations may account for 32
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4 8 12 16 20 24 28 Blood pressure and salt intake (males)
FIGURE 2. Increase in blood pressure with increasing salt in take. Mean blood pressure was correlated with and regressed on mean daily salt intake. Blood pressure values were plotted on a logarithmic scale. From Gleibermann L. et al. 33
the higher blood pressures, as these people had a larger body mass and lived in crowded living conditions. These findings in primitive cultures led to the hy pothesis that hypertension can be avoided in Western civilizations by curtailing salt intake. The hypothesis implies that salt intakes above about 30 mmol/day are an important, if not primary, cause of hypertension in industrialized cultures. This claim has been widely criticized, primarily because the data are correlational. The lack of hypertension in these societies may be caused by many factors other than salt intake. Primitive cultures generally consume relatively large amounts of potassium, drink little or no alcohol, and are primar ily vegetarian ; fiber intake is greater and consumption of saturated fats is much less. Unacculturated people also tend to be smaller, leaner, and more physically ac tive than their acculturated counterparts; and impor tantly, they do not gain weight with age. Psychologic factors may also play a role, as recognized by Gleiber mann who concluded that "it cannot be stated whether salt or other cultural changes or both are caus ing the increase in blood pressure." The clearly defined community roles of tribal societies encompass a set of 34,36
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Advantages and Limitations of the Epidemiological Perspective Correlations obtained from epidemiology are designed to identify associations between selected variables in a given population. The advantage lies in the ability to identify several environmental variables related to blood pressure; regression analysis then allows an estimation of the predictive power of each variable. Furthermore, estimations of interactions be tween variables and their combined influences on blood pressure can be assessed. The greatest shortcoming of population studies, is their limitation to correlational interpretation. Causality can be suggested but not concluded. Hence, positive associations between salt intake and blood pressure may suggest pressor effects of salt itself, or hypertensive in fluences of other agents linked to salt intake that may confound the association. For this reason, population studies are valuable for generating hypotheses about factors that may influence blood pressure. Confirmation of these hypotheses can only come from intervention studies that test the effects of each factor on blood pres
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140 mm Hg or diastolic pressure > 9 0 mm Hg or the use of antihypertensive agents, was positively related to sodium excretion. Yet as in the earlier analysis, this association was lost when reanalyzed using only the 48 "high salt" centers. The Intersalt investigators esti mated that a 100 mmol/day decrease in sodium intake would lower average blood pressures by 2.2 mm Hg systolic and 0.5 mm Hg diastolic, when adjusted for age, sex, potassium excretion, body mass index, and alcohol intake. These correlations are rather weak. Perhaps the true relation of salt intake to blood pressure is stronger but was clouded by imperfect data sampling. It is remark able, however, that correlations grow weaker as studies
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Driieke
D
espite intensive research, the relationship between dietary salt intake and blood pressure has remained imperfectly defined. While blood pressure responses following diminished salt intake have been investigated in numerous intervention trials, the outcomes are complex and not well understood. For example, Miller et al instructed a large group of normotensive individuals to reduce sodium intakes from 157 mmol/day to 68 mmol/day for a 1
From Institut National de la Sante et de la Recherche Medicale (INSERM) Unite 90, Hopital Necker, Paris, France. This work was supported in part by La Fondation pour la Recherche Medicale, Paris; Le Comite des Salines, Paris; and US Public Health Service National Institute of Diabetes and Digestive and Kidney Diseases Clinical Nutrition Research Unit P30 - DK40566, Oregon Health Sciences University, Portland, Oregon. Publication costs were defrayed by educational grants from the European Committee for the Study of Salt, Vienna and Paris; and the Salt Institute, Washington, DC. Address correspondence and reprint requests to Martin Muntzel, PhD, Department of Psychology and the Cardiovascular Center, University of Iowa, Iowa City, IA 52242.
homeostasis; potential mechanisms of salt-induced hypertension; the epidemiology of salt intake and blood pressure; the effects of salt restriction and supplementation on blood pressure regulation; the potential roles of sodium and chloride ions, as well as interactions with dietary potassium, calcium, and magnesium; current theories of salt sensitivity; the clinical risks of dietary salt depletion; and the dietary sources of salt. Am J Hypertens 1992;5:1S - 42S
KEY WORDS: Dietary sodium chloride, blood pressure, hypertension, salt sensitivity.
period of 12 weeks. The blood pressure responses following this reduction are illustrated in Figure 1. Although the population mean decreased significantly by 1 mm Hg, the responses were heterogeneous and raised the possibility that some individuals responded to sodium restriction with a decrease in blood pressure, others with no change, and still others with a blood pressure elevation. Obviously, the relation between salt intake and blood pressure is not simple and many questions need to be addressed. These questions, outlined below, make up a large part of the salt and blood pressure literature and provide an organizational framework for this review.
The Physiology of Salt Metabolism and Blood Pressure Control The cardiovascular response to salt restriction is determined by numerous physiologic mechanisms which simultaneously regulate blood pressure and sodium balance. An understanding of these systems provides a logical basis for more specific questions and for the design of appropriate studies. Thus, this section
Downloaded from http://ajh.oxfordjournals.org/ at Michigan State University on June 9, 2015
Salt has played an important role in the human diet since earliest times. However, increases in the availability and consumption of dietary salt have raised concerns that excessive intakes may cause hypertension. Although recent research has linked salt intake to variations in blood pressure, definitive conclusions have been lacking. Uncertainties in this area are due to the complex effects of salt on the cardiovascular system and on blood pressure regulation. Nevertheless, many of these complexities are now well understood and have been summarized in this review. Among the topics we examine are the effects of salt on fluid and electrolyte
Normotensive
Adults
rately defined by a curvilinear relationship. Other important questions concern the time length of salt restriction, a possible sensitive period to low salt during the life span, and whether salt loading, as opposed to salt deprivation, influences blood pressure.
FIGURE 1. Change in mean arterial blood pressure following dietary salt restriction in normotensive adults. The change is determined by subtracting initial blood pressure from that obtained during diet. From Miller J.Z. et al. 1
provides a review of the principles of cardiovascular physiology that interface with sodium homeostasis. Epidemiology of Salt Intake and Blood Pressure Associations between salt intake and blood pressure in large populations can be examined in epidemiologic studies. An advantage of epidemiology is that it demonstrates diet-blood pressure relationships in free-living populations consuming relatively fixed salt intakes for long periods of time. Hence, epidemiologic results indicate whether the hypothesized relation between salt and blood pressure exists in day-to-day conditions, and not only in the short-term clinical settings implemented during intervention trials. The epidemiology of salt and blood pressure can be examined through comparisons of salt intake and blood pressure across cultures, within cultures, and in migrating populations. Intervention Trials Intervention trials test whether correlations identified by epidemiologic results are direct, and not merely caused by confounding variables, or by false relationships created by chance variation in the data. In addition, by altering salt intake and holding other variables constant, intervention trials answer precise questions concerning the relation between salt and blood pressure. This type of experiment can determine whether greater reductions in salt intake stimulate greater diminutions in blood pressure. Related to this question is the problem of whether the blood pressure response to salt deprivation is linear or is more accu-
Salt Restriction as an Adjunct to Medication Dietary salt restriction may improve the capacities of many antihypertensive medications to lower blood pressure and to increase withdrawal from medication in a portion of the patient population. However, one must avoid generalizations as blood pressure responses to salt restriction combined with drug therapy seem to vary depending on the class of medication. Salt Sensitivity Dietary salt restriction generates a variable blood pressure response, including increases in some individuals and decreases in others. From a clinical point of view, an interesting possibility would be to identify subjects who consistently respond with blood pressure reductions. The search for genetic or physiologic markers of salt sensitivity has suggested some interesting directions, but it has not provided a simple answer as to why some persons are salt-sensitive and others are not. Nevertheless, salt-sensitive individuals have been characterized as being older, obese, and having higher initial blood pressures. In addition, persons of black ancestral origin have a higher degree of salt sensitivity. Other markers associated with greater sensitivity include low circulating renin levels, disturbances in calcium metabolism, excess secretion of the putative natriuretic hormone, deficits in sympathetic nervous system regulation, and an increased tendency for renal sodium retention. Finally, researchers are seeking possible genetic markers to predict the presence of salt sensitivity more accurately. Health Risks Associated with Low Salt Intakes Given the possibility that salt sensitivity may be identified with physiologic and genetic markers, these individuals may be singled out for low-salt therapy as a means to control blood pressure. However, some studies suggest that this dietary maneuver may result in health risks that may outweigh the benefits of blood pressure reduction.
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Blood Pressure Effects of Dietary Sodium and Chloride Loading Recent work has focused on the role of sodium and chloride ions in the control of arterial pressure. These studies have revealed numerous physiologic actions of the cationic and anionic components of sodium chloride as well as modest blood pressure effects. Nevertheless, it appears that only NaCl, and not other sodium or chloride salts, has a significant impact on the development of hypertension.
Problems of Adherence to Low-Salt Diets Low dietary salt therapy for hypertension control not only may involve important health risks, but may be difficult to maintain in a large number of individuals. Studies targeting the feasibility of long-term salt restriction have demonstrated the importance of individualized attention for dietary counseling, follow-up, and feedback. Furthermore, widespread salt restriction in industrialized countries may be difficult to achieve and maintain, especially in the younger sector which is more dependent on convenience and processed foods.
D I E T A R Y SALT INTAKE: B L O O D PRESSURE AND ELECTROLYTE H O M E O S T A S I S The molecule NaCl, commonly known as salt, participates in virtually every level of bodily function, from blood pressure control to the regulation of the cell membrane potential. Because of the great physiologic importance of salt, its regulation has been assigned to several interacting feedback mechanisms, all designed to guard a certain set-point of body salt. This redundancy of control works so well that astonishingly large variations in salt intake generate very small alterations in body sodium balance. In this section, the discussion of salt regulation will be limited to the mechanisms responsible for maintaining blood pressure and total body sodium balance during changes in dietary salt intake. Although these two functions are inextricably bound in their physiology, they will first be explained separately and then they will be united in the conclusion to provide an appreciation of the complexities of this interaction. 2
Dietary Salt and Blood Pressure Homeostasis Sodium chloride is the major ionic component that determines blood and extracellular osmolality, and as such it exerts direct control on extracellular and blood volumes. Therefore, reduced dietary salt intake may produce a contraction of blood volume resulting in decreased cardiac filling pressure, reduced cardiac preload and output, and an eventual fall in blood pressure. The autoregulation of blood flow in local tissues potentiates hypotensive responses. According to this mechanism, decreases in blood pressure result in decreased blood flow and, consequently, diminished oxygen supply to the tissues. For reasons not completely established, re-
Renin-Angiotensin-Aldosterone System Renin, a 40,000dalton protein with enzymatic properties, is released by the kidneys in response to reductions in body sodium and arterial blood pressure. Renin initiates a series of events in the blood stream leading to the eventual synthesis and proliferation of angiotensin II, the active protein in the renin pathway. Angiotensin II directly stimulates vascular smooth muscle contraction, increases peripheral arterial resistance, and under certain conditions elevates blood pressure. In addition, angiotensin II stimulates peripheral sympathetic nervous system activity, thereby aiding necessary increases in arterial resistance. Sympathetic Nervous System Reductions in dietary salt intake are perceived by the central nervous system directly by a diminution in sodium balance and indirectly by the consequent decline in blood pressure. These peripheral changes stimulate increases in sympathetic vasoconstrictor activity and elevations in circulating catecholamines, both contributing to elevations in cardiac output and peripheral resistance. Furthermore, elevated sympathetic renal efferent nerve activity initiates mechanisms responsible for renal sodium retention. These combined effects provide conditions favorable for blood pressure increase. 3
Antidiuretic Hormone (ADH) Antidiuretic hormone is released from the posterior hypothalamus in response to numerous stimuli including increased plasma osmolality, contraction of blood volume, and decreased blood pressure. After release into the circulation, ADH directly reduces renal water excretion, thereby preserving total body water content. In addition to regulating plasma osmolality, ADH has potent vasoconstrictor properties of its own, and can potentiate vascular smooth muscle constriction to other vasoactive agents, such as catecholamines and angiotensin II. The vasoactive properties of ADH appear to be important only under conditions of hypovolemic stress. Atrial Natriuretic Factor (ANF) Atrial natriuretic factor represents another volume and blood pressure regulatory hormone sensitive to changes in dietary salt intake. Cardiac atrial cells release ANF following volume expansion and the consequent atrial stretching. In the circulation, ANF is cleaved to an active fragment with vasorelaxing properties in the kidney and other vascular beds. Reduced salt intake will normally reduce blood volume and therefore reduce ANF release. Because ANF
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Blood Pressure Interactions with Other Dietary Ions Recent interventions have pointed to the importance of other dietary ions in the regulation of arterial pressure. Two of the more important factors, potassium and calcium, not only exhibit blood pressure effects of their own, but also modify the pressure responses to alterations in dietary salt. More complete knowledge of these complex interactions will be necessary for a full understanding of the influence of diet on the development of hypertension.
duced blood flows cause arteries to dilate in most tissues, tending to reestablish flows to normal. Because arterial blood pressure must be maintained within a narrow range to deliver a constant supply of oxygen to all tissues, a number of compensatory mechanisms are activated to avoid dangerously large decrements in pressure when dietary salt intake is altered.
induces vascular relaxation, reduced circulating levels of this hormone should promote the opposite effect, ie, elevated arterial pressure.
Dietary Salt and Electrolyte Homeostasis Changes in salt intake activate blood pressure control systems as well as other homeostatic mechanisms responsible for basal body NaCl balance. In blood pressure control, these mechanisms provide one of the finest examples of redundancy in biological systems. Consequently, serum sodium and total body sodium are maintained in the face of large variations in salt intake. The systems maintaining salt balance exist at all levels of biological control including behavior modification, alterations in hormone secretion, changes in sympathetic nervous system activity, and adjustments in renal function. Behavioral Mechanisms During volume depletion or periods of elevated blood osmolality, central control mechanisms and hormonal systems activate thirst mechanisms, thereby increasing fluid intakes. In the case of salt depletion, other, less well-defined mechanisms stimulate an elevation in salt appetite, producing salt-seeking behaviors that lead to increased ingestion of NaCl. Renin-Angiotensin-Aldosterone System Renin is released from the kidneys not only in response to low blood pressure, but also when NaCl deficits are perceived in the kidneys. As described earlier, renin induces the production of angiotensin II, which stimulates sodium conservation in the proximal convoluted tubules. Complementary to this mechanism, angiotensin II activates the synthesis and secretion of aldosterone, a steroid hormone responsible for further sodium retention in distal parts of the renal tubule. Sympathetic Nervous System Activity Sodium depletion stimulates sympathetic nervous system activity and sodium excess inhibits it. During salt depletion, sympathetic activation at the level of the efferent renal sympathetic nerves will activate sodium retention through three mechanisms: 1) an increase in renal afferent arteriole resistance producing a reduced glomerular filtration rate, 2) an increase in renal tubular reabsorption, and 3) an activation of the renin-angiotensin system.
Natriuretic Hormone Natriuretic hormone is thought to be released from the central nervous system in response to blood volume expansion by a stimulus probably similar to that for ANF. Once in the circulation, it is believed to inhibit the Na,K-ATPase pump in the renal tubules, thereby increasing renal excretion of sodium. The opposite physiologic condition, that is, reduced salt intake and the associated contraction of blood volume, should diminish natriuretic hormone levels, leading to increased renal retention of sodium. As yet, however, there is little direct evidence for the existence of the natriuretic hormone. Interactions Between Blood Pressure and Electrolyte Balance As mentioned earlier, blood pressure control and salt regulation cannot readily be separated. The renin-angiotensin system, sympathetic nervous system, and ANF all regulate salt balance and blood pressure more or less simultaneously; the functions are not distinct. This interdependence is further illustrated by the well-known pressure-natriuresis relationship. Stated simply, increases in blood pressure lead to increased renal sodium excretion, whereas decreases in pressure reduce sodium excretion. This relationship can be demonstrated in isolated kidney preparations and is basic to renal function. The dependence of blood pressure on blood volume is another example of the interdependence between salt and blood pressure. Thus, changes in urinary salt excretion may stimulate change in blood volume which, through alterations in cardiac output, may alter blood pressure. Section Summary The above description is only an overview of the exceedingly complex physiology of salt and blood pressure homeostasis. In fact, more important than a complete understanding of the physiology is a realization of this complexity, which may explain the heterogeneous blood pressure response to salt depletion. Figure 1 shows responses to salt depletion that appear to be specific for each person, attributed to the unique physiologic and genetic makeup of each subject. This natural biological variation explains a large part of the difficult and conflicting literature describing the relation between salt and blood pressure.
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Summary of Blood Pressure Mechanisms Dietary salt intake strongly influences blood volume and pressure. The importance of this influence is illustrated by multiple compensatory mechanisms that ensure stable blood pressure during variations in salt intake. Accordingly, dietary salt reduction elevates both renin-angiotensin and peripheral sympathetic nervous system activity, counteracting the tendency towards diminished blood volume and pressure. Low salt-generated increases in ADH and decreases in ANF further aid in re-elevating blood pressure to the normal range.
Atrial Natriuretic Factor Recent evidence suggests that ANF plays a direct role in sodium homeostasis. During sodium depletion, for example, contraction of the vascular space will decrease intra-atrial pressure, reducing the stimulus for ANF release. Because ANF reduces renal vascular resistance and increases glomerular filtration leading to enhanced sodium excretion, a diminution of ANF will result in the opposite effect, that is, a decrease in urinary sodium loss.
MECHANISMS OF SALT-GENERATED B L O O D PRESSURE ELEVATIONS
standing of the epidemiologic and intervention data that follow.
While it is well-accepted that NaCl elevates blood pressure in sensitive individuals, the mechanisms of this response have not been elucidated. Progress in this area has been slow because of physiologic and genetic variations in blood pressure responsiveness to salt intake. As suggested by current data, the subset of "responders," those subjects who respond to NaCl deprivation with a decrease in blood pressure, is probably not a homogeneous group. Of the entire group of responders in one study, some were characterized by a decrease in cardiac output while others exhibited a decrement in peripheral resistance. This is not surprising considering the diversity of pressure responses observed for nearly all cardiovascular stimuli. Consequently, blood pressure response to dietary salt manipulation must be examined on an individual basis; the direction of the response will vary according to the subject, and the mechanisms responsible for that response will again be specific to that individual's particular physiology.
Elevated Blood Volume and Cardiac Output Using experimental evidence and elegant computer modeling, Guyton et al developed a cybernetic framework proposing a critical role of the kidneys in salt-induced hypertension. According to this scheme, renal NaCl excretory defects combined with large sodium intakes exceed excretory capacity, leading to sodium and water retention and blood volume expansion. Augmented venous return increases cardiac preload, reflexively enhancing cardiac output and elevating arterial blood pressure. Under normal conditions, this elevated cardiac output is accompanied by increased peripheral vascular resistance to maintain pressure in balance with physiologic need, a process called long-term autoregulation. By elevating arterial pressure and boosting renal sodium and water excretion, these effects progressively diminish blood volume until blood pressure returns to normal. However, in hypertensive-prone kidneys, a sustained tendency to retain sodium and water leads to sustained long-term autoregulation, eventually generating permanent elevations in peripheral vascular resistance, along with renal vascular lesions, and ultimately hypertension. Consistent with this hypothesis, diminished capacities for sodium and water excretion have been observed in models of hypertension. One group suggested that this defect depends on diminished renal response to ANF. In agreement with the hypothesis of Guyton et al, rats made hypertensive with excess dietary NaCl often display transient elevations in cardiac output followed by sustained increases in vascular resistance. However, these elevations have only been observed in partial nephrectomy models and have been difficult to induce in intact animals, and may be explained by mechanisms other than NaCl-induced volume expansion. This pattern of physiologic events has also been reported in humans. However, there is little evidence that total body sodium, exchangeable sodium, plasma volume, or cardiac output are predictably disturbed in hypertension. In addition, researchers have had difficulty finding a quantitative relation between sodium retention and blood pressure change during salt loading.
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Central Role of the Kidneys in the Development of Hypertension Dietary salt can influence blood pressure only through an alteration of renal function. This theoretical framework arose from a series of transplantation studies which pointed to a critical role of the kidneys in the development and maintenance of hypertension. When kidneys from hypertensive rats were transplanted to their normotensive counterparts, these animals developed chronic high blood pressure. However, hypertensive rats receiving kidneys from normotensive animals showed no change in blood pressure. The subsequent hypothesis, known as the pressure-natriuresis relationship, indicated a pivotal role of the kidneys in long-term control of blood pressure. According to this cybernetic hypothesis, an influence that stimulates an elevation in blood pressure (eg, a rise in cardiac output or peripheral resistance) will generate increases in urinary sodium and water excretion, eventually effecting blood volume losses until blood pressure returns to normal. For salt loading to result in permanent changes in arterial pressure, renal function must be altered. Thus, all the theories proposed to explain the blood pressure effects of salt loading include an alteration of renal sodium handling as part of the mechanism. Comprising the leading hypotheses are salt-induced changes in blood volume and cardiac output, enhanced secretion of the putative natriuretic hormone, derangement of the sympathetic nervous system, and alterations of calcium metabolism. Because analysis of the strength of each hypothesis is beyond the scope of this article, each is discussed only to the extent required for a clear under6
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The Natriuretic Hormone Hypothesis Excess dietary salt intake may elevate blood pressure through a hormonal mediator. The most commonly postulated mediator is an inhibitor of Na,K-ATPase known as the natriuretic hormone. This hormone may function in parallel with the pressure-natriuresis mechanism to rid the body of excess sodium when intake is elevated. As described by Guyton et al, increased dietary sodium elevates intravascular volume and occasionally in13,14
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Elevated Sympathetic Nervous System (SNS) Activity Excess salt intake may elevate blood pressure through stimulation of peripheral SNS activity. Enhanced sympathetic outflow activates peripheral vasoconstriction and increases renal sodium retention through renal sympathetic nerve activity. Sodium chloride may boost sympathetic activity at the nerve endings or by elevating circulating natriuretic hormone levels. Excess salt may additionally enhance peripheral sympathetic activity through central effects. Consistent with this possibility, lesions in sympathetic control centers of 18,19
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experimental animals prevent the expression of salt-induced hypertension. Similarly, salt-induced blood pressure elevations alter transmitter activity in the anterior hypothalamus of the spontaneously hypertensive rat (SHR). This brain area plays an important role in the regulation of peripheral sympathetic outflow. Two hypotheses emerging from these data suggest altered central sympathetic activity, with subsequent disinhibition of peripheral outflow and vasoconstriction. The first, primarily a receptor mechanism, proposes salt-induced diminished affinity of central a ' P f ° their agonists, with a disrupted central sympathetic control leading to an eventual stimulation of peripheral activity. According to the second hypothesis, excess dietary salt may alter sodium channel activity in the anterior hypothalamus, leading to reduced central NE activity followed by elevated peripheral activity and the generation of chronic hypertension. Thus, excess dietary sodium may stimulate sympathetic vasoconstriction through alteration of peripheral and central regulation sites. Salt-associated elevations in sympathetic activity enhance vasoconstriction and potentiate renal sodium retention, the latter elevating blood pressure through volume expansion. Clearly, the physiology is complex: salt may increase blood pressure through one or both of these mechanisms. 20
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Alteration of Calcium and Potassium Metabolism Dietary sodium loading may generate calcium and potassium deficiencies leading to altered hormone balances, vascular smooth muscle contraction, and elevated blood pressure. Excess dietary salt enhances urinary calcium excretion in humans and experimental animals. " " If this condition is prolonged, the calcium deficit generates defects in cellular calcium pump activity, increased intracellular calcium, and vascular constriction. Further, calcium deficiency may engender metabolic adjustments including increases in circulating parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (l,25(OH)D ) levels. Both of these hormonal factors may increase cellular calcium influx in vascular smooth muscle cells and stimulate blood pressure rises. ' Salt loading also increases urinary potassium loss. This dietary maneuver is even associated with occasional decreases in plasma potassium concentration. It has been hypothesized that high sodium-induced potassium deficiency may lead to increased vasoconstriction and enhanced cardiac contractility. Potassium depletion may potentiate vasoconstriction, in part through inhibition of the Na,K-ATPase in vascular cells. Combined, these physiological alterations stimulate increases in arterial pressure. 23
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creases serum sodium concentration. By whatever receptor mechanism, these alterations are perceived by the brain, triggering a hypothetical release of natriuretic hormone. In the kidneys, this hormone reduces tubular reabsorption of sodium by inhibiting Na,K-ATPase, leading to natriuresis and diuresis. Chronic natriuretic hormone release may elevate arterial pressure. This rise is thought to be generated by wide-spread inhibition of Na,K-ATPase in vascular smooth muscle, depolarizing the cell membrane, and eventually increasing calcium influx. The resulting reduction in the sodium gradient across the cell membrane diminishes calcium efflux via the N a / C a exchange pump. Reduced efflux and increased influx elevates cytosolic calcium, promoting vascular smooth muscle contraction and elevated blood pressure. These identical cellular events operating at sympathetic nerve endings potentiate norepinephrine (NE) release and inhibit re-uptake, leaving more NE at the neuromuscular cleft. An elevation of sympathetic activity through this mechanism promotes the tendency for blood pressure elevation. Despite intense investigation, the nature, anatomical source, and mode of action of the natriuretic hormone have not been elucidated, primarily because of the complexity of this system. Natriuretic hormone may be composed of a series of compounds making up a regulatory system. Supporting the natriuretic hormone hypothesis, increased intracellular sodium has been reported in hypertensive humans compared with their normotensive counterparts. ' In addition, Goto et a l isolated compounds from human urine which inhibited Na,K pump activity and elevated cytosolic free calcium in isolated cells. Other researchers have demonstrated that dietary salt loading not only elicits increases in blood pressure in salt-sensitive patients, but also elevates lymphocyte calcium concentrations. These events were not correlated in patients not sensitive to dietary salt. In contrast, altered N a / K transport in hypertension has not been clearly demonstrated. Furthermore, the existence of the natriuretic hormone remains hypothetical, and therefore its role in the development of hypertension remains only speculative.
EPIDEMIOLOGY OF DIETARY SALT INTAKE AND HYPERTENSION
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Between-Population Studies Early cross-cultural epi demiology of salt and hypertension was dominated by the work of D a h l and Gleibermann. Dahl examined sodium intake and blood pressure in five world-wide populations from which he showed a near-linear, posi tive relationship. Although provocative, these findings were limited by small sample size and the nonuniform, prospective study design. Gleibermann reexamined this association using published data from a much larger cross-section of the world's population. Her findings (the results shown in Figure 2 apply to males only) again revealed a positive linear relationship between salt in take and blood pressure across 27 populations. From a medical standpoint, the lack of hypertension in nonindustrialized low-salt consuming populations was of primary interest. In these populations, over 20 of which have been described, sodium intake was invari ably less than 30 mmol/day, and blood pressure re mained constant or even diminished slightly through out life. A commonly cited report by Page et a l described six separate, relatively primitive populations in the Solomon Islands. Unique among them were the Lau, who prepared most of their meals in salty coastal waters, resulting in higher salt intakes (150 to 230 mmol/day) than the other groups (20 to 130 mmol/ day). The Lau exhibited the highest blood pressures (Fig ure 3), consistent with the hypothesis that higher salt intake may increase blood pressure. The lack of statistical analysis weakened this conclu sion. Furthermore, other explanations may account for 32
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FIGURE 2. Increase in blood pressure with increasing salt in take. Mean blood pressure was correlated with and regressed on mean daily salt intake. Blood pressure values were plotted on a logarithmic scale. From Gleibermann L. et al. 33
the higher blood pressures, as these people had a larger body mass and lived in crowded living conditions. These findings in primitive cultures led to the hy pothesis that hypertension can be avoided in Western civilizations by curtailing salt intake. The hypothesis implies that salt intakes above about 30 mmol/day are an important, if not primary, cause of hypertension in industrialized cultures. This claim has been widely criticized, primarily because the data are correlational. The lack of hypertension in these societies may be caused by many factors other than salt intake. Primitive cultures generally consume relatively large amounts of potassium, drink little or no alcohol, and are primar ily vegetarian ; fiber intake is greater and consumption of saturated fats is much less. Unacculturated people also tend to be smaller, leaner, and more physically ac tive than their acculturated counterparts; and impor tantly, they do not gain weight with age. Psychologic factors may also play a role, as recognized by Gleiber mann who concluded that "it cannot be stated whether salt or other cultural changes or both are caus ing the increase in blood pressure." The clearly defined community roles of tribal societies encompass a set of 34,36
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Advantages and Limitations of the Epidemiological Perspective Correlations obtained from epidemiology are designed to identify associations between selected variables in a given population. The advantage lies in the ability to identify several environmental variables related to blood pressure; regression analysis then allows an estimation of the predictive power of each variable. Furthermore, estimations of interactions be tween variables and their combined influences on blood pressure can be assessed. The greatest shortcoming of population studies, is their limitation to correlational interpretation. Causality can be suggested but not concluded. Hence, positive associations between salt intake and blood pressure may suggest pressor effects of salt itself, or hypertensive in fluences of other agents linked to salt intake that may confound the association. For this reason, population studies are valuable for generating hypotheses about factors that may influence blood pressure. Confirmation of these hypotheses can only come from intervention studies that test the effects of each factor on blood pres
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140 mm Hg or diastolic pressure > 9 0 mm Hg or the use of antihypertensive agents, was positively related to sodium excretion. Yet as in the earlier analysis, this association was lost when reanalyzed using only the 48 "high salt" centers. The Intersalt investigators esti mated that a 100 mmol/day decrease in sodium intake would lower average blood pressures by 2.2 mm Hg systolic and 0.5 mm Hg diastolic, when adjusted for age, sex, potassium excretion, body mass index, and alcohol intake. These correlations are rather weak. Perhaps the true relation of salt intake to blood pressure is stronger but was clouded by imperfect data sampling. It is remark able, however, that correlations grow weaker as studies
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