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(Hypertension. 1996;27:481-490.)
© 1996 American Heart Association, Inc.

Articles

Salt Sensitivity of Blood Pressure in Humans

Myron H. Weinberger

From Indiana University School of Medicine, Indianapolis.

Correspondence to Myron H. Weinberger, Indiana University School of Medicine, 541 Clinical Dr, Room 423, Indianapolis, IN 46202-5111. E-mail mweinbe@indyvax.iupui.edu.

	Abstract

Top Abstract Introduction Salt Sensitivity: Methods and... Demographic Factors Influencing... Familial and Genetic Factors... Physiological Factors Associated... Summary References

 
Abstract A variety of different techniques have been used for the assessment of the blood pressure response to changes in salt and water balance in humans. These have generally been found to be reproducible and to yield congruent results. This review surveys the characteristics of subjects identified as salt sensitive and salt resistant by different investigators from demographic and physiological perspectives.

Key Words: hypertension, sodium-dependent • sodium, dietary • blood pressure

	Introduction

Top Abstract Introduction Salt Sensitivity: Methods and... Demographic Factors Influencing... Familial and Genetic Factors... Physiological Factors Associated... Summary References

 
The relationship between dietary salt intake and the development of hypertension has been the subject of passionate, continuing debate for decades.^{1 2 3 4 5 6 7 8 9 10} Despite abundant epidemiological, experimental, and interventional observations demonstrating a link between salt and blood pressure, skepticism remains. In some instances, this skepticism is based on the observation that not all individuals have demonstrable changes in blood pressure after ingestion of increased or decreased amounts of sodium chloride. Other researchers point to the meager effects on blood pressure after modification of sodium intake in groups of normotensive or hypertensive subjects. Still others accept an effect of reduced salt intake on blood pressure but consider it to be of modest degree and one that is difficult to maintain given the hedonistic preference for salt of many individuals in acculturated societies. This view has been extrapolated therapeutically to hypertensive individuals by offering pharmacological therapy, frequently with natriuretic agents, to accomplish blood pressure reduction without requiring the individuals to alter their dietary habits. This review does not intend to participate in these emotional and subjective points of view but rather to examine the evidence supporting heterogeneity of human blood pressure responses to alterations in sodium and extracellular fluid balance and the mechanisms that have been invoked for them.

Suffice it to say that epidemiological observations, despite their flaws, have established a generally curvilinear relationship between dietary salt intake, whether inferred from urinary sodium excretion or dietary history, and the occurrence of hypertension and its consequences, primarily stroke.¹¹ In societies in which habitual salt intake is less than 50 to 100 mmol/d, hypertension and its complications are rare, whereas the frequency of both increase at higher levels of salt intake. Thus, the inability to demonstrate a strong relationship between sodium intake and blood pressure within a population in which habitual sodium intake is relatively generous (>120 mmol/d) does not deny such a relationship if individual differences in susceptibility or temporal factors may influence the blood pressure response to such intake. In other words, individuals who are susceptible to salt-induced alterations in blood pressure may be balanced by those in whom such an effect is negligible. Alternatively, if a long period of exposure to increased sodium intake is required for blood pressure manifestations to be apparent, the age of the population studied may influence the observations. For these reasons, information from more dramatic manipulations of sodium balance may provide greater insight into the relationship between salt and blood pressure.

	Salt Sensitivity: Methods and Definition

Top Abstract Introduction Salt Sensitivity: Methods and... Demographic Factors Influencing... Familial and Genetic Factors... Physiological Factors Associated... Summary References

 
The concept of heterogeneity of blood pressure responsiveness to alterations in dietary sodium intake was first suggested by studies in 19 hypertensive subjects who were observed after a "normal" (109 mmol/d), "low" (9 mmol/d), and then "high" (249 mmol/d) sodium intake.¹² Blood pressure fell significantly (P<.05) in the entire population with dietary salt restriction and increased significantly (P<.05) back to baseline levels after the high salt phase. When individual blood pressure responses to the low and high salt periods alone were compared, all but 1 subject demonstrated an increase. The investigators then arbitrarily separated the population into two groups, identifying one as salt sensitive (n=9), those who demonstrated at least a 10% increase in mean arterial pressure when the low and high salt pressures were compared, and the other as non–salt sensitive (n=10), those having smaller increases in blood pressure with salt loading. These observations in hypertensive patients were then extended to the normotensive population by studies in individuals who were subjected to an incremental range of sodium intake from 10 to 1500 mmol/d¹³ or to a 3-month period of modest (<80 mmol/d) dietary salt restriction.¹⁴ In the first study of 16 normotensive young men, blood pressure was measured after a 7-day period of 10 mmol/d sodium and then successive 3-day periods of 300, 600 or 800, and 1200 or 1500 mmol/d. Blood pressure rose significantly (P<.001) from the lowest to the highest salt intake. However, as shown in the Figure, the individual responses were variable and ranged from an increase of 1.5% to 34%. No subject demonstrated a decrease in blood pressure when the values following the lowest and highest sodium levels were compared.

View larger version (25K): [in this window] [in a new window]   Figure 1. Percentage change in mean arterial pressure in normotensive subjects receiving incremental increases in sodium. Blood pressure at the end of 7 days of low (10 mmol/d) salt intake was taken as baseline. All subjects demonstrated an increase in blood pressure with salt loading. Data adapted from Luft et al.13

In a longer study of modest salt restriction conducted in 82 normotensive subjects,^{14 15 16} a significant (P<.01) decrease in blood pressure was observed (mean, 4.0±1.1/3.2±1.0 mm Hg). However, when individual blood pressure responses were examined, decreases in systolic and diastolic pressures of 20 mm Hg were seen as well as increases of systolic pressure exceeding 10 mm Hg and of diastolic, 6 mm Hg. It is not likely that these changes were due to random variations of blood pressure because they were based on blood pressures measured in the home environment with a random-zero sphygmomanometer and use of the average of the last two of three consecutive readings obtained on five separate occasions in the baseline period and five separate occasions during the dietary restriction period; values were then analyzed statistically by repeated-measures ANOVA.

We arbitrarily defined salt sensitivity in these normotensive subjects as a decrease in mean arterial pressure of at least 3 mm Hg following the period of dietary salt restriction and defined salt resistance as an increase of the same magnitude.¹⁶ Those demonstrating changes between these levels were considered indeterminate with respect to classification. Using these criteria, we found that 42% of these normotensive subjects were salt sensitive and 18% were salt resistant, with the remainder having responses that we considered indeterminate.

A variety of investigators have reported results of studies in normotensive and hypertensive subjects using alterations in dietary sodium content and classifying the subsequent blood pressure responses.^{15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30} The majority of these observations have been made in hypertensive subjects, but some have included normotensive subjects as well. The criteria for the definition of salt "sensitivity," "nonsensitivity," "resistance," and "counterregulation" of blood pressure have varied markedly. Most of these studies have been performed in relatively small numbers of subjects, usually fewer than 50, thus making it difficult to control or identify potentially confounding demographic variables. Only a few studies^{25 29 30} have reported the reproducibility of the blood pressure responses to the dietary methods used, providing fuel for skeptical critics.

Several studies conducted by our group over the past 25 years have provided a great deal of information on this issue. As part of a carefully controlled evaluation of hypertensive patients for secondary forms of hypertension and as an aid to physiological subclassification of the patients for further study, we developed a rapid procedure for inducing extracellular sodium and volume expansion and contraction and applied this technique to 378 normotensive volunteers, who provided normative data, and 198 essential hypertensive patients.^{16 31} The protocol was conducted on a metabolic unit and began with the intravenous administration of 2 L normal (0.9%) saline over 4 hours in the morning.³² Blood pressure was measured at the completion of the infusion at noon. On the following day, sodium and volume depletion was induced by a 10 mmol sodium diet and three doses of oral furosemide (40 mg each). Blood pressure was again measured on the following morning. The responses were heterogeneous and formed a gaussian distribution in both normotensive and hypertensive groups.¹⁶ The hypertensive patients, as a group, were significantly (P<.001) more salt sensitive than the normotensive individuals. We arbitrarily classified salt sensitivity as a decrease in mean arterial pressure greater than or equal to 10 mm Hg and salt resistance as a decrease less than or equal to 5 mm Hg when the two blood pressure measurements were compared. The salt-resistant group included those individuals demonstrating an actual increase in blood pressure after salt and water depletion. Those with a decrease in blood pressure between 6 and 9 mm Hg were considered indeterminate. We found that 26% of the normotensive subjects were salt sensitive and 58% were salt resistant; in the hypertensive group, 51% were sensitive and 33% were resistant. More recently, we have studied subjects on two occasions over a period of 1 year and found the blood pressure responses to be highly reproducible (P<.02).³³ In addition, we have compared the response to the rapid sodium and volume expansion and contraction protocol with a dietary protocol with sodium intake greater than or equal to 200 mmol/d for 5 days followed by 7 days of sodium intake less than or equal to 15 mmol/d and observed significant (P<.02) congruence of the blood pressure responses to the different maneuvers in the same individual.³⁴ A similar significant congruence of blood pressure response has been reported in normotensive subjects studied during dietary and intravenous salt-loading protocols by other investigators.³⁵

	Demographic Factors Influencing Salt Sensitivity

Top Abstract Introduction Salt Sensitivity: Methods and... Demographic Factors Influencing... Familial and Genetic Factors... Physiological Factors Associated... Summary References

 
Despite differences in the methods used in the evaluation of salt sensitivity and the variability in how this phenomenon has been defined by different investigators, several consistent demographic factors have emerged from these diverse studies when sufficient numbers of subjects have been recruited to enable them to be identified. Blacks have been consistently shown to have a greater frequency of salt sensitivity than whites. We observed that 73% of black hypertensive patients were salt sensitive compared with 56% of a white hypertensive group; but in the normotensive population, the frequency of salt sensitivity among blacks (36%) was similar to that seen among whites (29%).¹⁶ Similar observations of a greater frequency of salt sensitivity among blacks have been reported in other studies.^{30 36}

Age has also been found to be related to salt sensitivity of blood pressure in the majority of studies. In the large epidemiological INTERSALT study,³⁷ the relationship between sodium excretion and blood pressure was most notable when examined on the basis of age. Only a few studies using interventions to assess salt sensitivity have included large enough numbers and a sufficient age range of subjects to be able to identify such a relationship. Increasing salt sensitivity has been noted with increasing age in several such studies.^{16 29 33 38 39} This relationship appears to be stronger in hypertensive than in normotensive individuals.³³ Moreover, we have recently reported observations in subjects who were followed for at least 10 years after the initial classification of salt sensitivity. We found that salt-sensitive individuals had a rise in blood pressure over time that was significantly (P<.001) greater than in those who were salt resistant.³³ This observation confirms the suggestion by Sullivan³⁰ indicating that normotensive salt-sensitive subjects are more likely to become hypertensive when followed over a period of time; however, no data were provided in support of this contention. A recent report of observations in 46 essential hypertensive patients suggests that salt sensitivity of blood pressure can be observed only in individuals over the age of 45 years.⁴⁰ However, reports of salt sensitivity in obese adolescents would imply that it can occur in younger subjects as well.²⁴

An influence of sex has been suggested by some investigators⁴¹ who found salt sensitivity among female hypertensive patients but not in males when changed from a diet containing 15 g/d salt to one containing 3 g/d. Other investigators have not confirmed this effect of sex on salt sensitivity.^{16 39} In view of the age-related effect cited by many investigators, such a separate sex effect may be difficult to discern. Another possible explanation is that since women are typically lighter in weight than men and since all of the studies examining salt sensitivity have administered a uniform amount of sodium to all subjects in each phase of the study, women may have received a greater salt load on a body weight basis than did men, thus making it more likely that a response would be observed in women.

If the "dose" of sodium per unit body weight was a major determinant of salt sensitivity, then one would expect the phenomenon to be less frequent in obese subjects than in subjects of normal or lean body weight. This has not been found to be the case, and in fact, salt sensitivity has been reported to be positively correlated with body weight in at least one study.²⁹ However, a more recent report by the same investigators indicated that this correlation was not seen.⁴⁰ Most large studies of salt sensitivity have failed to identify a relationship with body weight.¹⁶ A more consistent finding has been the alteration in salt sensitivity of blood pressure after weight loss in obese subjects.^{24 42}

Another intriguing aspect of blood pressure response to sodium appears to be the time of day that the sodium is consumed. In a study of seven normotensive Japanese women evaluated with 24-hour ambulatory blood pressure monitoring while ingesting 12 g of salt in their diet, it was observed that the average blood pressure was higher and the circadian pattern was altered when 9 g was consumed at lunchtime and the remainder in the evening compared with 9 g in the evening and the balance at lunchtime.⁴³ Thus, this preliminary finding suggests that the timing of sodium ingestion influences the blood pressure response.

	Familial and Genetic Factors

Top Abstract Introduction Salt Sensitivity: Methods and... Demographic Factors Influencing... Familial and Genetic Factors... Physiological Factors Associated... Summary References

 
Some researchers have suggested that a family history of hypertension is associated with salt sensitivity of blood pressure, implying that this phenomenon may be genetically mediated. One group of investigators, conducting studies in two apparently different populations, have reported contradictory findings regarding this issue.^{29 40} There are several possible explanations for this confusion, one of which is the questionable validity of estimates of familial blood pressure status that are often based on conjecture and speculation rather than actual blood pressure measurement or documentation. In a Japanese population, a positive family history was more frequently reported among salt-sensitive subjects.⁴⁴ In another study, which used the blood pressure response to 0.6 mg/d 9--fludrocortisone (Florinef) given for 3 weeks for the definition of salt sensitivity, the investigators found a significantly greater blood pressure response in normotensive sons of hypertensive fathers than in similar individuals who had no paternal history of hypertension.⁴⁵

The possibility of a genetically mediated mechanism for the blood pressure response to alterations in sodium or water balance was suggested by our studies.⁴⁶ We found that salt sensitivity was more likely to be observed in individuals with the homozygous haptoglobin 1-1 genotype than in those with the 2-2 genotype and that individuals with the heterozygotic 2-1 genotype had responses that were intermediate between the other two groups. These findings were seen in both normotensive and hypertensive populations participating in two entirely different protocols for the assessment of salt responsiveness.⁴⁶ This observation was recently confirmed by studies in a Japanese population, in whom the frequency of the haptoglobin 1-1 genotype is much less common than in Americans. This study demonstrated a greater frequency of salt sensitivity among Japanese with the haptoglobin 1-2 genotype than among those who were homozygous for 2-2.⁴⁷ These investigators also examined polymorphisms for angiotensin-converting enzyme and were unable to identify differences in salt sensitivity based on the three different patterns (II, ID, and DD).⁴⁷

Recently, a genetic basis for other forms of "salt-sensitive" hypertension, that resulting from a chimeric mutation of the 11ß-hydroxylase/aldosterone synthase gene (glucocorticoid remediable hypertension)⁴⁸ as well as that resulting from a mutation in the ß-subunit of the epithelial sodium channel (Liddle's syndrome),⁴⁹ has been described. It is possible that some individuals with salt-sensitive blood pressure may be found to have more subtle genetic abnormalities of any of these forms, which may permit early identification of susceptibility to the blood pressure–raising effects of salt in the future.

	Physiological Factors Associated With Salt Sensitivity

Top Abstract Introduction Salt Sensitivity: Methods and... Demographic Factors Influencing... Familial and Genetic Factors... Physiological Factors Associated... Summary References

 
Renal Function
Abundant evidence from a variety of studies in humans suggests a renal abnormality or multiple alterations in renal function in salt-sensitive hypertension. Earlier studies have provided indirect evidence for differences in renal function in older subjects, blacks, and individuals with first-degree relatives with hypertension.^{50 51} Whereas these studies were conducted in normotensive subjects, more recent studies conducted in hypertensive men demonstrated racial differences in the response of glomerular filtration rate to dietary sodium loading.⁵² Even though no significant differences in blood pressure response to the salt load were seen when black and white subjects were compared, the former had a significant increase in glomerular filtration, suggesting hyperfiltration and leading the authors to conclude that renal perfusion pressure was a greater determinant of glomerular filtration in black hypertensive patients than in their white counterparts.⁵² It should be emphasized that these indirect reports did not describe differences in blood pressure response to salt in the subjects studied.^{50 51 52} Another group studied hypertensive individuals and categorized their blood pressure responses as well as hemodynamic alterations to low (20 mmol/d) and high (200 mmol/d) sodium intake.⁵³ They found that the salt-sensitive subjects were all blacks who demonstrated a decrease in renal blood flow in response to the high salt diet, whereas the salt-resistant group, which included all of the white subjects as well as some blacks, showed an increase in renal blood flow.⁵³ Furthermore, in a study of 22 Italian hypertensive patients observed after 7 days of 250 mmol salt per day and 7 days of 20 mmol/d, urinary albumin excretion was noted to be significantly greater in the 12 subjects defined as salt sensitive.⁵⁴ There were no observable differences in glomerular filtration rate, renal plasma flow, or filtration fraction between the two groups during the low sodium period. However, during the high salt diet, renal plasma flow decreased and filtration fraction and intraglomerular pressure increased in the salt-sensitive but not in the salt-resistant group. The investigators of both studies interpreted these findings as indicative of a selective increase in glomerular capillary pressure with high salt intake in the salt-sensitive subjects only.^{53 54} Two groups have observed that salt-sensitive subjects differ from their salt-resistant counterparts in their ability to achieve sodium balance when subjected to a low sodium diet.^{34 55} In both studies, which used 7 days or more of dietary sodium restriction (20 mmol/d), a significantly longer half-time in urinary sodium excretion was observed in the salt-sensitive subjects. Some investigators have suggested that alterations in glomerular surface area or the actual density of glomeruli may be responsible for salt-sensitive hypertension.^{56 57} In support of this hypothesis, observations in both experimental animals and humans have been cited that provide substantial indirect evidence that salt sensitivity is associated with a reduction in nephron number or glomerular surface area.⁵⁶

The Renin-Angiotensin-Aldosterone System
Most^{16 19 29 30 38 39} but not all^{45 58} investigators have reported lower levels of plasma renin activity and, often, of plasma aldosterone concentrations in salt-sensitive subjects. It is not clear whether those studies that were unable to identify reduced activity of the renin-angiotensin-aldosterone system used adequate procedures for evaluating the values in relationship to the state of sodium balance. The implications of these observations are twofold. First, since suppression of plasma renin activity may reflect a relative expansion of extracellular fluid volume and/or sodium balance and since salt sensitivity represents an increase in the blood pressure response to sodium and volume depletion (at least in the studies using such an approach), one would predict that the greatest fall in blood pressure would be likely in the most volume-expanded subjects, that is, in those with the lowest renin levels. An alternative explanation is also feasible. Since the renin-angiotensin-aldosterone system protects against sodium and volume depletion and maintains vascular homeostasis during such situations, individuals in whom the system is relatively unresponsive could be expected to have a greater permissive fall in blood pressure in such circumstances. Evidence in support of this hypothesis can be found from our observations when we compared blood pressure responses to a rapid sodium and volume expansion and contraction maneuver with responses in the same individuals after 5 days of a high salt diet and 7 days of a low salt diet.³⁴ In every case, saline infusion and low sodium diet plus furosemide (rapid protocol) were performed first, and the dietary study was conducted at least 3 months later. We found that the response of plasma renin activity to sodium and water depletion induced by the low salt diet and furosemide predicted (correlated with, P<.001) the blood pressure response to the low salt diet in the second study, which was conducted much later.³⁴ In other words, the subjects with the smallest increase in plasma renin activity following sodium and water depletion had the greatest fall in blood pressure after the low sodium diet and vice versa.

A subgroup of hypertensive patients has been described in whom the "normal" alterations in renal blood flow associated with a high dietary sodium intake and a "normal" response of plasma aldosterone to administered angiotensin II are not seen. This subgroup has been defined as non-modulators, and many but not all of the subjects in this subgroup have been characterized as salt sensitive in terms of their blood pressure response to alterations in dietary sodium intake.⁵⁹ Of 15 non-modulating hypertensive patients studied, 9 had an increase in diastolic pressure after change from a low (20 mmol/d) to a high (200 mmol/d) sodium intake, a proportion similar to the 5 of 10 modulating hypertensive patients who also demonstrated a sodium-related increase in diastolic pressure in that study.⁵⁹ The aberrant responses of the non-modulators appeared to be reversed when angiotensin-converting enzyme inhibitors were given.⁵⁹ The investigators describing these individuals were careful to exclude those with suppressed levels of plasma renin activity and thus, to a large degree, older subjects and blacks,⁶⁰ who have been reported by others to have the highest prevalence of salt sensitivity. These observations have been extended to normotensive subjects, and a recent report from the same group indicates that one non-modulating normotensive individual in whom long-term follow-up was obtained became hypertensive with the passage of time.⁶¹ The relationship between the non-modulating trait and salt sensitivity has been repeatedly inferred, but the documentation appears to be inconsistent because not all non-modulators demonstrated a rise in blood pressure with salt loading and some modulators did.⁵⁹ These findings, if confirmed, would further support a link between the kidney, renin-angiotensin-aldosterone system, and salt sensitivity of blood pressure.

Atrial Natriuretic Factor
Several investigators have examined the role of atrial natriuretic factor (ANF) in salt sensitivity of blood pressure. Since this peptide is responsible for renal handling of sodium and water and is modulated by alterations in volume status, it is a logical candidate for involvement in the response of blood pressure to such changes. One study suggests that salt-sensitive hypertensive men have lower levels of ANF after a high salt intake than subjects whose blood pressure is not salt sensitive.⁵⁸ In another study, in which the investigators characterized their hypertensive patients as being low-renin hypertensive patients, non-modulators, or modulators, the investigators reported that the non-modulators had a decreased response of ANF to an intravenous saline load.⁶² The authors interpreted their findings as indicative of an alteration in the distribution of the volume load in the different groups. These same investigators reported observations in a smaller group of 22 hypertensive men in whom the blood pressure response to changes in sodium balance permitted them to classify 8 as salt sensitive and 7 as salt resistant. When ANF was infused, those who were salt sensitive demonstrated an increase in both insulin and glucose levels after cessation of ANF, whereas the salt-resistant subjects did not.⁶³ This link between salt sensitivity and abnormalities of insulin and glucose will be covered in greater detail below.

Another factor responsible for the renal handling of salt and water that has been implicated in salt sensitivity of blood pressure has been the kallikrein-kinin system. It has been reported that salt-sensitive hypertensive patients have lower levels of urinary kallikrein than those who are salt resistant.²⁸ Moreover, these investigators reported an inverse relationship between ANF and kallikrein in salt-sensitive subjects,²⁸ although they also reported that non-modulators had a decreased response of ANF to saline infusion.⁶² This apparent discrepancy suggests that salt sensitivity and non-modulation, at least as defined by this group, may not be synonymous, although they observed salt sensitivity of blood pressure in the low-renin and non-modulating groups only.⁶² In another study,⁶⁴ the same group of investigators observed that 10 salt-sensitive hypertensive patients had a decrease in blood pressure after oral administration of kallikrein that was not seen in salt-resistant subjects despite similar natriuretic responses to kallikrein in the two groups. These investigators also found lower levels of urinary kallikrein and higher levels of ANF in their salt-sensitive hypertensive patients.⁶⁴ Other investigators have provided additional support for differences in kallikrein activity in salt-sensitive and salt-resistant subjects.^{65 66}

The Sympathetic Nervous System
A variety of studies have implicated the sympathetic nervous system in salt sensitivity of blood pressure. Although impressive, not all of the findings of many investigators examining components of this system have provided support for this hypothesis. Campese et al¹⁸ were the first to suggest a role of sympathetic activity in salt-sensitive human hypertension when they observed higher levels of plasma norepinephrine in salt-sensitive compared with salt-resistant hypertensive patients. However, these findings have not been confirmed by all investigators; many have reported no differences in plasma or urinary norepinephrine levels between salt-sensitive and salt-resistant groups.^{16 29 38 58} Venous plasma norepinephrine may not adequately reflect systemic or renal sympathetic activity, which are more relevant sites for the influence of this system on blood pressure and sodium metabolism. In addition, measurements of norepinephrine alone may not fully reflect variations in nervous system control of renal sodium handling. A recent study reported direct measurements of muscle sympathetic nerve activity in black and white hypertensive subjects at rest and with handgrip or cold pressor stress.⁶⁷ Although the investigators did not characterize the salt responsiveness of blood pressure in this study, they were unable to detect differences in muscle sympathetic nerve activity between the groups, which included black hypertensive subjects, who are known to have a greater frequency of salt sensitivity.⁶⁷

The role of the dopaminergic system in renal sodium handling and a direct influence of the state of sodium balance on this system were demonstrated more than 20 years ago.⁶⁸ Our group evaluated the relationship between dopamine and the noradrenergic system and alterations in sodium and water balance in normotensive and hypertensive men.⁶⁹ We measured urinary dihydroxyphenylacetic acid (DOPAC), the major urinary metabolite of dopamine, and norepinephrine after periods of low (10 mmol/d) and high (800 mmol/d) sodium intake. We derived a "natriuretic index" by comparing the excretion of DOPAC with that of norepinephrine. The ratio increased more than twofold with the high sodium diet in normotensive men. We further observed that hypertensive men, and particularly blacks, had lower levels of the natriuretic index than did the normotensive subjects.⁶⁹ Recent reports from other investigators indicate that nine salt-sensitive hypertensive patients had higher urinary excretion of dihydroxyphenylalanine and reduced dopamine excretion during a high salt diet than seven salt-resistant hypertensive patients.⁷⁰ These findings suggest that the dopaminergic system and perhaps the noradrenergic system in the kidney may be different in salt-sensitive and salt-resistant hypertensive patients. To date, clear confirmation of a causal relationship based on pharmacological interventions is not available.

Adrenergic Receptors
Despite inconsistent reports of differences in plasma or urinary levels of norepinephrine between salt-sensitive and salt-resistant individuals, another aspect of the biology of the sympathetic nervous system, adrenergic receptor activity, may be important. Feldman et al⁷¹ have demonstrated that ß-adrenergic receptor activity is responsive to changes in sodium balance and that ß-receptor activity decreases in hypertensive patients. Skrabal and colleagues⁷² have reported alterations in adrenergic receptor activity with changes in sodium intake in normotensive subjects. Specifically, they observed upregulation of ₂-receptors and downregulation of ß₂-receptors during high sodium intake. They then hypothesized that an increase in the ratio between ₂- and ß₂-receptors during a high salt diet could promote vasoconstriction and decreased vasodilation in resistance vessels and increased proximal tubular sodium reabsorption, which would favor a salt-sensitive blood pressure response.⁷² They tested this hypothesis by measuring blood pressure and adrenoceptor activity in cultured fibroblasts obtained from 20 normotensive men classified on the basis of their blood pressure response to alterations in dietary sodium intake.⁷³ They found that the salt-sensitive subjects had a reduced number of ß₂-receptors on their cultured fibroblasts, and they observed a correlation between the change in blood pressure with the alteration of sodium intake and the number of ß₂-receptors.⁷³ These findings contrast with the findings of Mills and colleagues,⁷⁴ who used isoproterenol-stimulated cAMP production by lymphocytes as an indirect measure of ß-receptor activity. Using this technique, the investigators reported that black hypertensive patients had the most sensitive ß-receptors as well as the highest receptor density when compared with white hypertensive patients and normotensive subjects of both racial groups.⁷⁴ They also observed an inverse correlation between plasma levels of epinephrine and ß-receptor density. They did not, however, classify the blood pressure responses of their subjects to changes in sodium balance.

Several investigators have studied vascular responsiveness in salt-sensitive and salt-resistant hypertensive patients.^{75 76} Although these studies did not examine receptor behavior, they demonstrated that salt-sensitive hypertensive patients had decreased large vessel compliance⁷⁵ and increased pressor responses to angiotensin II and norepinephrine.⁷⁶

Endothelin and Nitric Oxide
Current interest has been directed toward the potential role of locally acting substances such as endothelin and nitric oxide in the blood pressure response to salt. Endothelin is known to have diuretic and natriuretic effects. Plasma and urinary levels of endothelin-1 were measured in 19 normotensive and 17 hypertensive subjects.⁷⁷ No differences were seen in plasma endothelin levels, but urinary endothelin was three times higher in normotensive than hypertensive individuals. Salt-sensitive subjects had lower urinary endothelin levels than salt-resistant individuals.⁷⁷ Further investigation of this preliminary finding may yield new information about the role of this system in hypertension generally and in salt-sensitive hypertensive subjects specifically.

Animal studies have suggested a role for the nitric oxide system in salt-sensitive models of hypertension. Since nitric oxide also causes renal vasodilation and natriuresis, a reduction in nitric oxide synthesis could increase the pressor effects of salt administration. This was demonstrated in rats given N^G-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, which produced an increase in blood pressure compared with vehicle administration with the same dietary salt load.⁷⁸ The role of nitric oxide in renal handling of sodium and the effects of alterations in sodium balance on arterial pressure are exciting areas of exploration in human biology.

Ion Transport
It is important to recognize that sodium alone may not be responsible for salt-sensitive hypertension, as studies in both experimental animals⁷⁹ and humans^{80 81} have demonstrated that when sodium is given as the chloride salt, the blood pressure response is greater than when the same amount of sodium is administered in nonchloride forms. These observations implicate the chloride ion in the pathogenesis of salt-induced blood pressure change. The practical significance of this finding is not clear, because more than 95% of sodium ingested in the human diet is in the chloride form.

Abnormalities in intracellular ion transport have long been postulated as being involved in human hypertension in general and in salt-sensitive forms in particular. However, many of the early reports of abnormalities in ion transport identified from studies of erythrocyte biology in vitro were confounded by issues of drug treatment; the contribution of obesity, racial, ethnic, or genetic differences; and other factors that were difficult to separate from the hypertensive process. Furthermore, questions about the causal nature of identified abnormalities were also raised by some critics.

In a recent study conducted in 19 hypertensive patients after 2 months of adherence to a low (50 mmol/d) and high (200 mmol/d) sodium intake, the investigators observed an increase in intracellular (erythrocyte) calcium and sodium concentrations and a reduction in magnesium concentration during salt loading, primarily in salt-sensitive subjects.⁸² Moreover, the investigators reported a correlation between the changes in ion concentration and the blood pressure response to the salt load.⁸² Sodium-lithium countertransport has also been implicated as an important abnormality in hypertensive patients.⁸³ In an attempt to link the red blood cell transport abnormality to an alteration in renal tubular sodium handling, we studied both erythrocyte sodium-lithium countertransport in vitro and lithium clearance in vivo in normotensive and hypertensive humans. We found that the hypertensive patients had an increased sodium-lithium countertransport, confirming numerous earlier reports. We also found that despite similar baseline values for the fractional excretion of sodium between normotensive and hypertensive individuals, the fractional excretion of lithium was higher in those with elevated blood pressure.⁸³ Moreover, volume expansion caused a greater natriuresis and greater increase in fractional excretion of lithium among the hypertensive patients. These findings suggested to us that hypertensive patients do not have increased proximal tubular sodium reabsorption and that the exaggerated natriuresis often observed in hypertension is the result of increased distal tubular sodium delivery.⁸³ These observations have been confirmed in a group of Italian hypertensive patients.⁸⁴

Not only have abnormalities of intracellular sodium, calcium, and magnesium concentrations been implicated in salt-sensitive hypertension,^{82 85} but alterations in extracellular pH and bicarbonate have been found even before the development of hypertension in salt-sensitive normotensive subjects.⁸⁶ These studies showed that a decrease in cumulative bicarbonate excretion occurred when the salt-sensitive subjects were given sodium citrate or ammonium chloride compared with their salt-resistant counterparts.⁸⁶ More recent studies have further pursued the issue of sodium-hydrogen ion exchange. A correlation has recently been shown between erythrocyte sodium-hydrogen ion exchange and microalbuminuria in essential hypertensive patients.⁸⁷ This antiport system has been linked to salt sensitivity⁸⁸ and cytosolic calcium transport⁸⁹ in one hypothesis. The latter has suggested, very plausibly, that these abnormalities may be reflected by increased contractility of vascular smooth muscle and increased sodium reabsorption by the renal tubule and may be related to insulin resistance in skeletal muscle by related alterations in intracellular calcium concentrations and increased activity of protein kinase C.⁸⁹

During high sodium intake, increases in lymphocyte calcium concentration have been reported in salt-sensitive but not in salt-resistant hypertensive patients.⁹⁰ Salt-sensitive patients have been found to have increased ionized and total serum calcium levels and a calciuric response to a high salt diet compared with salt-resistant hypertensive patients.⁹¹ The investigators hypothesized that salt loading shifted calcium from the protein-bound to ionized form.⁹¹ Resnick⁹² has reported that salt-sensitive subjects have an increase in cytosolic free calcium and a decrease in free magnesium levels; also, salt sensitivity is dependent on extracellular calcium concentration, whereas salt resistance is influenced by both renin and intracellular calcium concentrations.⁹³ Both 1,25-dihydroxyvitamin D and the newly identified parathyroid hypertensive factor facilitate calcium transport from the extracellular space to the cell, and both are found to be increased in blacks and low-renin hypertensive subjects.^{93 94}

The role of these observations in salt sensitivity of blood pressure was further supported by studies of the effect of oral calcium supplementation in salt-sensitive hypertensive patients.^{95 96} In one study, administration of 2.16 g/d supplemental calcium attenuated the rise in blood pressure observed with a high (300 mmol/d) sodium diet.⁹⁵ During calcium supplementation, increases in urinary sodium excretion and erythrocyte magnesium content were observed.⁹⁵ In another study, a supplemental amount of calcium carbonate (1.5 g/d) was given for 8 weeks during a normal dietary sodium intake that significantly reduced blood pressure in patients who had been previously demonstrated to be salt sensitive, whereas the same calcium supplement was associated with an increase in blood pressure in salt-resistant individuals.⁹⁶ The calcium-sensitive subjects had lower renin levels and higher urinary calcium excretion at baseline as well as after supplementation than did the calcium-resistant subjects.⁹⁶ These observations suggest that the urinary calcium "leak" reported in hypertensive patients is a feature of salt sensitivity.

Potassium has also been shown to play a role in salt sensitivity of blood pressure. Marked dietary sodium loading is known to cause potassium depletion.¹³ When potassium loss was prevented by potassium supplementation during sodium loading, the salt-induced blood pressure elevation was attenuated.⁹⁷ Other investigators have shown a "cardioprotective" effect of potassium independent of its effects on blood pressure,^{98 99} which makes this interaction of additional importance in salt-sensitive hypertension.

Insulin
Hypertensive patients have been shown to be insulin resistant, and because insulin can promote renal sodium reabsorption, several investigators have suggested that hyperinsulinemia may be involved in the pathogenesis of salt sensitivity of blood pressure.¹⁰⁰ This concept is based primarily on the improvement of both blood pressure and insulin sensitivity in obese adolescents after weight loss.¹⁰⁰ Hyperinsulinemia and salt sensitivity of blood pressure were found to be associated in young blacks.²⁷ However, not all investigators have found salt-sensitive individuals to be hyperinsulinemic. Among seven salt-sensitive normotensive subjects, the investigators observed insulin levels that were similar to those of salt-resistant subjects in the face of glucose levels that were 50% higher.¹⁰¹ These findings suggest that even before hypertension has developed, insulin resistance but not hyperinsulinemia is present. Ferri and colleagues⁶³ were only able to demonstrate hyperinsulinemia and insulin resistance in salt-sensitive subjects after infusion of ANF. Other investigators have been unable to document a difference in insulin levels between salt-sensitive and salt-resistant subjects although differences in regional blood flow in response to insulin were observed during a high salt diet.¹⁰² At least one study in a small number of hypertensive patients suggests that it is salt-resistant subjects who are insulin resistant, as a correlation was observed between salt sensitivity and glucose disposal rate.¹⁰³ A study of Japanese hypertensive patients failed to demonstrate a relationship between salt sensitivity and glucose-insulin dynamics.¹⁰⁴ In that study, a low salt diet was associated with a deterioration of insulin sensitivity as evaluated by the response of insulin and glucose to a glucose challenge.¹⁰⁴

	Summary

Top Abstract Introduction Salt Sensitivity: Methods and... Demographic Factors Influencing... Familial and Genetic Factors... Physiological Factors Associated... Summary References

 
Abundant evidence from epidemiological and interventional studies has established heterogeneity in the blood pressure responses of humans to alterations in sodium and extracellular fluid balance. Such changes have been demonstrated in both normotensive and hypertensive subjects. Although the manipulations and criteria used for the assessment of salt responsiveness in humans have differed among investigators, there has been general agreement regarding the major observations. The techniques used have been found to be reproducible when repeated in the same subject, and the responses of at least two different protocols have yielded congruent responses when tested in the same subjects. Some consistent demographic factors, such as older age, black race, and perhaps female sex, have been shown to be associated with an increased frequency of salt sensitivity. Evidence has also been found to support the notion that blood pressure response to changes in salt balance may be genetically determined.

Extensive studies have been conducted to identify the physiological abnormality responsible for the heterogeneity of salt responses. Alterations in the renal handling of salt loads have been shown in salt-sensitive subjects as well as several abnormalities of the renin-angiotensin-aldosterone system. Salt-sensitive subjects are reported to have lower levels of renin and aldosterone than their salt-resistant counterparts. It is not clear whether this is a primary event, a response to real or perceived extracellular volume expansion, or a permissive component that allows a greater decrease in blood pressure with sodium and volume depletion. ANF and renal kallikrein have also been implicated by some studies. A role for the sympathetic nervous system or its receptors has also been suggested by some investigators. Abnormalities of ion transport, involving vascular smooth muscle as well as renal tubular cells, have been invoked, perhaps linked not only to sodium transport but to the ion transport of calcium and potassium as well. Other investigators have proposed a role for abnormalities in the response to insulin in salt sensitivity of blood pressure, but this link is not clearly established. Recent studies of endothelin and nitric oxide indicate that they are also plausible candidates for involvement in salt-sensitive vascular responses.

At present, we recognize that a variety of factors can induce, or prevent, blood pressure responsiveness to the manipulation of salt balance. Future studies should elucidate the genetic basis for this phenomenon and identify factors, inherent or acquired, contributing to it; the compensatory mechanisms that typically guard against the pressor actions of salt loads and that may be impaired in some individuals; and more effective ways of treating this response. Finally, such information should provide the basis for an approach to the primary prevention of salt-sensitive forms of hypertension in humans.

	References

Top Abstract Introduction Salt Sensitivity: Methods and... Demographic Factors Influencing... Familial and Genetic Factors... Physiological Factors Associated... Summary References

 
1. Dahl LK. The possible role of chronic excess salt consumption in the pathogenesis of essential hypertension. Am J Cardiol. 1961;8:571-575.

2. Gleiberman L. Blood pressure and dietary salt in human populations. Ecol Food Nutr. 1973;2:143-155.

3. Pickering GW. Dietary sodium and human hypertension. In: Laragh JH, Buhler FR, Seldin DW, eds. Frontiers in Hypertension Research. New York, NY: Springer-Verlag; 1981:37-42.

4. MacGregor GA. Sodium is more important than calcium in essential hypertension. Hypertension. 1985;7:628-637. [Abstract/Free Full Text]

5. McCarron DA. Is calcium more important than sodium in the pathogenesis of essential hypertension? Hypertension. 1985;7:607-627. [Abstract/Free Full Text]

6. Dustan HP, Kirk KA. Corcoran lecture: The case for and against salt in hypertension. Hypertension. 1989;13:696-705. [Abstract/Free Full Text]

7. Elliott P. Observational studies of salt and blood pressure. Hypertension. 1991;17(suppl I):I-3-I-8.

8. Muntzel M, Drueke T. A comprehensive review of the salt and blood pressure relationship. Am J Hypertens. 1992;5:1S-42S. [Medline] [Order article via Infotrieve]

9. Swales JD. Salt and blood pressure. Blood Pressure. 1992;1:201-204. [Medline] [Order article via Infotrieve]

10. Freis ED. The role of salt in hypertension. Blood Pressure. 1992;1:196-200. [Medline] [Order article via Infotrieve]

11. Yamori Y, Nara Y, Mizushima S, Sawamura M, Horie R. Nutritional factors for stroke and major cardiovascular diseases. Health Rep. 1994;6:9-12. [Medline] [Order article via Infotrieve]

12. Kawasaki T, Delea CS, Bartter FC, Smith H. The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am J Med. 1978;64:193-198.[Medline] [Order article via Infotrieve]

13. Luft FC, Rankin LI, Bloch R, Weyman AE, Willis LR, Murray RH, Grim CE, Weinberger MH. Cardiovascular and humoral responses to extremes of sodium intake in normal black and white men. Circulation. 1979;60:697-706. [Free Full Text]

14. Miller JZ, Daugherty SA, Weinberger MH, Grim CE, Christian JC, Lang CL. Blood pressure response to dietary sodium restriction in normotensive adults. Hypertension. 1983;5:790-795. [Abstract/Free Full Text]

15. 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 Dis. 1987;40:245-250. [Medline] [Order article via Infotrieve]

16. Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986;8(suppl II):II-127-II-134.

17. Sullivan JM, Ratts TE, Taylor JC, Kraus DH, Barton BR, Patrick DR, Reed SW. Hemodynamic effects of dietary sodium in man: a preliminary report. Hypertension. 1980;2:506-514. [Free Full Text]

18. Campese VM, Romoff MS, Levitan J, Saglikes Y, Fredier R, Massry SG. Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitive patients with essential hypertension. Kidney Int. 1982;21:371-378. [Medline] [Order article via Infotrieve]

19. Koolen MI, Bussemaker-Verduyn E, den Boer E, van Brummelen P. Clinical, biochemical and haemodynamic correlates of sodium sensitivity in essential hypertension. J Hypertens. 1983;1(suppl 2):21-23.

20. Skrabal F, Herholz H, Newmayr M, Hanberger L, Ledochowski M, Sporer R, Hortnagl H, Schwarz S, Schonitzer D. Salt sensitivity in humans is linked to enhanced sympathetic responsiveness and enhanced tubular reabsorption. Hypertension. 1984;6:152-158. [Abstract/Free Full Text]

21. Dustan HP, Kirk KA. Relationship of sodium balance to arterial pressure in black hypertensive patients. Am J Med Sci. 1988;295:378-383. [Medline] [Order article via Infotrieve]

22. Sowers JR, Zemel MB, Zemel P, Beck FWJ, Walsh MF, Zawada ET. Salt sensitivity in blacks: salt intake and natriuretic substances. Hypertension. 1988;12:485-490. [Abstract/Free Full Text]

23. Sullivan JM, Prewitt RL, Ratts TE. Sodium sensitivity in normotensive and borderline hypertensive humans. Am J Med Sci. 1988;295:370-377. [Medline] [Order article via Infotrieve]

24. Rocchini AP, Key J, Bondie 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 Med. 1989;321:580-585. [Abstract]

25. Sharma AM, Schattenfroh S, Kribben A, Distler A. Reliability of salt sensitivity testing in normotensive subjects. Klin Wochenschr. 1989;67:632-634. [Medline] [Order article via Infotrieve]

26. Hollenberg NK, Williams GH. Sodium-sensitive hypertension: implications of pathogenesis for therapy. Am J Hypertens. 1989;2:809-815.[Medline] [Order article via Infotrieve]

27. Falkner B, Hulman S, Kushner H. Hyperinsulinemia and blood pressure sensitivity to sodium in young blacks. J Am Soc Nephrol. 1992;3:940-946. [Abstract]

28. Ferri C, Bellini C, Carlomagno A, Perrone A, Santucci A. Urinary kallikrein and salt sensitivity in essential hypertensive males. Kidney Int. 1994;46:780-788. [Medline] [Order article via Infotrieve]

29. Overlack A, Ruppert M, Kolloch R, Gobel B, Kraft K, Diehl J, Schmitt W, Stumpe KO. Divergent hemodynamic and hormonal responses to varying salt intake in normotensive subjects. Hypertension. 1993;22:331-338. [Abstract/Free Full Text]

30. Sullivan JM. Salt sensitivity: definition, conception, methodology, and long-term issues. Hypertension. 1991;17(suppl I):I-61-I-68.

31. Grim CE, Weinberger MH, Higgins JT, Kramer NJ. A rapid and efficient protocol for the diagnosis of secondary forms of hypertension. JAMA. 1977;237:1331-1335. [Abstract/Free Full Text]

32. Kem DC, Weinberger MH, Mayes DM, Nugent CA. Saline suppression of plasma aldosterone in hypertension. Arch Intern Med. 1971;128:380-386. [Abstract/Free Full Text]

33. Weinberger MH, Fineberg NS. Sodium and volume sensitivity of blood pressure: age and pressure change over time. Hypertension. 1991;18:67-71. [Abstract/Free Full Text]

34. Weinberger MH, Stegner JE, Fineberg NS. A comparison of two tests for the assessment of blood pressure responses to sodium. Am J Hypertens. 1993;6:179-184. [Medline] [Order article via Infotrieve]

35. Sharma AM, Schorr U, Cetto C, Distler A. Dietary v intravenous salt loading for the assessment of salt sensitivity in normotensive men. Am J Hypertens. 1994;7:1070-1075. [Medline] [Order article via Infotrieve]

36. Falkner B, Kushner H. Interaction of sodium sensitivity and stress in young adults. Hypertension. 1991;17(suppl I):I-162-I-165.

37. Rodriquez BL, Labarthe DR, Huang B, Lopez-Gomez J. Rise of blood pressure with age. Hypertension. 1994;24:779-785. [Abstract/Free Full Text]

38. Osanai T, Kanazawa T, Yokono Y, Uemara T, Okuguchi T, Onodera K. Effect of aging on sensitivity of blood pressure to salt. Nippon Ronen Igakkai Zasshi. 1993;30:30-34. [Medline] [Order article via Infotrieve]

39. Ishibashi K, Oshima R, Matsuura H, Watanabe M, Ishida M, Ishida T, Ozono R, Kajiyama G, Kanbe M. Effects of age and sex on sodium chloride sensitivity: association with plasma renin activity. Clin Nephrol. 1994;42:376-380.[Medline] [Order article via Infotrieve]

40. Overlack A, Ruppert M, Kolloch R, Kraft K, Stumpe KO. Age is a major determinant of the divergent blood pressure responses to varying salt intake in essential hypertension. Am J Hypertens. 1995;8:829-836. [Medline] [Order article via Infotrieve]

41. Kojima S, Murakami K, Kimura G, Sanai T, Yoshida K, Imanishi M, Abe H, Kawamura M, Kawano Y, Ashida T, Yoshimi H, Kuramochi M, Omae T, Ito K. A gender difference in the association between salt sensitivity and family history of hypertension. Am J Hypertens. 1992;5:1-7. [Medline] [Order article via Infotrieve]

42. Tuck ML. Role of salt in the control of blood pressure in obesity and diabetes mellitus. Hypertension. 1991;17(suppl I):I-135-I-142.

43. Kawasaki T, Itoh K, Cugini P. Influence of reapportionment of daily salt intake on circadian blood pressure pattern in normotensive subjects. J Nutr Sci Vitaminol. 1994;40:459-466.

44. Murakami K, Kojima S, Kimura G, Sanai T, Yoshida K, Imanishi M, Abe H, Kawamura M, Kawano Y, Ashida T, Omae T, Ito K. The association between salt sensitivity of blood pressure and family history of hypertension. Clin Exp Pharmacol Physiol. 1992;20:61-63.

45. Ferrari P, Travaglini M, Schild C, Allemann Y, Shaw S, Weidmann P. Enhanced blood pressure response to mineralocorticoid stimulation in normotensive members of hypertensive families. Blood Pressure. 1992;1:86-91. [Medline] [Order article via Infotrieve]

46. Weinberger MH, Miller JZ, Grim CE, Luft FC, Fineberg NS, Christian JC. Sodium sensitivity and resistance of blood pressure are associated with different haptoglobin phenotypes. Hypertension. 1987;10:443-446. [Abstract/Free Full Text]

47. Kojima S, Inenaga T, Matsuoka H, Kuramochi M, Omae T, Nara Y, Yamori Y. The association between salt sensitivity of blood pressure and some polymorphic factors. J Hypertens. 1994;12:797-801. [Medline] [Order article via Infotrieve]

48. Lifton RP, Dluhy RG, Powers M, Rich G, Cook S, Ulick S, Lalouel JM. A chimaeric 11 ß-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992;355:262-265. [Medline] [Order article via Infotrieve]

49. Shimkets RA, Warnock DG, Bositis CM, Nelso-Williams C, Hansson JH, Schambelan M, Gill JRJ. Liddle's syndrome: heritable human hypertension caused by mutations in the ß subunit of the epithelial sodium channel. Cell. 1994;79:407-414. [Medline] [Order article via Infotrieve]

50. Luft FC, Fineberg NS, Miller JZ, Rankin LI, Grim CE, Weinberger MH. The effects of age, race and heredity on glomerular filtration rate following volume expansion and contraction in normal man. Am J Med Sci. 1980;279:15-24. [Medline] [Order article via Infotrieve]

51. Weinberger MH. Racial differences in renal sodium excretion: relationship to hypertension. Am J Kidney Dis. 1993;21(suppl 1):41-45.

52. Parmer RJ, Stone RA, Cervenka JH. Renal hemodynamics in essential hypertension: racial differences in response to changes in dietary sodium. Hypertension. 1994;24:752-757. [Abstract/Free Full Text]

53. Campese VM, Parise M, Karubian F, Bigazzi R. Abnormal renal hemodynamics in black salt-sensitive patients with hypertension. Hypertension. 1991;18:805-812. [Abstract/Free Full Text]

54. Bigazzi R, Bianchi S, Baldari D, Sgherri G, Baldari G, Campese VM. Microalbuminuria in salt-sensitive patients. Hypertension. 1994;23:195-199. [Abstract/Free Full Text]

55. Wedler B, Brier ME, Wiersbitzky M, Gruska S, Wolf E, Kallwellis R, Aronoff GR, Luft FC. Sodium kinetics in salt-sensitive and salt-resistant normotensive and hypertensive subjects. J Hypertens. 1992;10:663-669. [Medline] [Order article via Infotrieve]

56. Brenner BM, Anderson S. The interrelationships among filtration surface area, blood pressure, and chronic renal disease. J Cardiovasc Pharmacol. 1992;19(suppl 6):S1-S7.

57. Kimura G, Frem GJ, Brenner BM. Renal mechanisms of salt sensitivity in hypertension. Curr Opin Nephrol Hypertens. 1994;3:1-12. [Medline] [Order article via Infotrieve]

58. Gerdts E, Myking OL, Omvik P. Salt sensitive essential hypertension evaluated by 24 hour ambulatory blood pressure. Blood Pressure. 1994;3:375-380. [Medline] [Order article via Infotrieve]

59. Redgrave J, Rabinowe S, Hollenberg NK, Williams GH. Correction of abnormal renal blood flow response to angiotensin II by converting enzyme inhibition in essential hypertension. J Clin Invest. 1985;75:1285-1290.

60. Williams GH, Tuck ML, Sullivan JM, Dluhy RG, Hollenberg NK. Parallel adrenal and renal abnormalities in young patients with essential hypertension. Am J Med. 1982;72:907-914. [Medline] [Order article via Infotrieve]

61. Gordon MS, Gordon MB, Hollenberg NK, Williams GH. Nonmodulating trait may precede the development of hypertension. Am J Hypertens. 1994;7(part 1):789-793.

62. Ferri C, Bellini C, Coassin S, Baldoncini R, Luparini RL, Perrone A, Santucci A. Abnormal atrial natriuretic peptide and renal responses to saline infusion in nonmodulating essential hypertensive patients. Circulation. 1994;90:2859-2869. [Abstract/Free Full Text]

63. Ferri C, Bellini C, Desideri G, Di Francesco L, De Mattia G, Santucci A, Balsano F. Salt-sensitivity is associated with a hyperinsulinemic and hyperglycemic response to atrial natriuretic peptide infusion in human essential hypertension. Diabetologia. 1994;37:308-312. [Medline] [Order article via Infotrieve]

64. Bellini C, Ferri C, Piccoli A, Carlomagno A, Di Francesco L, Bonavita MS, Santucci A, Balsano F. The influence of salt sensitivity on the blood pressure response to exogenous kallikrein in essential hypertensive patients. Nephron. 1993;65:28-35. [Medline] [Order article via Infotrieve]

65. Bonner G, Thieven B, Rutten H, Chrosch R, Krone W. Renal kallikrein is a determinant of salt sensitivity. J Hypertens. 1993;11(suppl 5):S210-S211.

66. Blackwood AM, Inoue J, Sagnella GA, Miller MA, Markandu ND, MacGregor GA. Are the changes in urinary kallikrein excretion on altering sodium intake an index of salt sensitivity? J Hum Hypertens. 1994;8:619-621. [Medline] [Order article via Infotrieve]

67. Calhoun DA, Mutinga ML, Wyss JM, Oparil S. Muscle sympathetic nervous system activity in black and Caucasian hypertensive subjects. J Hypertens. 1994;12:1291-1296. [Medline] [Order article via Infotrieve]

68. Alexander RW, Gill JR, Yamabe H, Lovenberg W, Keiser HR. Effects of dietary sodium and of acute saline infusion on the interrelationship between dopamine excretion and adrenergic activity in man. J Clin Invest. 1974;54:194-200.

69. Weinberger MH, Luft FC, Henry DP. The role of the sympathetic nervous system in the modulation of sodium excretion. Clin Exp Hypertens. 1982;A(4-5):719-735.

70. Gill JR Jr, Grossman E, Goldstein DS. High urinary dopa and low urinary dopamine-to-dopa ratio in salt-sensitive hypertension. Hypertension. 1991;18:614-621. [Abstract/Free Full Text]

71. Feldman RD, Lawton WJ, McArdle WL. Low sodium diet corrects the defect in lymphocyte beta-adrenergic responsiveness in hypertensive subjects. J Clin Invest. 1987;79:647-652.

72. Skrabal F, Kotanko P, Luft FC. Inverse regulation of alpha-2 and beta-2 adrenoceptors in salt-sensitive hypertension: an hypothesis. Life Sci. 1989;45:2061-2076. [Medline] [Order article via Infotrieve]

73. Kotanko P, Hoglinger O, Skrabal F. Beta 2-adrenoceptor density in fibroblast culture correlates with human NaCl sensitivity. Am J Physiol. 1992;263(part 1):C623-C627.

74. Mills PJ, Dimsdale JE, Ziegler MG, Nelesen RA. Racial differences in epinephrine and ß₂-adrenergic receptors. Hypertension. 1995;25:88-91. [Abstract/Free Full Text]

75. Draaijer P, Kool MJ, Maessen JM, van Bortel LM, de Leeuw PW, van Hooff JP, Leunissen KM. Vascular distensibility and compliance in salt-sensitive and salt-resistant borderline hypertension. J Hypertens. 1993;11:1199-1207. [Medline] [Order article via Infotrieve]

76. Campese VM, Karubian F, Chervu I, Parise M, Sarkies N, Bigazzi R. Pressor reactivity to norepinephrine and angiotensin in salt-sensitive hypertensive patients. Hypertension. 1993;21:301-307. [Abstract/Free Full Text]

77. Hoffman A, Grossman E, Goldstein DS, Gill JR Jr, Keiser HR. Urinary excretion rate of endothelin-1 in patients with essential hypertension and salt sensitivity. Kidney Int. 1994;45:556-560. [Medline] [Order article via Infotrieve]

78. Tolins JP, Shultz PJ. Endogenous nitric oxide synthesis determines sensitivity to the pressor effect of salt. Kidney Int. 1994;46:230-236. [Medline] [Order article via Infotrieve]

79. Whitescarver SA, Ott CE, Jackson BA, Guthrie GP Jr, Kotchen TA. Salt-sensitive hypertension: contribution of chloride. Science. 1984;223:1430-1432. [Abstract/Free Full Text]

80. Kurtz TW, Al-Bander HA, Morris RC Jr. `Salt-sensitive' essential hypertension in men. N Engl J Med. 1987;317:1043-1048. [Abstract]

81. Luft FC, Zemel MB, Sowers JA, Fineberg NS, Weinberger MH. Sodium bicarbonate and sodium chloride: effects on blood pressure and electrolyte homeostasis in normal and hypertensive man. J Hypertens. 1990;8:663-670. [Medline] [Order article via Infotrieve]

82. Resnick LM, Gupta RK, DiFabio B, Barbagallo M, Mann S, Marion R, Laragh JH. Intracellular ionic consequences of dietary salt loading in essential hypertension. J Clin Invest. 1994;94:1269-1276.

83. Weinberger MH, Smith JB, Fineberg NS, Luft FC. Red cell sodium-lithium countertransport and fractional excretion of lithium in normal and hypertensive humans. Hypertension. 1989;13:206-212. [Abstract/Free Full Text]

84. Niutta E, Barlassina C, Colombo R, Dossi F, Pellizzoni M, Cusi DM, Cesana B, Bianchi G. Renal lithium clearance in the different stages of hypertension. J Hypertens. 1991;9:1135-1142. [Medline] [Order article via Infotrieve]

85. Kurtz TW, Morris RC Jr. Sodium-calcium interactions and salt-sensitive hypertension. Am J Hypertens. 1990;3(part 2):152S-155S.

86. Sharma AM, Cetto C, Schorr U, Spies KP, Distler A. Renal acid-base excretion in normotensive salt-sensitive humans. Hypertension. 1993;22:884-890. [Abstract/Free Full Text]

87. Giampietro O, Matteuci E, Cataplano G, Dell'Omo G, Talarico L, Di Muro C, Di Bello V, Pedrinelli R. Microalbuminuria and erythrocyte sodium-hydrogen exchange in essential hypertension. Hypertension. 1995;25:981-985. [Abstract/Free Full Text]

88. Aviv A. The lymphocyte Na⁺/H⁺ antiport and its activation by increased NaCl intake: the link with salt sensitivity and cellular Ca²⁺ regulation. Eur J Clin Invest. 1994;24:525-528. [Medline] [Order article via Infotrieve]

89. Aviv A. Cytosolic Ca²⁺, Na⁺/H⁺ antiport, protein kinase C trio in essential hypertension. Am J Hypertens. 1994;7:205-212. [Medline] [Order article via Infotrieve]

90. Alexiewicz JM, Gaciong Z, Parise M, Karubian F, Massry SG, Campese VM. Effect of dietary sodium intake on intracellular calcium in lymphocytes of salt-sensitive hypertensive patients. Am J Hypertens. 1992;5:536-541. [Medline] [Order article via Infotrieve]

91. Lind L, Lithell H, Gustafsson IB, Pollare T, Ljunghall S. Calcium metabolism and sodium sensitivity in hypertensive subjects. J Hum Hypertens. 1993;7:53-57. [Medline] [Order article via Infotrieve]

92. Resnick LM. Cellular calcium and magnesium metabolism in the pathophysiology and treatment of hypertension and related metabolic disorders. Am J Med. 1992;93:11S-20S. [Medline] [Order article via Infotrieve]

93. Resnick LM. Calciotropic hormones in salt-sensitive essential hypertension: 1,25-dihydroxyvitamin D and parathyroid hypertensive factor. J Hypertens. 1994;12(suppl 1):S3-S9.

94. Resnick LM, Lewanczuk RZ, Laragh JH, Pang PK. Parathyroid hypertensive factor-like activity in human essential hypertension: relationship to plasma renin activity and dietary salt sensitivity. J Hypertens. 1993;11:1235-1241. [Medline] [Order article via Infotrieve]

95. Saito K, Sano H, Furuta Y, Yamanishi J, Omatsu T, Ito Y, Fukuzaki H. Calcium supplementation in salt-dependent hypertension. Contrib Nephrol. 1991;90:25-35. [Medline] [Order article via Infotrieve]

96. Weinberger MH, Wagner UL, Fineberg NS. The blood pressure effects of calcium supplementation in humans of known sodium responsiveness. Am J Hypertens. 1993;6:799-805. [Medline] [Order article via Infotrieve]

97. Weinberger MH, Luft FC, Bloch R, Henry DP, Pratt JH, Weyman AE, Rankin LI, Murray RH, Willis LR, Grim CE. The blood pressure-raising effects of high dietary sodium intake: racial differences and the role of potassium. J Am Coll Nutr. 1982;1:139-148. [Abstract]

98. Tobian L. Salt and hypertension: lessons from animal models that relate to human hypertension. Hypertension. 1991;17(suppl I):I-52-I-58.

99. Young DB, Lin H, McCabe RD. Potassium's cardiovascular protective mechanisms. Am J Physiol. 1995;268:R825-R837. [Abstract/Free Full Text]

100. Rocchini AP. The relationship of sodium sensitivity to insulin resistance. Am J Med Sci. 1994;307(suppl 1):S75-S80.

101. Sharma AM, Schorr U, Distler A. Insulin resistance in young salt-sensitive normotensive subjects. Hypertension. 1993;21:273-279. [Abstract/Free Full Text]

102. Egan BM, Stepniakowski K, Nazzaro P. Insulin levels are similar in obese salt-sensitive and salt-resistant hypertensive subjects. Hypertension. 1994:23(suppl I):I-1-I-7.

103. Lind L, Lithell H, Gustafsson IB, Pollare T, Ljunghall S. Metabolic cardiovascular risk factors and sodium sensitivity in hypertensive subjects. Am J Hypertens. 1992;5:502-505. [Medline] [Order article via Infotrieve]

104. Iwaoka T, Umeda T, Inouye J, Naomi S, Sasaki M, Fujimoto Y, Gui C, Ideguchi Y, Sato T. Dietary NaCl restriction deteriorates oral glucose tolerance in hypertensive patients with impairment of glucose tolerance. Am J Hypertens. 1994;7:460-463.[Medline] [Order article via Infotrieve]

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				D. Ge, S. Su, H. Zhu, Y. Dong, X. Wang, G. A. Harshfield, F. A. Treiber, and H. Snieder Stress-Induced Sodium Excretion: A New Intermediate Phenotype to Study the Early Genetic Etiology of Hypertension? Hypertension, February 1, 2009; 53(2): 262 - 269. [Abstract] [Full Text] [PDF]

				G. D. Simonetti, L. Raio, D. Surbek, M. Nelle, F. J. Frey, and M. G. Mohaupt Salt Sensitivity of Children With Low Birth Weight Hypertension, October 1, 2008; 52(4): 625 - 630. [Abstract] [Full Text] [PDF]

				J. Chen, D. Gu, C. E. Jaquish, C.-S. Chen, D. C. Rao, D. Liu, J. E. Hixson, L. L. Hamm, C. C. Gu, P. K. Whelton, et al. Association Between Blood Pressure Responses to the Cold Pressor Test and Dietary Sodium Intervention in a Chinese Population Arch Intern Med, September 8, 2008; 168(16): 1740 - 1746. [Abstract] [Full Text] [PDF]

				M. M. Diaz Encarnacion, G. M. Warner, C. E. Gray, J. Cheng, H. K. H. Keryakos, K. A. Nath, and J. P. Grande Signaling pathways modulated by fish oil in salt-sensitive hypertension Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1323 - F1335. [Abstract] [Full Text] [PDF]

				C. Zeng, V. A. M. Villar, G. M. Eisner, S. M. Williams, R. A. Felder, and P. A. Jose G Protein-Coupled Receptor Kinase 4: Role in Blood Pressure Regulation Hypertension, June 1, 2008; 51(6): 1449 - 1455. [Full Text] [PDF]

				A. J. King, M. Novotny, G. M. Swain, and G. D. Fink Whole body norepinephrine kinetics in ANG II-salt hypertension in the rat Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2008; 294(4): R1262 - R1267. [Abstract] [Full Text] [PDF]

				X. Chen, T. W. Moon, K. R. Olson, R. A. Dombkowski, and S. F. Perry The effects of salt-induced hypertension on {alpha}1-adrenoreceptor expression and cardiovascular physiology in the rainbow trout (Oncorhynchus mykiss) Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1384 - R1392. [Abstract] [Full Text] [PDF]

				C. Barlassina, C. Dal Fiume, C. Lanzani, P. Manunta, G. Guffanti, A. Ruello, G. Bianchi, L. Del Vecchio, F. Macciardi, and D. Cusi Common genetic variants and haplotypes in renal CLCNKA gene are associated to salt-sensitive hypertension Hum. Mol. Genet., July 1, 2007; 16(13): 1630 - 1638. [Abstract] [Full Text] [PDF]

				D. Gu, T. Rice, S. Wang, W. Yang, C. Gu, C.-S. Chen, J. E. Hixson, C. E. Jaquish, Z.-J. Yao, D.-P. Liu, et al. Heritability of Blood Pressure Responses to Dietary Sodium and Potassium Intake in a Chinese Population Hypertension, July 1, 2007; 50(1): 116 - 122. [Abstract] [Full Text] [PDF]

				O. Schmidlin, A. Forman Anthony Sebastian, and R. C. Morris Jr What Initiates the Pressor Effect of Salt in Salt-Sensitive Humans?: Observations in Normotensive Blacks Hypertension, May 1, 2007; 49(5): 1032 - 1039. [Abstract] [Full Text] [PDF]

				B. Rodriguez-Iturbe and N. D. Vaziri Salt-sensitive hypertension--update on novel findings Nephrol. Dial. Transplant., April 1, 2007; 22(4): 992 - 995. [Full Text] [PDF]

				A. B. Weder Evolution and Hypertension Hypertension, February 1, 2007; 49(2): 260 - 265. [Full Text] [PDF]

				J. A. DeSimone and V. Lyall Taste Receptors in the Gastrointestinal Tract III. Salty and sour taste: sensing of sodium and protons by the tongue Am J Physiol Gastrointest Liver Physiol, December 1, 2006; 291(6): G1005 - G1010. [Abstract] [Full Text] [PDF]

				A. Sachdeva and A. B. Weder Nocturnal Sodium Excretion, Blood Pressure Dipping, and Sodium Sensitivity Hypertension, October 1, 2006; 48(4): 527 - 533. [Full Text] [PDF]

				Y. Fang, J.-J. Mu, L.-C. He, S.-C. Wang, and Z.-Q. Liu Salt Loading on Plasma Asymmetrical Dimethylarginine and the Protective Role of Potassium Supplement in Normotensive Salt-Sensitive Asians Hypertension, October 1, 2006; 48(4): 724 - 729. [Abstract] [Full Text] [PDF]

				M. Abe, P. O'Connor, M. Kaldunski, M. Liang, R. J. Roman, and A. W. Cowley Jr. Effect of sodium delivery on superoxide and nitric oxide in the medullary thick ascending limb Am J Physiol Renal Physiol, August 1, 2006; 291(2): F350 - F357. [Abstract] [Full Text] [PDF]

				M. Moser and J. F. Setaro Clinical practice. Resistant or difficult-to-control hypertension. N. Engl. J. Med., July 27, 2006; 355(4): 385 - 392. [Full Text] [PDF]

				N. K. Hollenberg The Influence of Dietary Sodium on Blood Pressure. J. Am. Coll. Nutr., June 1, 2006; 25(suppl_3): 240S - 246S. [Abstract] [Full Text] [PDF]

				R. C. Morris Jr., O. Schmidlin, L. A. Frassetto, and A. Sebastian Relationship and Interaction between Sodium and Potassium. J. Am. Coll. Nutr., June 1, 2006; 25(3 Suppl): 262S - 270S. [Abstract] [Full Text] [PDF]

				I. H. Schulman, P. Aranda, L. Raij, M. Veronesi, F. J. Aranda, and R. Martin Surgical Menopause Increases Salt Sensitivity of Blood Pressure Hypertension, June 1, 2006; 47(6): 1168 - 1174. [Abstract] [Full Text] [PDF]

				T. Iwamoto Vascular Na+/Ca2+ exchanger: implications for the pathogenesis and therapy of salt-dependent hypertension Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R536 - R545. [Abstract] [Full Text] [PDF]

				P. Coruzzi, G. Parati, L. Brambilla, V. Brambilla, M. Gualerzi, A. Novarini, P. Castiglioni, and M. Di Rienzo Effects of Salt Sensitivity on Neural Cardiovascular Regulation in Essential Hypertension Hypertension, December 1, 2005; 46(6): 1321 - 1326. [Abstract] [Full Text] [PDF]

				H. Ehmke Neurogenic Mechanisms and Salt Sensitivity Hypertension, December 1, 2005; 46(6): 1259 - 1260. [Full Text] [PDF]

				J. H. Pratt Central Role for ENaC in Development of Hypertension J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3154 - 3159. [Abstract] [Full Text] [PDF]

				W. B. Farquhar, E. E. Paul, A. V. Prettyman, and M. E. Stillabower Blood pressure and hemodynamic responses to an acute sodium load in humans J Appl Physiol, October 1, 2005; 99(4): 1545 - 1551. [Abstract] [Full Text] [PDF]

				M. H. Weinberger Salt Restriction in the Treatment of Isolated Systolic and Combined Hypertension: Is That Enough? Hypertension, July 1, 2005; 46(1): 31 - 32. [Full Text] [PDF]

				P. Meneton, X. Jeunemaitre, H. E. de Wardener, and G. A. Macgregor Links Between Dietary Salt Intake, Renal Salt Handling, Blood Pressure, and Cardiovascular Diseases Physiol Rev, April 1, 2005; 85(2): 679 - 715. [Abstract] [Full Text] [PDF]

				O. Gumieniak, T. S. Perlstein, P. N. Hopkins, N. J. Brown, L. J. Murphey, X. Jeunemaitre, N. K. Hollenberg, and G. H. Williams Thyroid Function and Blood Pressure Homeostasis in Euthyroid Subjects J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3455 - 3461. [Abstract] [Full Text] [PDF]

				P Foex and J. Sear Hypertension: pathophysiology and treatment CEACCP, June 1, 2004; 4(3): 71 - 75. [Abstract] [Full Text] [PDF]

				J. P. Kooman, F. M. van der Sande, and K. M. L. Leunissen Sodium, blood pressure and cardiovascular pathology: is it all volaemia? Nephrol. Dial. Transplant., May 1, 2004; 19(5): 1046 - 1049. [Full Text] [PDF]

				A. Aviv, N. K. Hollenberg, and A. Weder Urinary Potassium Excretion and Sodium Sensitivity in Blacks Hypertension, April 1, 2004; 43(4): 707 - 713. [Abstract] [Full Text] [PDF]

				F. K Shieh, E. Kotlyar, and F. Sam Aldosterone and cardiovascular remodelling: focus on myocardial failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1): 3 - 13. [Abstract] [PDF]

				J. T. Wright Jr, M. Rahman, A. Scarpa, M. Fatholahi, V. Griffin, R. Jean-Baptiste, M. Islam, M. Eissa, S. White, and J. G. Douglas Determinants of Salt Sensitivity in Black and White Normotensive and Hypertensive Women Hypertension, December 1, 2003; 42(6): 1087 - 1092. [Abstract] [Full Text] [PDF]

				J. W. Osborn, P. Ariza-Nieto, J. P. Collister, S. Soucheray, B. Zimmerman, and S. Katz Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2142 - H2149. [Abstract] [Full Text] [PDF]

				D R Manna, M A Bruijnzeels, H G A Mokkink, and M Berg Ethnic specific recommendations in clinical practice guidelines: a first exploratory comparison between guidelines from the USA, Canada, the UK, and the Netherlands Qual. Saf. Health Care, October 1, 2003; 12(5): 353 - 358. [Abstract] [Full Text] [PDF]

				A. D. Dobrian, S. D. Schriver, T. Lynch, and R. L. Prewitt Effect of salt on hypertension and oxidative stress in a rat model of diet-induced obesity Am J Physiol Renal Physiol, October 1, 2003; 285(4): F619 - F628. [Abstract] [Full Text] [PDF]

				M. N. Kerstens, F. G. H. van der Kleij, A. H. Boonstra, W. J. Sluiter, J. Koerts, G. Navis, and R. P. F. Dullaart Salt Loading Affects Cortisol Metabolism in Normotensive Subjects: Relationships with Salt Sensitivity J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4180 - 4185. [Abstract] [Full Text] [PDF]

				R. C. Givens, Y. S. Lin, A. L. S. Dowling, K. E. Thummel, J. K. Lamba, E. G. Schuetz, P. W. Stewart, and P. B. Watkins CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults J Appl Physiol, September 1, 2003; 95(3): 1297 - 1300. [Abstract] [Full Text] [PDF]

				C.-H. Chen, Y.-P. Lin, W.-C. Yu, W.-C. Yang, and Y.-A. Ding Volume Status and Blood Pressure During Long-Term Hemodialysis: Role of Ventricular Stiffness Hypertension, September 1, 2003; 42(3): 257 - 262. [Abstract] [Full Text] [PDF]

				J. L. Houghton, D. S. Strogatz, M. T. Torosoff, V. E. Smith, S. A. Fein, P. A. Kuhner, E. F. Philbin, and A. A. Carr African Americans With LVH Demonstrate Depressed Sensitivity of the Coronary Microcirculation to Stimulated Relaxation Hypertension, September 1, 2003; 42(3): 269 - 276. [Abstract] [Full Text] [PDF]

				F. J He and G. A MacGregor Review: Salt, blood pressure and the renin-angiotensin system Journal of Renin-Angiotensin-Aldosterone System, March 1, 2003; 4(1): 11 - 16. [Abstract] [PDF]

				J. H. Pratt, W. T. Ambrosius, R. Agarwal, G. J. Eckert, and S. Newman Racial Difference in the Activity of the Amiloride-Sensitive Epithelial Sodium Channel Hypertension, December 1, 2002; 40(6): 903 - 908. [Abstract] [Full Text] [PDF]

				J. He and P. K Whelton Commentary: Salt intake, hypertension and risk of cardiovascular disease: an important public health challenge Int. J. Epidemiol., April 1, 2002; 31(2): 327 - 331. [Full Text] [PDF]

				R. J. Johnson, J. Herrera-Acosta, G. F. Schreiner, and B. Rodriguez-Iturbe Subtle Acquired Renal Injury as a Mechanism of Salt-Sensitive Hypertension N. Engl. J. Med., March 21, 2002; 346(12): 913 - 923. [Full Text] [PDF]

				F. D. Grant, J. R. Romero, X. Jeunemaitre, S. C. Hunt, P. N. Hopkins, N. H. Hollenberg, and G. H. Williams Low-Renin Hypertension, Altered Sodium Homeostasis, and an {alpha}-Adducin Polymorphism Hypertension, February 1, 2002; 39(2): 191 - 196. [Abstract] [Full Text] [PDF]

				W. M. Vollmer, F. M. Sacks, J. Ard, L. J. Appel, G. A. Bray, D. G. Simons-Morton, P. R. Conlin, L. P. Svetkey, T. P. Erlinger, T. J. Moore, et al. Effects of Diet and Sodium Intake on Blood Pressure: Subgroup Analysis of the DASH-Sodium Trial Ann Intern Med, December 18, 2001; 135(12): 1019 - 1028. [Abstract] [Full Text] [PDF]

				F. J. He, N. D. Markandu, and G. A. MacGregor Importance of the Renin System for Determining Blood Pressure Fall With Acute Salt Restriction in Hypertensive and Normotensive Whites Hypertension, September 1, 2001; 38(3): 321 - 325. [Abstract] [Full Text] [PDF]

				J. Loscalzo Salt-Sensitive Hypertension and Inducible Nitric Oxide Synthase: Form-Function Dichotomy of a Coding Region Mutation, Mutatis Mutandis Circ. Res., August 17, 2001; 89(4): 292 - 294. [Full Text] [PDF]

				Y. Konishi, N. Okada, M. Okamura, T. Morikawa, M. Okumura, K. Yoshioka, and M. Imanishi Sodium Sensitivity of Blood Pressure Appearing Before Hypertension and Related to Histological Damage in Immunoglobulin A Nephropathy Hypertension, July 1, 2001; 38(1): 81 - 85. [Abstract] [Full Text] [PDF]

				Y. R. Su and A. G. Menon Epithelial Sodium Channels and Hypertension Drug Metab. Dispos., April 1, 2001; 29(4): 553 - 556. [Abstract] [Full Text]

				A.-S. Rigaud and B. Forette Hypertension in Older Adults J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2001; 56(4): 217M - 225. [Abstract] [Full Text]

				F. H. Messerli and R. E. Schmieder Salt and Hypertension: Going to the Heart of the Matter Arch Intern Med, February 26, 2001; 161(4): 505 - 506. [Full Text] [PDF]

				A. Aviv Salt and Hypertension: The Debate That Begs the Bigger Question Arch Intern Med, February 26, 2001; 161(4): 507 - 510. [Full Text] [PDF]

				E. Bragulat, Alejandro de la Sierra, M. T. Antonio, and A. Coca Endothelial Dysfunction in Salt-Sensitive Essential Hypertension Hypertension, February 1, 2001; 37(2): 444 - 448. [Abstract] [Full Text] [PDF]

				F. Elijovich, C. L. Laffer, E. Amador, H. Gavras, M. R. Bresnahan, and E. L. Schiffrin Regulation of Plasma Endothelin by Salt in Salt-Sensitive Hypertension Circulation, January 16, 2001; 103(2): 263 - 268. [Abstract] [Full Text] [PDF]

				N. M Kaplan The dietary guideline for sodium: should we shake it up? No Am. J. Clinical Nutrition, May 1, 2000; 71(5): 1020 - 1026. [Abstract] [Full Text] [PDF]

				J. C. ter Maaten, S. J. L. Bakker, E. H. Serne, P. M. ter Wee, A. J. M. Donker, and R. O. B. Gans Insulin's acute effects on glomerular filtration rate correlate with insulin sensitivity whereas insulin's acute effects on proximal tubular sodium reabsorption correlate with salt sensitivity in normal subjects Nephrol. Dial. Transplant., October 1, 1999; 14(10): 2357 - 2363. [Abstract] [Full Text] [PDF]

				E. Lovati, P. Ferrari, B. Dick, K. Jostarndt, B. M. Frey, F. J. Frey, U. Schorr, and A. M. Sharma Molecular Basis of Human Salt Sensitivity: The Role of the 11{beta}-Hydroxysteroid Dehydrogenase Type 2 J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3745 - 3749. [Abstract] [Full Text] [PDF]

				W. T. Ambrosius, L. J. Bloem, L. Zhou, J. F. Rebhun, P. M. Snyder, M. A. Wagner, C. Guo, and J. H. Pratt Genetic Variants in the Epithelial Sodium Channel in Relation to Aldosterone and Potassium Excretion and Risk for Hypertension Hypertension, October 1, 1999; 34(4): 631 - 637. [Abstract] [Full Text] [PDF]

				O. Schmidlin, A. Forman, M. Tanaka, A. Sebastian, and R. C. Morris Jr NaCl-Induced Renal Vasoconstriction in Salt-Sensitive African Americans : Antipressor and Hemodynamic Effects of Potassium Bicarbonate Hypertension, February 1, 1999; 33(2): 633 - 639. [Abstract] [Full Text] [PDF]

				R. C. Morris Jr, A. Sebastian, A. Forman, M. Tanaka, and O. Schmidlin Normotensive Salt Sensitivity : Effects of Race and Dietary Potassium Hypertension, January 1, 1999; 33(1): 18 - 23. [Abstract] [Full Text] [PDF]

				F. J. He, N. D. Markandu, G. A. Sagnella, and G. A. MacGregor Importance of the Renin System in Determining Blood Pressure Fall With Salt Restriction in Black and White Hypertensives Hypertension, November 1, 1998; 32(5): 820 - 824. [Abstract] [Full Text] [PDF]

				M. Barton, L. V. d'Uscio, S. Shaw, P. Meyer, P. Moreau, and T. F. Luscher ETA Receptor Blockade Prevents Increased Tissue Endothelin-1, Vascular Hypertrophy, and Endothelial Dysfunction in Salt-Sensitive Hypertension Hypertension, January 1, 1998; 31(1): 499 - 504. [Abstract] [Full Text] [PDF]

				S. G. Chrysant, M. R. Weir, A. B. Weder, D. A. McCarron, M. Canossa-Terris, J. D. Cohen, R. F. Mennella, L. W. Kirkegaard, A. J. Lewin, and M. H. Weinberger There Are No Racial, Age, Sex, or Weight Differences in the Effect of Salt on Blood Pressure in Salt-Sensitive Hypertensive Patients Arch Intern Med, November 24, 1997; 157(21): 2489 - 2494. [Abstract] [PDF]

				M. M. E. Krekels, N. C. Schaper, and P. W. de Leeuw Sensitivity of Blood Pressure and Renin Activation During Sodium Restriction Hypertension, November 1, 1997; 30(5): 1216 - 1222. [Abstract] [Full Text]

				A. Aviv and H. Aviv Reflections on Telomeres, Growth, Aging, and Essential Hypertension Hypertension, May 1, 1997; 29(5): 1067 - 1072. [Abstract] [Full Text]

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