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(Hypertension. 1997;30:1216-1222.)
© 1997 American Heart Association, Inc.
Articles |
Sensitivity of Blood Pressure and Renin Activation During Sodium Restriction
From the Department of Medicine, University Hospital Maastricht, Maastricht, the Netherlands.
Correspondence and reprints to P.W. de Leeuw, MD, PhD, Department of Medicine, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, Netherlands.
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Abstract |
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Abstract The objective of the present study was to explore the interrelationships among cumulative sodium loss, renin activation, and blood pressure changes during sodium restriction in essential hypertensive patients. Specifically, we wanted to know whether the degree of sodium sensitivity of blood pressure depends on renin activation during steady state or on initial renin activation during the first days of sodium restriction. Sixty-seven untreated essential hypertensive patients were admitted to a metabolic ward for 8 days and put on a sodium restricted diet of 55 mmol/d from the second to the last day. Urinary excretions of sodium, potassium, and creatinine were determined along with mean arterial pressure and weight during 7 days. Besides measurements in steady state condition (after 7 days), active plasma renin concentration, aldosterone, and catecholamines were also assessed during the first 3 days of sodium restriction. Analyzable data are available for 55 patients. Baseline sodium excretion and the activation of renin during the first 3 days both appeared to be predictors of total sodium loss after 7 days. Changes in blood pressure were not related to changes in sodium balance, but they were to baseline blood pressure, baseline norepinephrine, and renin activation during the early phase of sodium restriction. In addition, blood pressure appeared to fall more when the normal relationship between sodium loss and early (but not late) activation of renin was disturbed. We conclude that sodium sensitivity of blood pressure during sodium restriction is associated with a relative unresponsiveness of the renin system during the early phase of sodium loss rather than to absolute renin levels during steady state.
Key Words: sodium sensitivity • renin • sodium balance
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Introduction |
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Although sodium sensitivity of blood pressure has been the subject of many investigations, the mechanisms underlying this condition have not yet been elucidated. Among the potential pathophysiological mechanisms involved are sympathetic overactivity,1 2 3 possibly in conjunction with an increased ratio of
-2 over ß-2
adrenoceptors,4 and altered sodium handling by the
kidney.5 6 7 Sodium sensitivity appears to be related to
older age, black race, and low levels of renin and
prorenin.8 9 10 11 In addition, it has been linked to a blunted
rise in renin with sodium restriction.2 11 12 13 14 However,
interpretation of available data is difficult, because in many of the
studies dealing with sodium sensitivity no information is given
regarding changes in body fluid volumes or cumulative sodium balance.
Moreover, little is known about the time course of changes in sodium
balance and renin that determine the final change in blood pressure.
This prompted us to study the interrelationships among changes in
cumulative sodium balance, renin, and blood pressure during a period of
sodium restriction in more detail. Because sodium sensitivity should be
considered a gradual phenomenon,8 we analyzed the
data on the basis of the degree of blood pressure changes rather than
an arbitrary cutoff point. |
Methods |
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Patients
Sixty-seven patients with essential hypertension were included in this study after having given written informed consent. Secondary hypertension had been ruled out by routine clinical and laboratory investigations, and antihypertensive medication, if any, was stopped at least 3 weeks before the study. No other abnormalities were present in these patients, and none of them had been treated with diuretics within 12 months before the start of the study. To be eligible, supine diastolic blood pressure had to be above 95 mm Hg and 24-hour urinary sodium excretion had to be at least 70 mmol and to fluctuate by less than 20% on multiple occasions.
In addition, serum creatinine concentration had to be below 120 µmol/L.
Protocol
All patients were admitted to a metabolic ward for 8
days and kept on a diet containing 55 mmol of sodium per day;
potassium intake was fixed at 70 mmol per day. The diet was
designed by the hospital dietitian and adjusted to the subjects'
caloric intake. Meals were prepared by the metabolic
kitchen. Since blood pressure may show a nonspecific fall on the day of
admission, the study proper was started on the second hospital
day.
Twenty-four–hour urine collections for determination of sodium, potassium, and creatinine were started immediately after admission and continued throughout the study period. Cumulative sodium balances were calculated from the first day of dietary restriction (ie, the second hospital day) onward. Completeness of urine collections was verified from creatinine excretion. For each patient, data from a 24-hour urinary collection were accepted for analysis only when creatinine excretion in that collection deviated by no more than 5% from the average creatinine excretion during the entire study period in that patient.
During daytime, defined as the period between 7 AM and 11 PM, MAP was measured every hour by a Dinamap Vital Signs Monitor (Criticon) and averaged for each day. In addition, weight was determined daily. During the first 3 days of sodium restriction, blood was drawn at 8 AM, while subjects were still supine, for the measurement of APRC, Ang II, ALDO, and catecholamines. After 7 days, when a steady state condition had been reached, these variables were assessed once more.
APRC was determined by an immunoradiometric assay,15 whereas ALDO was measured by radioimmunoassay.16 Ang II was also measured by radioimmunoassay after extraction of plasma.17 Catecholamines (norepinephrine and epinephrine) were assessed by a radioenzymatic (Catechol-O-methyltransferase) method using high-performance liquid chromatography for separation of radioactive products.18
Statistical Analysis
Results are expressed as mean±SD. Regression analysis
was applied to detect associations between variables. Associations
that were found to be significant in univariate
analysis were grouped together and tested again in a
multivariate analysis. A sliding mean
analysis technique was used to explore the relationship between
changes in blood pressure and certain aspects of volume control. A
value of P<.05 was considered to denote statistical
significance.
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Results |
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In 12 of the 67 patients at least 1 of the 7 urine collections was incomplete, making it impossible to calculate cumulative sodium losses after the dietary intervention in these subjects. These patients were therefore excluded from analysis. Baseline characteristics of the remaining 55 patients are presented in the Table
. The study population consisted of
36 men and 19 women who were all of European descent. Mean age was 43
years with a range from 22 to 67 years. At the start of the study,
blood pressure was, on average, in the hypertensive range but 3
patients proved to have normal blood pressure at that time.
Twenty-four–hour creatinine excretion correlated strongly
with body weight (P<.0002) and remained stable during the
entire study period. Mean 24-hour urinary sodium excretion on admission
was 121 mmol but varied over a wide range. In 6 subjects initial
sodium excretion was less than 70 mmol per 24 hours. In the whole
group, baseline concentrations of catecholamines, renin,
Ang II, and aldosterone in plasma were within normal
limits, but in 11 of the 55 patients (20%) renin levels were low.
These low-renin patients did not differ from the others with respect to
age, weight, initial blood pressure, and baseline sodium excretion.
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Cumulative Sodium Balance
Twenty-four–hour urinary sodium output fell gradually, as
expected, during the first few days of dietary restriction. A new
steady state, during which sodium output again matched intake,
generally was reached by the fourth day, but time courses varied from 3
to 6 days. While cumulative sodium balance became negative in the
majority of patients, in 10 of them (18%) a positive balance was found
at steady state. The latter was due to an extreme fall in urinary
sodium output (ie, less than 20 mmol/24 h) that had become
apparent on the second day of the dietary intervention. This remarkable
reduction in sodium excretion could not be explained by inadequate
urine collections because 24-four–hour creatinine output
in patients in whom cumulative sodium balance became positive was as
stable as that in the others.
In the whole group cumulative sodium balance fell by an average of
112 mmol (range, -455 to +155 mmol), which was associated
with a mean weight loss of 1.8 kg (range, -4 to 0 kg). The total
amount of sodium excreted over 7 days was not related to age or to
initial weight or blood pressure. However, as shown in Fig 1, cumulative sodium loss was positively
related to sodium excretion on the first day of salt restriction
(y=1.6x–77; r=.68;
P<.001). In addition, an inverse correlation was found
between renin concentration on the first day of the intervention and
cumulative sodium loss (y=203–5.1x;
r=-.36; P<.01). In the
multivariate analysis, however, only initial
sodium excretion remained as a significant determinant of total sodium
loss.
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Neurohumoral Responses
Renin concentrations rose appropriately during sodium restriction,
but individual renin responses varied widely: from a fall of 17 mU/L to
a rise of 47 mU/L after 3 days and from a fall of 12 mU/L to a rise of
62 mU/L after 1 week. Changes in renin proved to be independent from
baseline levels. The early renin response (ie, the change in renin from
the first to the third day) appeared to be inversely related to age
(y=19.7–0.35x; r=-.36;
P<.01), whereas the final response (the change in renin
after 1 week) was not. When patients were classified according to their
renin response on the third day, those with the least response had the
greatest increase in renin from day 3 to day 7, whereas a slight fall
in renin was seen in those patients with the largest increment in renin
during the first 3 days.
Both the early and the final renin responses were inversely related to preintervention MAP (y=36–0.26x; r=-.45; P<.001; and y=65–0.45x; r=-.39; P<.05, respectively). Although no relationship was apparent between either the early or the final renin response on the one hand and initial sodium excretion on the other, a positive relationship was found between sodium excretion on the first day and renin levels on the last day (y=0.11x–5.8; r=.44; P<.05). When the various factors were tested in a multivariate analysis model, age and preintervention MAP remained as the only independent determinants of the early and final renin responses, respectively. In other words, a higher age and a higher blood pressure blunted the changes in renin.
By and large, Ang II and ALDO followed the same patterns as those observed for renin. There were, indeed, very close relationships between changes in renin and in Ang II on the one hand and between changes in Ang II and in ALDO on the other. In contrast to the alterations in the renin-angiotensin-aldosterone system, catecholamine concentrations remained stable throughout the study period.
Blood Pressure Responses
After 7 days of sodium restriction, changes in MAP varied from
-49 to +6 mm Hg (mean fall, 16 mm Hg). Blood pressure fell
by more than 10 mm Hg in 36 of the 55 (65%) patients. Changes in
blood pressure were not related to age, initial sodium excretion, or
renin on day 1. However, significant relationships were observed
between the absolute change in MAP and MAP on the first day
(y=31+0.37x; r=.53;
P<.0001) and between the change in MAP and
norepinephrine levels on day 1
(y=-5.5+5.9x; r=.46;
P<.001). Both factors also remained significant in the
multivariate analysis, indicating that a higher
blood pressure and a higher level of norepinephrine before
the intervention were associated with a greater fall in pressure.
Interrelationships Between Changes in Sodium Balance,
Renin and Blood Pressure
When patients in whom renin was unchanged or had fallen on the
third day of sodium restriction were compared with those in whom renin
had risen by that time, calculated half-life of the fall in sodium
excretion was twice as long in the former group. Accordingly, this
group displayed a significantly greater sodium output on the third and
fourth days of the dietary restriction, although not on any of the
other days (Fig 2). Moreover, the early
renin response appeared to be a predictor of total sodium loss because
a significant inverse relationship was found between the change in
renin from the first to the third day on the one hand and cumulative
sodium loss after 7 days on the other
(y=131–3.5x; r=-.30;
P<.05; Fig 3a). Thus, a
blunted early renin response was associated with greater sodium loss.
However, the relationship reversed (y=3.6x+65;
r=.40; P<.05) when the final renin response
after 7 days was taken as the explanatory variable, indicating that
at steady state a greater sodium loss was related to a larger rise in
renin.
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Multivariate analysis proved sodium excretion on the first day (P<.001) and both the initial (P<.001) and the final (P<.01) renin responses to be independently related to total sodium loss with an overall explanatory power of 70%. Also, in this multivariate analysis absolute renin levels on the first day were not independently related to cumulative sodium loss.
As illustrated in Fig 3b
, the change in MAP that had occurred
at the end of the study period appeared to be significantly related to
the early rise in renin (y=0.4x–17.4;
r=.40; P<.005). No such relationship, however,
was found with the final change in renin. Since changes in blood
pressure were also related to blood pressure and
norepinephrine levels on the first day (see above), we
performed multivariate regression analysis to
evaluate the relative importance of these factors. In fact, all three
factors turned out to be significant and independent predictors of the
final change in pressure with an explained variance of 46%.
Although cumulative sodium loss and the final change in blood pressure
both were related to the early rise in renin, sodium losses and blood
pressure after 1 week were not significantly related to each other.
When patients were again divided into those with or those without an
adequate early renin response, a significant relationship between
changes in pressure and changes in urinary sodium excretion was found
in the latter only (Fig 4). Therefore, we
tested whether the ultimate change in blood pressure was correlated
with the "strength" of the relationship between early renin
activation and sodium loss. To this end we applied the technique of
moving averages. Patients were ranked according to the magnitude of
their blood pressure changes, and starting with the lowest value the
correlation coefficient for the relationship between the early rise in
renin and the final change in sodium balance was calculated for the
first 20 patients. Subsequently, the same relationship was calculated
after adding the next higher data point while deleting the first data
point and so forth.19 Results of this analysis are
depicted in Fig 5. The data show that as
the fall in pressure is less, the relationship between early renin
responsiveness and cumulative sodium loss at the end of the study
becomes stronger and more statistically significant. Conversely, a
larger fall in pressure is associated with the lack of a significant
relationship between the early renin response and sodium loss.
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Finally, we constructed renal function curves that relate changes in
pressure to changes in urinary sodium output. While these curves were
substantially steeper in the group of patients with adequate renin
activation than in the group with a blunted response, overall
differences between both groups just failed to reach statistical
significance (P=.07; Fig 6).
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Discussion |
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The mechanisms whereby sodium restriction lowers blood pressure in salt-sensitive individuals are still poorly understood. Although some investigators have suggested that salt-sensitive subjects differ from salt-resistant ones in their ability to achieve sodium balance on a low salt diet, others have failed to demonstrate consistent differences in sodium balance between salt-sensitive and salt-resistant patients.20 21 Moreover, at least two groups have shown that alterations in blood pressure during dietary salt restriction are independent from changes in cumulative sodium loss.22 23 However, in these studies a rather rigorous protocol was followed to achieve sodium depletion, including the administration of furosemide. Thus, while these results may be indicative of a state of true volume depletion, they do not necessarily reflect the relationship between volume and pressure under less extreme conditions. In the present study we adopted a more liberal approach. After admission to the hospital all patients were put on a mild sodium restricted diet (55 mmol/d), which probably better reflects real life situations. All patients had continued their habitual diet until the intervention, because we deliberately wanted to achieve a wide variation in cumulative sodium losses at the end of the dietary period. Despite the sodium restriction, we found that cumulative sodium balance became positive in 10 patients. This was due to an extreme fall in sodium output from the second day of the dietary intervention onward and confirms earlier data from our group.24 Not unexpectedly, we found that the total amount of sodium lost during the dietary period correlated with urinary sodium excretion on the first day of the study. In other words, changes in cumulative sodium balance after institution of a sodium restricted diet are to a large extent predicted by the level of salt intake in the preceding period. Nevertheless, despite the large splay in cumulative sodium losses, we failed to find a relationship between changes in sodium balance and changes in blood pressure when the whole group of patients was considered. In this respect our data corroborate and extend those from the earlier studies.22 23 They also tally nicely with the results of others who failed to find a relationship between the amount of sodium accumulated and the concurrent changes in blood pressure during sodium loading.3 23 25
When changes in blood pressure during sodium restriction are not (or at
least not primarily) determined by the degree of volume loss, other
factors must be responsible. Since the
renin-angiotensin-aldosterone system is
involved in both hemodynamic regulation and in volume
homeostasis, we took multiple blood samples during the study to assess
the responsiveness of this system. Contrary to others8 we
could not find a relationship between baseline renin and final changes
in blood pressure. Still, our data do show a linkage between the degree
of renin responsiveness and the magnitude of blood pressure changes.
Although not very impressive, a positive relationship was observed
between the early renin response (ie, during the first 3 days of sodium
restriction) and the difference between final and initial blood
pressures, indicating that a greater renin response during the first
few days of sodium restriction was associated with a lesser fall in
pressure (Fig 3b). In principle this confirms the data from others who
have also shown that salt sensitivity is coupled to a blunted
responsiveness of the renin system.1 20 21 22 26 27 28
Interestingly, though, our data also demonstrate that final changes in
renin (ie, after 1 week) do not correlate anymore with changes in blood
pressure. Given the fact that salt sensitivity is not limited to
subjects with suppressed renin but also occurs among people with normal
renin levels,21 our findings seem to suggest that an
abnormal dynamic behavior of renin during the early phase of sodium
loss rather than the steady state level of renin is associated with the
phenomenon of salt sensitivity. Since an abnormal renin response is
more likely to occur in patients with low renin levels or in elderly
patients, it is not surprising, therefore, that salt sensitivity is
more prevalent in these groups.
The question now arises why hormonal responses that occur early during sodium restriction have such an impact on blood pressure a few days later. Although we can only speculate about the answer, it is noteworthy that the early renin response more or less coincides with the period that the organism is "seeking" a new steady state to match urinary sodium excretion to sodium intake. Interestingly, patients with a blunted renin response displayed a longer half-life of the fall in sodium excretion with an associated greater sodium loss from the body than those with a normal renin response. Such a difference in half-life of sodium balance, for that matter, may have more relevance to sodium sensitivity than total body sodium.25 Given the association between renin responsiveness and changes in sodium excretion, it is tempting to speculate that renin is involved in determining the half-life of sodium balance in the sense that a brisk renin response may shorten this half-life. If this is true, stimulation of renin could be seen as a defense mechanism that is primarily needed to limit sodium losses. In agreement with this hypothesis we found an inverse relationship between early changes in renin and total sodium loss after 1 week. Thus, the more renin rises during the first few days of sodium restriction, the less sodium is lost. On the other hand, however, a positive association was found between final changes in renin and total sodium loss. Our explanation for these findings is as follows: when sodium intake is suddenly decreased, cumulative sodium balance falls and, as our data show, in proportion to initial sodium intake. The greater the decrement in sodium balance (or the longer the half-life) the more renin eventually rises. Thus, renin levels at the end of the dietary period seem to be dependent on the amount of sodium loss rather than the other way around. In other words, a brisk renin response during the early days apparently limits the final sodium loss, and as a consequence further stimulation of renin will be slowed down. On the other hand, in patients with a more sluggish early response we found a more pronounced rise in renin from day 3 to day 7, suggesting that ongoing sodium loss finally enhanced renin release. As a corollary of these observations one would be inclined to conclude that a greater initial stimulation of renin is associated with both a lesser volume depletion and a lesser fall in pressure and that, therefore, volume and pressure changes ought to be correlated. Although such a correlation could not be detected in our data when the whole group of patients was considered, we did find a relationship between changes in urinary sodium excretion and changes in blood pressure in those subjects who displayed an inadequate early renin response. Our data suggest, therefore, that sodium dependency of blood pressure is somehow modulated by the responsiveness of renin.
In an attempt to put these observations into better perspective we
stretched the analysis of our data a little further by
exploring the dynamic relationship between the fall in pressure on the
one hand and the volume-renin connection on the other. To this end we
plotted the correlation coefficient that described the relation between
the early renin response and the final change in cumulative sodium
balance as a function of the fall in blood pressure using a sliding
mean analysis technique. As the plot in Fig 4 clearly shows,
there is a tight and statistically significant relationship between
initial renin stimulation and sodium loss in the patients in whom blood
pressure falls only slightly. However, a progressively greater drop in
pressure is associated with uncoupling of this renin-sodium
relationship. These observations may now provide an explanation for the
lack of a relationship between changes in cumulative sodium balance and
changes in blood pressure. For the same decline in cumulative sodium
balance, the change in blood pressure may not depend so much on whether
renin rises or not but upon whether renin rises fast enough as a
function of sodium loss. Perhaps renin activation during salt
restriction serves a dual purpose: in the first place it is needed to
conserve sodium and maintain body sodium stores within acceptable
limits. At the same time, however, the rise in renin causes the
pressure-natriuresis curve to be shifted to the right in order to keep
the equilibrium point at the same pressure level.22 29 30
A more sluggish renin response will then be associated with less steep
renal function curves, which we have, indeed, found albeit that the
difference between the groups with normal and reduced renin
responsiveness just failed to reach statistical significance. Once a
new steady state has been attained, the role of circulating renin may
become less important as compared with other mechanisms, eg, intrarenal
renin. This would also explain why some investigators failed to find an
association between renin and salt sensitivity.31 32
The data from the present study do not allow us to make inferences about the causes of a disturbed renin-volume relationship. According to our analyses, higher age, a higher initial blood pressure, and higher norepinephrine levels may all play a part, but further studies are needed to explore this. We should stress, though, that the responsiveness of renin and of norepinephrine might have been greater when sodium intake had been reduced even further, ie, below 50 mmol/d. According to Simpson, 33 the prolonged half-life of sodium balance could also point to a relative excess of body sodium before the salt restriction. Although we cannot exclude the possibility of volume expansion at the start of our study, this option is less likely because in an earlier study we did not find a relationship between the degree of sodium sensitivity and plasma volume.34
In conclusion, we have shown that the degree of sodium sensitivity during sodium restriction is not solely determined by changes in cumulative sodium balance but rather by a complex interplay between sodium loss and early (but not late) renin activation. In our view, it is not a suppressed renin system that is related to salt sensitivity, but rather the fact that the system is relatively unresponsive. Accordingly, it is our opinion that studies on the pathophysiology of sodium sensitivity of blood pressure should focus more on dynamic processes taking place early during dietary intervention rather than on differences at steady state.
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Selected Abbreviations and Acronyms |
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Received July 24, 1996; first decision September 11, 1996; accepted April 16, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Fujita T, Henry WL, Bartter FC, Lake CR, Delea CS. Factors influencing blood pressure in salt-sensitive patients with hypertension. Am J Med. 1980;69:334-344.[Medline] [Order article via Infotrieve]
-
Koolen MI, Van Brummelen P. Adrenergic activity
and peripheral hemodynamics in relation to
sodium sensitivity in patients with essential hypertension.
Hypertension. 1984;6:820-825.
[Abstract/Free Full Text] - Campese VM, Romoff MS, Levitan D, Saglikes Y, Friedler RM, 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]
- Skrabal F, Kotanko P, Meister B, Doll P, Gruber G. Up-regulation of alpha2 adrenoreceptors and down-regulation of beta2 adrenoreceptors by high-salt diet in normotensive men: enhanced up-regulation of operative (alpha2:beta2) adrenoreceptor ratio predicts salt sensitivity. J Hypertens. 1986;4(suppl 6):S196-S199.
- 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]
- Kimura G, Ashida T, Abe H, Kawano Y, Yoshimi H, Sanai T, Imanishi M, Yoshida K, Kawamura M, Kojima S, Kuramochi M, Omae T. Sodium sensitive and sodium retaining hypertension. Am J Hypertens. 1990;3:854-858.[Medline] [Order article via Infotrieve]
- Williams GH, Hollenberg NK. `Sodium-sensitive' essential hypertension: emerging insights into pathogenesis and therapeutic implications. Contemp Nephrol. 1985;3:303-331.
- 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.
- Stamler J, Rose G, Elliott P, Dyer A, Marmot M, Kesteloot H, Stamler R. Findings of the international cooperative INTERSALT study. Hypertension. 1991;17(suppl I):I-9-I-15.
- Dustan HP, Kirk KA. Relationship of sodium balance to arterial pressure in black hypertensive patients. Am J Med Sci. 1988;31:378-383.
- Pecker MS, James GD, Laragh JH, Sealy JE. Plasma prorenin is inversely related to the salt sensitivity in borderline to mild hypertension. J Am Soc Nephrol. 1993;4:537. Abstract.
- Longworth DL, Drayer JIM, Weber MA, Laragh JH. Divergent blood pressure responses during short term sodium restriction in hypertension. Clin Pharmacol Ther. 1980;27:544-546.[Medline] [Order article via Infotrieve]
- Parfrey PS, Markandu ND Roulston JE, Jones BE, Jones JC, MacGregor GA. Relation between arterial pressure, dietary sodium intake and renin system in essential hypertension. Br Med J. 1981;283:94-97.
- Koolen MI, Van Brummelen P. Sodium sensitivity in essential hypertension: role of the renin-angiotensin-aldosterone system and predictive value of an intravenous frusemide test. J Hypertens. 1984;2:55-59.[Medline] [Order article via Infotrieve]
- Simon D, Hartmann BJ, Badouaille G, Caillot G, Guyenne TT, Corvol P, Pau B, Marchand J. Two-site direct immunoassay specific for active renin. Clin Chem. 1991;38:1959-1962.[Abstract]
- Kubasik NP, Warren K, Sine HE. Evaluation of a new commercial radioassay kit for aldosterone using an iodinated tracer. Clin Biochem. 1978;12:59-61.
- Nussberger J, Brunner DB, Waeber B, Brunner HR. True versus immunoreactive angiotensin II in human plasma. Hypertension. 1985;7(suppl I):I-1-I-7.
- Endert E. Determination of epinephrine and norepinephrine in plasma by a radio-enzymatic assay using high pressure liquid chromatography for the separation of the radiochemical products. Clin Chim Acta. 1979;96:233-239.[Medline] [Order article via Infotrieve]
- Chau NP, Safar ME, Weiss YA, London GM, Simon AC, Milliez PL. Relationships between cardiac output, heart rate and blood volume in essential hypertension. Clin Sci Mol Med. 1978;54:175-180.[Medline] [Order article via Infotrieve]
-
Campese VM. Salt sensitivity in hypertension:
renal and cardiovascular implications.
Hypertension. 1994;23:531-550.
[Abstract/Free Full Text] -
Weinberger MH. Salt sensitivity of blood
pressure in humans. Hypertension. 1996;27:481-490.
[Abstract/Free Full Text] - Fraser R, Davies DL, Zoccali C, Usherwood T, Beretta-Piccoli C, Brown JJ, Cumming AMM, Lever AF, Robertson JIS, Watt R. Relation of blood pressure and body sodium content during sodium depletion in normal and hypertensive subjects. J Cardiovasc Pharmacol. 1984;6(suppl 1):S107-S114.
-
Dustan HP, Kirk KA. Corcoran Lecture: the case
for and against salt in hypertension. Hypertension. 1989;13:696-705.
[Abstract/Free Full Text] - Krekels MME, Houben AJHM, Lavrijssen ATJ, Van Es PN, De Leeuw PW. Heterogeneous patterns of sodium excretion during sodium restriction in essential hypertensive patients. J Hum Hypertens. 1996;10(suppl 3):S123-S126.
- 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]
-
Overlack A, Ruppert M, Kolloch R, Göbel 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] -
Sullivan JM, Ratts TE. Sodium sensitivity in
human subjects: hemodynamic and hormonal
correlates. Hypertension. 1988;11:717-723.
[Abstract/Free Full Text] -
Van Paassen P, De Zeeuw D, Navis G, De Jong PE.
Does the renin-angiotensin system determine the renal and
systemic hemodynamic responses to sodium in patients
with essential hypertension? Hypertension. 1996;27:202-208.
[Abstract/Free Full Text] - Girardin E, Caverzasio J, Iwai J, Bonjour JP, Muller AF, Grandchamp A. Pressure natriuresis in isolated kidneys from hypertension-prone and hypertension-resistant rats. Kidney Int. 1980;18:10-19.[Medline] [Order article via Infotrieve]
- Guyton AC. Arterial Pressure and Hypertension. Philadelphia, Pa: WB Saunders; 1980.
- Gerdts E, Myking OL, Omvik P. Salt sensitive essential hyper-tension evaluated by 24 hour ambulatory blood pressure. Blood Press. 1994;3:375-380.[Medline] [Order article via Infotrieve]
- Draaijer P, De Leeuw P, Maessen J, Van Hooff J, Leunissen K. Salt-sensitivity testing in patients with borderline hypertension: reproducibility and potential mechanisms. J Hum Hypertens. 1995;9:263-269.[Medline] [Order article via Infotrieve]
- Simpson FO. Sodium intake, body sodium, and sodium excretion. Lancet. 1988;2:25-29.[Medline] [Order article via Infotrieve]
- Krekels MME, Van Es PN, Leunissen KML, De Leeuw PW. Sodium sensitivity of blood pressure in hypertensives is not related to sodium, but rather to renin. J Hum Hypertens. 1996;10(suppl 3):S127-S130.
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