IN TRANSLATION

Pathogenesis of Hypertension: Interactions Among Sodium, Potassium,

and Aldosterone
Eckhart Bssemaker, MD,1 Uta Hillebrand, MD,1 Martin Hausberg, MD,2
Hermann Pavenstdt, MD,1 and Hans Oberleithner, MD3
Arterial hypertension is a major cause of disease-related morbidity and mortality worldwide. It is
nearly absent in populations that consume natural foods low in sodium. However, in industrial countries,
where the individual intake of sodium is at least 10 times higher, the prevalence of hypertension is
40%. Major population-based studies link a high-sodium and low-potassium diet to an increase in
blood pressure. A hallmark of arterial hypertension is endothelial dysfunction characterized by decreased synthesis of nitric oxide (NO). Plasma sodium and potassium are major determinants for the
mechanical stiffness of endothelial cells. High plasma sodium levels stiffen endothelial cells and block
NO synthesis. Aldosterone is a prerequisite for this action. However, high plasma potassium levels
soften endothelial cells and activate NO release. There is increasing evidence that sodium can be stored
transiently in considerable amounts and osmotically inactive in the interstitium. Taken together, it is
recommended to maintain plasma sodium levels in the low physiologic range and potassium levels in
the high physiologic range while suppressing plasma aldosterone as much as possible. A restriction in
sodium intake that is accompanied by increased intake of potassium can profoundly improve the
prevalence of hypertension and cardiovascular disease.
Am J Kidney Dis 55:1111-1120. 2010 by the National Kidney Foundation, Inc.
INDEX WORDS: Aldosterone; nitric oxide; atomic force microscopy; spironolactone; endothelial
dysfunction.

BACKGROUND
Primary hypertension is the sum of interactions between multiple environmental and genetic factors.1,2 The role of dietary salt in causing
arterial hypertension and other harmful cardiovascular effects independent of blood pressure derives from epidemiologic studies, experimental
models (particularly in primates), physiologic
and biochemical studies, controlled clinical trials, and genetic and mortality studies.3
CASE VIGNETTE
A 52-year-old man presented with an office blood pressure of 175/105 mm Hg. Antihypertensive therapy consisted
of metoprolol succinate, hydrochlorothiazide, amlodipine,
and ramipril. Ambulatory blood pressure monitoring indicated a mean blood pressure of 153/102 mm Hg and nondipper status. Serum potassium level was 4.2 mEq/L (4.2
mmol/L), serum sodium level was 143 mEq/L (143 mmol/
L), and serum creatinine level was 1.1 mg/dL (97.2 mol/L).
Albuminuria was quantified as albumin excretion of 18
mg/L, and septum hypertrophy was prominent on cardiac
echocardiography. Tests for secondary causes of hypertension were unrevealing. Information for nonpharmacologic
interventions was provided by the treating physician, including instruction for decreasing sodium intake by decreasing
consumption of processed foods. Additionally, increased
potassium intake was suggested through increased consumption of vegetables and fruits. Advice was given to start
aerobic physical activity and decrease body weight. Eight

weeks later, his weight had decreased by 1.4 kg, and blood
pressure had improved to 160/95 mm Hg. Because he was
still not meeting treatment goals, 25 mg of spironolactone
was added to his medication regimen, resulting in a decrease
in blood pressure to 145/90 mm Hg 4 weeks later. Serum
potassium level modestly increased to 4.3 mEq/L (4.3 mmol/
L), and serum sodium level was 141 mEq/L (141 mmol/L).
Spironolactone dosage was increased to 50 mg/d. Twelve
weeks later, ambulatory blood pressure monitoring was
repeated. Mean blood pressure was profoundly decreased to
137/81 mm Hg, almost reaching treatment goals, and the
patient was well with no obvious side effects caused by the
treatment regimen. At 6 months after initiation of spironolactone therapy, urine albumin excretion was decreased to 5
mg/L. In this patient, moderate dietary modifications and

From the 1Medizinische Klinik und Poliklinik D, Universittsklinikum Mnster, Mnster; 2Medizinische Klinik I,
Stdtisches Klinikum Karlsruhe, Karlsruhe; and 3Institut fr
Physiologie II, Westflische Wilhelms-Universitt, Mnster,
Germany.
Received August 14, 2009. Accepted in revised form
December 3, 2009. Originally published online as doi:10.1053/
j.ajkd.2009.12.022 on March 11, 2010.
Address correspondence to Eckhart Bssemaker, MD,
Medizinische Klinik und Poliklinik D, Universittsklinikum
Mnster, Albert-Schweitzer-Str 33, 48149 Mnster, Germany. E-mail: buessema@hotmail.com
2010 by the National Kidney Foundation, Inc.
0272-6386/10/5506-0019$36.00/0
doi:10.1053/j.ajkd.2009.12.022

American Journal of Kidney Diseases, Vol 55, No 6 (June), 2010: pp 1111-1120

1111

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Bssemaker et al

aldosterone antagonism were highly effective in decreasing

blood pressure and cardiovascular risk, indicated by the
decrease in microalbuminuria.

PATHOGENESIS
Sodium in Hypertension
Humans exposed to a high-salt diet may develop hypertension.4 In such individuals, the
kidney has limited ability to excrete the daily
load of sodium and tends to retain the salt, most
likely osmotically inactive, in skin and other
extracellular compartments.5 This internal sodium escape buffer, which likely is inadequate
in humans with high blood pressure, suggests
that extrarenal sodium balance has an important
role in blood pressure control.6 Salt and water
balance is regulated by a multitude of factors/
mediators. It is beyond doubt that one of the key
factors is aldosterone. This mineralocorticoid
hormone controls the activity of epithelial sodium channels in the renal collecting duct. It also
acts on epithelial sodium channels in endothelial
cells,7,8 where it may cause the cell to swell,9,10
stiffen,11,12 and alter its release of nitric oxide
(NO).13-15 Little is known about how dietary salt
increases blood pressure. Salt consumption increases thirst and fluid uptake. As a consequence,
there is a transient increase in plasma volume
and a subsequent increase in arterial blood pressure before extracellular volume returns to normal.16 Obviously, the organism tries to regain the
original extracellular volume (eg, by decreasing
volume through vascular smooth muscle contraction) at the expense of increased arterial blood
pressure. This view agrees that diuretics decrease
blood pressure. However, this well-known effect
of diuretics cannot be explained exclusively by a
decrease in extracellular volume. Other components of extracellular fluid, for example, electrolyte concentrations, could be important determinants. Recently, plasma sodium concentration
has been suggested to have a direct role in the
control of blood pressure because a small increase in plasma sodium level (1-3 mmol/L) was
found in individuals with hypertension.17,18 This
observation is consistent with the finding that
primary hypertension is virtually absent in populations that consume no 50 mmol/d of sodium
chloride.19

Potassium in Hypertension
In contrast, potassium, the main intracellular
cation, often has been viewed as a minor factor in
the pathogenesis of hypertension. However, there
is abundant evidence to suggest that a potassium
deficit also can have a critical role in the development of hypertension and its cardiovascular sequelae. In numerous studies, increased potassium intake had a beneficial effect on the
cardiovascular system.20-24 Taken together, a
diet low in sodium and rich in potassium is most
favorable.
Role of Sodium and Potassium in
Hypertensive Individuals
Several human studies have shown the interaction between sodium/potassium intake and arterial hypertension. INTERSALT (the International Study of Salt and Blood Pressure), which
included approximately 10,000 participants from
32 countries, showed a median urinary sodium
excretion of 170 mmol/d (9.9 g/d of sodium
chloride). Isolated populations that eat natural
foods have an individual potassium intake 150
mmol/d and sodium intake of only 20-40 mmol/d
(ie, dietary potassium-sodium ratio 3).25 In
contrast, people in industrialized nations eat
mainly processed foods and thereby ingest 30-70
mmol/d of potassium and as much as 100-400
mmol/d of sodium (the usual dietary potassiumsodium ratio is 0.4).19
Population studies similarly have shown an
inverse correlation between potassium intake and
blood pressure, prevalence of hypertension, or
risk of stroke.26-29 After adjusting for potentially
confounding variables, the INTERSALT researchers estimated that a decrease in potassium
excretion by 50 mmol/d was associated with an
increase in systolic pressure of 3.4 mm Hg and
an increase in diastolic pressure of 1.9 mm Hg.
The urinary potassium-sodium ratio in
INTERSALT showed an inverse relationship
with arterial blood pressure. The potassiumsodium ratio showed a stronger statistical relationship to blood pressure than either urinary sodium
or potassium excretion alone.25 Interestingly,
African Americans, in comparison to the white
population, have a higher prevalence of hypertension and lower potassium intake, whereas sodium intake in whites and blacks is similar.27 For

Sodium and Potassium in Hypertension

example, in the Evans County Study, 23% of

whites and 38% of blacks had diastolic blood
pressure 90 mm Hg. The 24-hour urinary
potassium excretion averaged 40 mmol/d for
whites and 24 mmol/d for blacks.30 However, a
word of caution has to be included here because
these data are now 30 years old. In persons of the
same socioeconomic level, this is unlikely to still
be valid. Taken together, restriction in sodium
intake accompanied by increased potassium intake should profoundly improve the prevalence
of blood pressure and cardiovascular disease.
Recent studies have evaluated the role of sodium restriction in hypertensive patients. In an
ethnically heterogeneous population of mildly
hypertensive whites, blacks, and Asians, moderate sodium restriction resulted in a significant
decrease in blood pressure (from 146/91 to 141/88
mm Hg).31 Another study of patients with resistant (treated) hypertension showed the important
effect of salt restriction on office and 24-hour
ambulatory blood pressure. Low-salt (50 mmol/d)
compared with high-salt (250 mmol/d) diets decreased office systolic and diastolic blood pressures by 22.7 and 9.1 mm Hg, respectively.32
Vascular Smooth Muscle Tone: Role of Sodium
and Potassium
Sodium and potassium homeostasis has an
important role in endothelium-dependent vasodilation, which is defective in primary hypertension.33 Sodium retention decreases the synthesis
of NO, one of the main arteriolar vasodilators
produced by endothelial cells, and increases
plasma level of asymmetric dimethyl L-arginine
(ADMA), an endogenous inhibitor of NO production.34 Sodium restriction has the opposite effects. A high-potassium diet and increases in
serum potassium levels even within the physiologic range cause endothelium-dependent vasodilation by hyperpolarizing the endothelial cell
through stimulation of the sodium pump and
activation of plasma membrane potassium channels.35,36 Endothelial hyperpolarization is transmitted to vascular smooth muscle cells, resulting
in decreased cytosolic calcium, which in turn
promotes vasodilation. Experimental potassium
depletion inhibits endothelium-dependent vasodilatation.35

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Role of Aldosterone for the

Vascular Endothelium
Together, aldosterone, sodium, and potassium
have a pivotal role in the pathogenesis of arterial
hypertension and cardiovascular disease through
effects in vascular endothelium. Several clinical
studies show that aldosterone impairs vascular
reactivity.37-40 However, the mechanisms are not
completely understood. Aldosterone increases reactive oxygen species in endothelial cells and
decreases the bioavailability of NO.41 This is
associated with impaired endothelium-mediated
vasodilation42 that can be reversed with aldosterone antagonists.43 Decreased NO bioavailability evoked by aldosterone appears to be attributable to decreased endothelial NO synthase
(eNOS) activity. This may be the result of decreased levels of tetrahydrobiopterine because
normal levels depend on adequate NADPH (reduced nicotinamide adenine dinucleotide phosphate) concentrations.41
A recent study shows that aldosterone decreases glucose-6-phosphate dehydrogenase activity.41 This results in diminished NADPH and
thus increases oxidative stress, with the consequences of decreased eNOS activity and increased reactive oxygen species. Moreover, it
has been shown in this study that aldosterone
antagonists restore glucose-6-phosphate dehydrogenase activity and thereby improve vascular
reactivity in vivo. Aldosterone effects could be
mimicked by experimental deficiency of glucose6-phosphate dehydrogenase.
Aldosterone treatment adversely affects adhesion molecules. Increased deposition of ICAM-1
(intercellular adhesion molecule 1) has been
shown in the vascular wall of aldosteroneinfused rats.44 Spironolactone and endothelin
antagonist treatments decrease ICAM-1 content
and reverse NADPH depletion in the vascular
wall. Aldosterone directly induces endothelin
expression in vivo.45
Importantly, aldosterone effects on endothelial
function, oxidative stress, adhesion molecules,
and endothelium-derived contracting factors are
associated with vascular fibrosis and profound
vascular stiffening.39 Large-artery stiffness is
related to aldosterone concentrations in hypertensive patients.37 Aldosterone causes cardiac fibrosis, as shown in patients with heart failure.46

1114

Moreover, increased aldosterone levels induce

renal vascular and tubulointerstitial fibrosis in
several patient populations, such as patients with
diabetes and those with heart failure or kidney
disease.42
A recent study by Lacolley et al39 shows that
aldosterone and salt administration in rats is able
to increase the large-artery stiffness associated
with fibronectin accumulation independent of
vessel wall stress. These arterial modifications
represent an early step in the development of
hypertension and cardiac fibrosis. All these
changes were reversed when rats were treated
with the mineralocorticoid receptor blocker
eplerenone. These results suggest a direct role
for mineralocorticoid receptors in mechanical
and structural alterations of large blood vessels.
Interaction Between Endothelial Cell Structure
and Function
There is recent evidence that endothelial cell
structure determines endothelial cell function.
The micromechanical structure of the endothelial cell membrane is characterized by a polygonal mesh of mostly actin and vimentin fibers.47
This complex structure is in a state of constant
remodeling.48 Mechanical stimuli that act on the
endothelial cell determine endothelial cell remodeling.49 It is intriguing that endothelial cell shape
and NO have profound influences on the cytoskeleton. In a recent study, shape-engineered endothelial cells were characterized.50 Spindle-shaped
cells show decreased NO production and increased stiffness that are related to dense actin
stress fibers. In contrast, large circular endothelial cells show increased NO production, are soft,
and lack dense actin stress fibers. It is conceivable that NO bioavailability determines endothelial cell cytoskeleton and elastic properties because NO may depolymerize actin.51 However,
increased endothelial cell elasticity may be associated with translocation of eNOS to the cell
membrane and hence increased eNOS activity.52
There is further evidence that endothelial cell
elastic properties and NO production are related
to each other. Peng et al53 studied NO production
in endothelial cells that were grown in tubes and
subjected to pulsatile flow.53 When the elastic
response of endothelial cells to pulsatile flow
was restricted by using a rigid tube, eNOS production was markedly decreased and associated

Bssemaker et al

with increased endothelial cell vulnerability to

UV radiation. This indicates that the elastic properties of endothelial cells are closely related to
NO production, and endothelial morphologic
properties determine endothelial cell elasticity.
Thus, endothelial cell stiffness appears as a
marker of endothelial cell function. These important parameters, endothelial cell morphologic
characteristics and mechanics, can be assessed in
living endothelial cells only by using atomic
force microscopy.
Link Between Endothelial Cell Stiffness and
Overall Arterial Stiffness
The terms endothelial stiffness and endothelial elasticity, although functionally related,
should not be seen as analogous terms for arterial stiffness and arterial elasticity. Softening
of endothelial cells would not directly decrease
arterial stiffness. The latter primarily depends on
the composition of the extracellular matrix, including the content of collagen, fibronectin, and
other static components. In addition, a dynamic
component, that is, the state of contraction of
vascular smooth muscle cells, is involved. However, increased NO release by high extracellular
potassium/low sodium functionally links endothelial cell stiffness, at least in part, to arterial
stiffness. Similarly, as reported for endothelial
cells, a gradual increase in extracellular potassium has hyperpolarized and relaxed vascular
smooth muscle cells by stimulating the adenosine triphosphatase sodium-potassium pump
(Na-K-ATPase) and/or activating inwardly
rectifying potassium channels.54-58
Plasma Sodium and Endothelial Cell Function
As outlined previously, there is a large body of
evidence that an increase in extracellular sodium
increases blood pressure and causes endothelial
dysfunction. We therefore tested at the cellular
level the proposal that endothelial stiffness and
deformability are influenced by small changes in
plasma sodium concentration. Atomic force microscopy, a nanotechnique that can be used to
measure the stiffness of living endothelial cells,
was used for these studies59 (Fig 1).
In the presence of a mineralocorticoid receptor
blocker (eg, eplerenone) and/or in the absence of
aldosterone, cell stiffness was unaffected by alterations in extracellular sodium. However, in the

Sodium and Potassium in Hypertension

1115

Figure 1. Measuring endothelial cell stiffness using the atomic force microscopy (AFM)-based indentation technique. (A)
Assay set up. A nanoscale probe on the end of a cantilever is brought into contact with a cultured endothelial cell maintained
on a heated stage. Deflection of the probe is measured using photodiode capture of a laser light reflected from a spot on top
of the cantilever. Piezoelectric material under the sample holder allows precise control of movement. In the stiffness assay,
the probe tip is pressed against the cell to indent the membrane; this bends the cantilever, for which movement is quantified
by the laser beam. The result is a force-distance curve of a single cell, in which the slope is directly related to the force
(expressed in newtons and defined here as stiffness) necessary to indent the cell. (B) Indentation curve with 2 different
slopes. No force is registered when the AFM probe tip is not yet in contact with the cell (right portion of graph). After
engagement of the cell surface with the particle tip (middle image) the cantilever will be bent as the cell is indented. From the
2 linear portions of the indentation curve, cell stiffness can be calculated during the first few hundred nanometers of
indentation (cortical cell stiffness) or 800 nm of indentation (cell center). Adapted from Oberleithner et al61 with permission
of the National Academy of Sciences.

presence of aldosterone (ie, under physiologic

conditions), cells stiffen as extracellular sodium concentrations increase to 140 mmol/L
(Fig 2). This finding suggests that plasma
sodium concentration determines endothelial cell
elasticity, an important parameter in the control
of blood pressure. Of note, generation of NO in
cultured endothelial cells under shear stress
conditions is decreased when sodium concentration in the medium is increased from 135 to 150
mmol/L (in the presence of aldosterone). These
results have been confirmed by a recent work by
Li et al.60 They showed that an increase in salt
concentration within the range observed in hypertensive patients or individuals with high salt
intake significantly suppresses eNOS activity.
These investigators conclude that this salt-

induced decrease in NO generation in endothelial cells may contribute to the pathogenesis of

hypertension.
Plasma Potassium and Endothelial Cell Function
However, experimental data for cells, arteries,
animals, and humans suggest that increased potassium intake decreases blood pressure and improves vascular function with respect to generation of the endothelium-derived vasodilators NO
and endothelium-derived hyperpolarizing factor(s). Consequently, it was tested whether potassium could affect endothelial cells and change
endothelium-derived NO production. In cultured
endothelial cells of bovine aorta, an acute increase in potassium in the physiologic range

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Bssemaker et al

Figure 2. Endothelial cell stiffness depends on the

extracellular sodium concentration. Dotted lines represent
the estimated slopes of the relation stiffness change over
sodium change (based on data from Oberleithner et al59).

actin.61 Solation describes a rapid decrease in

local viscosity beneath the plasma membrane
such that an increase in potassium softens the
cortical actin cytoskeleton by changing F-actin
to G-actin. G-Actin colocalizes with NOS and
increases eNOS activity. Such a mechanism
would control endothelial deformability and NO
release and thus influence systemic blood pressure.
Taken together, these studies at the cellular
level indicate that sodium exerts deleterious effects on the endothelium, whereas potassium
improves endothelial function. Of note, the adverse effect exerted by high extracellular sodium
depends on aldosterone. Furthermore, these studies of the cellular level agree with clinical results
of INTERSALT; namely, that an increase in
potassium-sodium ratio is beneficial.

swells and softens endothelial cells and increases

NO release. Another observation of this study
should be emphasized: high extracellular sodium
concentration (in the presence of aldosterone)
prevents these changes (Fig 3).
The potassium effects most likely were elicited by so-called solation of the submembranous

Role of Sodium and Potassium in Large-Artery

Stiffness and Systemic Vascular
Resistance in Humans
Relationships between sodium and potassium
intake and blood pressure in humans have been
focused mainly on a systolic blood pressure,
diastolic blood pressure, or hypertension end

Figure 3. Relationship between extracellular potassium concentration and cell stiffness. Acute experiments (ie, potassium concentration step changes within minutes) were performed at low (130 mmol/L) and high sodium (150 mmol/L)
concentrations in extracellular fluid. Osmolality was kept constant in both conditions. Adapted from Oberleithner et al61 with
permission of the National Academy of Sciences.

Sodium and Potassium in Hypertension

point. However, 2 other parameters, pulse pressure and mean arterial pressure, add valuable
information in terms of vascular conditions and
cardiovascular risk. Pulse pressure characterizes
the pulsatile component of blood pressure, with
its increase mostly reflecting decreased vascular
compliance and stiffening of large central arteries. Mean arterial pressure characterizes a steady
component of blood pressure, its increase relating to increased resistance of small peripheral
arteries and the microvascular network.62 Buyck
et al63 showed that increased dietary sodium or
potassium intake is associated significantly with
changes in blood pressure parameters. Interestingly, high sodium intake was associated positively with pulse pressure, whereas high potassium intake was associated negatively with
systolic, diastolic, and mean blood pressure. The
positive association between dietary sodium intake and pulse pressure observed in this study
provides further evidence for the current concept
linking sodium to an increase in blood pressure
through modification and stiffening of the arterial wall, whereas a negative correlation between
dietary potassium intake and both systolic and
diastolic blood pressure support the view that
potassium is a vasodilating electrolyte in our
nutrients.

RECENT ADVANCES
As stated, high sodium intake is related to the
development and maintenance of arterial hypertension. This has been shown in different animal
models and humans. However, the sensitivity of
blood pressure to salt in individuals is variable,
and mechanisms for salt-sensitive hypertension
are speculative. Recent work by Machnik et al64
presents additional information about the salt
volumeblood pressure relationship. Given the
current principle that extracellular body fluids
are in equilibrium, excess interstitial sodium is
readily mobilized into the bloodstream for final
urinary excretion. However, human sodium balance studies and experimental data suggest that
sodium accumulation in the body is not necessarily paralleled by commensurate water retention
to maintain iso-osmolality of body fluids.5,65-68
They hypothesized a 3-compartment model in
which hypertonicity within a restricted compartment might occur. In a high-salt rat model, sodium accumulation that occurs in excess of water

1117

results in local interstitial hypertonicity. This

provokes a tissue-specific regulatory cascade. In
this cascade, vascular endothelial growth factor
C acts as an osmoprotective protein mediating a
direct regulatory response of mononuclear phagocyte system cells to maintain constant interstitial
volume. This extrarenal response restructures the
preexisting lymph capillary network and increases eNOS expression. Blockade of this response leads to excess interstitial hypertonic fluid
and decreased eNOS expression. Because both
excess sodium retention and decreased eNOS
expression could increase blood pressure,59,69
the investigators concluded that mononuclear
phagocyte systemderived secretion of vascular
endothelial growth factor C in states of sodiuminduced interstitial hypertonicity buffers blood
pressure.
This mechanism suggests that the interstitium
is a buffering compartment for sodium, protecting the body from an increase in extracellular
volume and blood flow. The latter subsequently
would increase systemic vascular resistance as
an autoregulatory mechanism, finally causing
hypertension. The described mechanism could
help understand salt-sensitive hypertension.
A diurnal rhythm of urinary sodium, potassium, and chloride excretion is well established.70-72 Alteration of this circadian pattern is
associated with pathophysiologic conditions, including hypertension and cardiovascular disease.73,74 Very recent work has shed some light
on the underlying molecular mechanisms for the
circadian fluctuation in electrolyte excretion, suggesting a new pathway for the regulation of
epithelial sodium channel (encoded by the
SCNN1A gene in humans) by the circadian clock.
The investigators show in mice that the circadian
clock protein Period 1 (equivalent to the PER1
gene in humans) is regulated by aldosterone and
in turn mediates aldosterone action on the expression of epithelial sodium channel messenger
RNA. Importantly, the effect of Period 1 gene
knockdown on epithelial sodium channel expression occurred even in the absence of aldosterone stimulation and also was observed in Period
1deficient mice. These data implicate an important role of the circadian clock in the control of
sodium balance.75

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Bssemaker et al

SUMMARY
It is beyond doubt that high sodium intake is
strongly related to the prevalence of high blood
pressure, whereas the opposite is observed in
humans with high potassium intake. Data support the view that an increase in potassiumsodium ratio would decrease blood pressure in
the general population and decrease cardiovascular mortality significantly. Efforts to control sodium and potassium intake using educational
programs and nutritional guidelines for healthy
populations and those at high risk of cardiovascular disease (hypertensive persons and individuals
with diabetes) presently are underway in most
industrialized countries.
The role of aldosterone in kidney is well
established. Here, we focus on the impact of
aldosterone and NO on the vascular endothelium, both crucial in the control of systemic
blood pressure. We addressed recent work suggesting that the interstitium could serve to a
certain extent as a buffer system for sodium,
preventing the development of hypertension on a
high-salt diet.
Based on clinical, cellular, and molecular evidence, it is recommended to maintain plasma
sodium levels in the low and potassium levels in
the high physiologic range, whereas plasma aldosterone levels should be kept as low as possible.
Restriction in sodium intake accompanied by
increased potassium intake should profoundly
improve the prevalence of hypertension and cardiovascular disease.
ACKNOWLEDGEMENTS
We thank our colleagues in London, UK, Professors Hugh
E. deWardener and Graham A. MacGregor, for many fruitful
discussions on salt and hypertension.
Support: This work was supported by grants from the
Deutsche Forschungsgemeinschaft (OB 63/17-1 and Koselleck grant OB 63/18).
Financial Disclosure: The authors declare that they have
no relevant financial interests.

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