Kidney International, Vol. 66 (2004), pp.
24542466
Plasma sodium and hypertension
HUGH E. DE WARDENER, FENG J. HE, and GRAHAM A. MACGREGOR
Department of Clinical Chemistry, Imperial College, Charing Cross Hospital Campus, London, United Kingdom; and Blood
Pressure Unit, St. Georges Hospital Medical School, London, United Kingdom
Plasma sodium and hypertension. Dietary salt is the major cause
of the rise in the blood pressure with age and the development of
high blood pressure in populations. However, the mechanisms
whereby salt intake raises the blood pressure are not clear. Ex-
isting concepts focus on the tendency for an increase in extracel-
lular fluid volume (ECV), but an increased salt intake also in-
duces a small rise in plasma sodium, which increases a transfer of
fluid from the intracellular to the extracellular space, and stimu-
lates the thirst center. Accordingly, the rise in plasma sodium is
responsible for the tendency for an increase in ECV. Although
the change in ECV may have a pressor effect, the associated
rise in plasma sodium itself may also cause the blood pressure
to rise. There is some evidence in patients with essential hy-
pertension and the spontaneously hypertensive rat (SHR) that
plasma sodium may be raised by 1 to 3 mmol/L. An experimen-
tal rise in sodium concentration greater than 5 mmol/L induces
pressor effects on the brain and on the renin-angiotensin sys-
tem. Such a rise can also induce changes in cultured vascular
tissue similar to those that occur in the vessels of humans and
animals on a high sodium diet, independent of the blood pres-
sure. We suggest that a small increase in plasma sodium may
be part of the mechanisms whereby dietary salt increases the
blood pressure.
High blood pressure is now recognized as the major
cause of cardiovascular disease worldwide. In England,
high blood pressure, which is both a certified cause of
death and a contributory factor in over 170,000 deaths, is
the most common cause of death [1]. In 1998, the preva-
lence of hypertension (a blood pressure greater than
140/90 mm Hg) was 41% in males and 33% in females,
rising in males from 16% at 16 to 24 years of age to 74%
at 75 years, and in females from 4% to 78% [2]. The rise in
arterial pressure is related to dietary salt [3, 4], and dietary
salt also increases the mass of the left ventricular wall [5],
stiffens conduit arteries [6], and thickens and narrows re-
sistance arteries [7] independent of the blood pressure.
The rise in arterial pressure and other harmful cardio-
Key words: plasma sodium, hypertension.
Received for publication November 27, 2003
and in revised form March 7, 2004, and May 28, 2004
Accepted for publication June 23, 2004


C 2004 by the International Society of Nephrology
2454
COMMENTARY
vascular effects of dietary salt are related to the primary
inadequacy of the kidney to excrete sodium [8, 9]. The
impairment of the kidneys ability to excrete sodium is
either genetic, as in essential hypertension and the spon-
taneously hypertensive rat (SHR) [10], or it can be super-
imposed as in obesity [11], primary hyperaldosteronism,
or renal disease. The primacy of the kidneys control of
sodium excretion in the regulation of the blood pressure
has been confirmed by the finding that of 20 genes so
far identified to be associated with essential hyperten-
sion or responsible for rare Mandelian forms of high and
low blood pressure, all are involved in the regulation of
sodium handling by the kidney [12].
Evidence for the role of dietary salt in the rise in arterial
pressure in essential hypertension, the SHR, and in the
other cardiovascular effects that dietary salt induces inde-
pendent of the blood pressure, come from epidemiologic
studies [1315] within and between populations, exper-
imental models, particularly in primates [16, 17], phys-
iologic and biochemical studies [10], controlled clinical
trials [1820] in normotensive and hypertensive individ-
uals, and familial [21, 22], genetic [23, 24], and mortality
studies [25]. In spite of this accumulation of information,
the connecting and causative links between dietary salt
and the rise in arterial pressure in essential hypertension
and the SHR, and the other harmful effects it causes inde-
pendent of the blood pressure, are uncertain. This paper
reviews the evidence that small changes in plasma sodium
may play a role.
POSSIBLE INITIATING FACTORS RESPONSIBLE
FOR THE PRESSOR EFFECT OF DIETARY
SODIUM
In the study of essential hypertension and the SHR, the
relevant input of sodium chloride is that which is habitu-
ally consumed, which, in humans in developed countries,
is subject to large day-to-day variations. Sodium balance
is controlled almost entirely by the kidneys ability to vary
the urinary excretion of sodium. The immediate effects
of dietary sodium are to alter plasma sodium and, con-
sequently, the extracellular fluid volume (ECV). These
 de Wardener et al: Plasma sodium and hypertension
Table 1. Changes in plasma sodium with alterations in salt intake
Participant
Sagnella et al [29] 6 normotensives
Sullivan et al [30] 27 normotensives
19 hypertensives
6 normotensives
Roos et al [31] 8 normotensives
Heer et al [32] 32 normotensives
Johnson et al [33] 15 isolated systolic hypertensives
8 diastolic systolic hypertensives
17 normotensives
Kawano et al [34] 7 hypertensives (nonsalt-sensitive)
8 hypertensives (salt-sensitive)
Luft et al [35] 14 normotensives
changes must therefore be primarily responsible for the
subsequent alterations that affect the blood pressure.
The mechanisms that link the input of sodium chloride
to the blood pressure have been studied mainly follow-
ing acute changes. Their relevance to the search for the
mechanisms responsible for the rise in blood pressure
that develops in humans over many decades is question-
able. There have been relatively few studies of the effect
of prolonged changes in salt intake, particularly the ef-
fect of a prolonged increase. An acute increase in sodium
input can induce a rise in blood pressure by either rais-
ing plasma sodium even when the ECV is falling [26, 27],
or by increasing the ECV even when the plasma sodium
is falling [28]. This would indicate that acute changes in
both plasma sodium and ECV are each potentially capa-
ble of independently controlling the blood pressure. The
sections which follow describe the evidence in support of
a hypothesis which proposes that prolonged increases in
salt intake, or when the habitual intake of salt is high, par-
ticularly when there is a diminished ability of the kidney
to excrete sodium, as in essential hypertension and the
SHR, the associated rise in arterial pressure is initiated
and sustained in part by a persistent increase in plasma
sodium.
SODIUM INTAKE, PLASMA AND CEREBRAL
SPINAL FLUID (CSF) SODIUM, AND BLOOD
PRESSURE
Acute changes in dietary salt intake on plasma sodium
In both normotensive and hypertensive humans, a large
and sudden increase in dietary sodium usually causes a
2 to 4 mmol/L rise in plasma sodium [2935] (Table 1).
In a study of gradually increasing salt intake from 10 to
250 mmol/day by a daily amount of 50 mmol, there was
an increase in plasma sodium of approximately 3 mmol/L
[29]. There were also significant correlations between the
increase in plasma sodium and the reduction in plasma
renin activity and aldosterone, and the rise in atrial na-
triuretic peptide (ANP) [abstract; He FJ et al, Am J
Hypertens 17:181A182A, 2004]. In studies of salt re-
2455
Change in salt intake Duration Change in plasma sodium
10 to 250 mmol/day 5 days 138.5 to 141.5 mmol/L (P < 0.05)
10 to 200 mmol/day 4 days 137.8 to 140.5 mmol/L (P < 0.01)
10 to 200 mmol/day 4 days 139.3 to 141.0 mmol/L (P < 0.01)
10 to 400 mmol/day 4 days 138.7 to 142.5 mmol/L (P < 0.01)
20 to 200 mmol/day 5 days 143 to 145 mmol/L (P = NS)
50 to 550 mmol/day 7 days 143.4 to 144.0 mmol/L (P = NS)
50 to 300 mmol/day 14 days 141.9 to 144.9 mmol/L (P < 0.01)
50 to 300 mmol/day 14 days 142.1 to 144.7 mmol/L (P < 0.01)
50 to 300 mmol/day 14 days 140.3 to 141.9 mmol/L (P < 0.01)
20 to 300 mmol/day 7 days 139.4 to 142.1 mmol/L (P < 0.05)
20 to 300 mmol/day 7 days 139.9 to 141.8 mmol/L (P < 0.05)
10 to 300 mmol/day 3 days 137 to 138 mmol/L (P = NS)
duction in humans, there are consistent falls in plasma
sodium. For instance, in two acute studies of salt reduc-
tion from 350 mmol/day to 10 mmol/day for 5 days, a
highly significant reduction in plasma sodium of approx-
imately 3 mmol/L was found in both black and white hy-
pertensives, and white normotensives [36, 37]. The fall
in plasma sodium was closely related to the increase in
plasma renin activity. In double-blind studies using Slow
Sodium (Ciba) and placebo, a more modest reduction in
salt intake from 175 to 95 mmol (10 to 5 g/day), there was
a small but significant fall in plasma sodium [abstract; He
FJ et al, Am J Hypertens 17:181A182A, 2004].
In normal dogs (weight 15 kg), plasma sodium af-
ter 24 hours on a high sodium diet (82.0 mmol/day)
was 145.7 1 mmol/L, and on a low sodium
diet (7.5 mmol/day) was significantly lower, 142.8
0.4 mmol/L [38]. In the Dahl SS rat, a high sodium
diet for 4 days significantly raised plasma sodium from
142.2 mmol/L to 145.2 mmol/L [39]. In the normal rat
there is a report [40] that, when measured during the
night, plasma sodium rose from 137 to 142 mmol/L on
the first night of an increase in salt intake, and remained
raised thereafter for one week. Others [41], however,
have found that an acute increase in salt intake for
7 days in the Dahl salt-sensitive and resistant rat, and
the Sprague-Dawley rat did not raise plasma sodium of
blood obtained during the day.
Acute increases in dietary salt intake on CSF sodium
In 15 patients with essential hypertension, CSF sodium
concentration was 147.7 0.4 while on a high salt diet
(1618 g/day) for 7 days, and on a low salt intake (1
3 g/day), it was 145 0.5 (P < 0.001) [34]. In another
group of 24 hypertensives [42] who were given 7 g, 3 g, and
25 g of dietary salt for 7 days on each intake, in that order,
the CSF sodium changes were related to the patients
salt sensitivity; on 25 g of salt, the CSF sodium of the
13 salt-sensitive patients was 149.3 mmol/L, and in the
salt-resistant group it was 143.5 mmol/L. On the 7 g of
salt per day diet the CSF sodium concentrations were
not different.
2456 de Wardener et al: Plasma sodium and hypertension
There is one report that a high sodium diet had no
effect on CSF sodium in the Dahl salt-resistant rat and
the Sprague-Dawley rat, but that a rise in CSF sodium
occurred in the Dahl salt-sensitive rat [41]. Similarly, a
high sodium diet raised CSF sodium in the SHR and the
Dahl salt-sensitive rat, but had no effect on the Dahl salt-
resistant and Wistar Kyoto (WKY) rat [43]. Others who
obtained CSF from SHR and WKY rats on a high sodium
diet at 3- to 4-day intervals only obtained a rise in CSF
sodium on the third day in both the SHR and the WKY
rats [44].
The effect of acute changes in dietary sodium intake
on plasma sodium and blood pressure
In humans, the effect of an abrupt increase in sodium
intake for 5 to 28 days on the blood pressure is re-
lated to age. In the young (below 26 years), blood pres-
sure does not rise, although there may be an increase
in plasma sodium, ECV, blood volume, and exchange-
able sodium [29, 31, 32, 45, 46]. In two of these studies
plasma sodium did not rise [32, 45]. In contrast, in indi-
viduals over 60 years of age, most of whom had a raised
blood pressure, an acute increase in sodium intake was
associated with a rise in both plasma sodium (+1.6 to
3 mmol/L) and blood pressure [33, 34]. In the earlier men-
tioned study of normotensives in whom salt intake was
gradually increased from 10 mmol/day by 50 mmol/day
increments, there was an increase in plasma sodium, and
a highly significant relationship between the increase in
plasma sodium and an increase in pulse pressure. In the
studies on the effect of an acute and large reduction of
salt intake in black and white hypertensive individuals,
there was a significant fall in blood pressure with salt re-
duction associated with a significant fall in plasma sodium
[36, 37], but there was no significant relationship between
the change in blood pressure and the change in plasma
sodium [abstract; He FJ et al, Am J Hypertens 17:181A
182A, 2004]. In double-blind studies of more modest salt
restriction, however, there were significant falls in blood
pressure, and a small but significant reduction in plasma
sodium [abstract; He FJ et al, Am J Hypertens 17:181A
182A, 2004]. This change in plasma sodium was weakly,
but significantly, correlated with the change in blood pres-
sure (r = 0.18, P = 0.047).
In the Sprague-Dawley and Dahl salt-resistant rat,
an acute increase in salt intake did not change plasma
sodium or blood pressure, but in the Dahl salt-sensitive
rat, in which the increase in salt intake was associated
with a rise in plasma and CSF sodium, there was a rise in
blood pressure [41]. Qi et al [39] measured the changes in
blood pressure that occurred in inbred Dahl salt-sensitive
rat (SS/JR) and salt-resistant rats (SR/JR) when the oral
intake of salt was increased for 4 days, while body weight
was maintained constant by a servo-control system. In the
SS/JR rat, a change in the salt content of the food from
0.2% to 4% when there was no increase in body weight
increased plasma sodium by 3.0 mmol/L, and blood pres-
sure by 32.2 mm Hg. In another identical experiment in
the SS/JR rat, except that body weight was not controlled
and, therefore, body weight increased, there was a rise in
plasma sodium of 1.5 mmol/L, and of blood pressure by
15 mm Hg. In contrast, in the inbred Dahl salt-resistant
rat SR/JR, when body weight was controlled and the 4%
salt diet was given, plasma sodium did not rise, and there
was no change in blood pressure.
The effect of acute changes in salt input by intravenous
or peritoneal dialysis on plasma sodium, ECV,
and blood pressure
An increase in ECV associated with intravenous infu-
sions of saline in animals can raise blood pressure, even
if there is a fall in plasma sodium of 20 mmol/L [28, 47,
48]. The rise in pressure is associated with a rise in cardiac
output [47, 48]. The predominance of ECV over plasma
sodium in controlling the blood pressure following acute
intravenous changes of sodium input was confirmed by
Greene et al [49]. They used outbred Brookhaven Na-
tional Laboratory, Upton, New York, Dahl S and Dahl R
rats, the body weight of which was servo-controlled to be
constant during the intravenous administration of either
1 mEq or 20 mEq of sodium per day for 4 days. When body
weight was controlled, the intravenous administration of
a high salt load did not cause the arterial pressure of the
Dahl S or Dahl R rats to increase, although there was a
rise in plasma sodium from 143.5 to 152.4 mmol/L. But if
the high salt load was administered when the body weight
was not controlled, there was an increase in body weight,
plasma volume, and cardiac output, and a 2 mmol/L rise
in plasma sodium in both the Dahl S and R, but only the
Dahl S rat had a rise in arterial pressure. The unchang-
ing arterial pressure of the Dahl R rat was associated
with a fall in total peripheral resistance. The differences
between these results and those of Qi et al [39], who in-
creased salt intake orally, are discussed later.
Friedman et al [27] used intraperitoneal dialysis of
saline solutions for 5 hours in the rat. Plasma sodium
changes varied from 15 mmol/L, depending on the con-
centration of the dialysate. The systolic blood pressure
rose or fell in direct relation to the plasma sodium. As-
sociated changes in ECV could not explain the changes
in blood pressure because they changed in the opposite
direction to blood pressure.
Habitual salt intake, plasma sodium, and blood
pressure in humans
In humans, there do not seem to be any direct measure-
ments of plasma sodium in relation to the habitual intake
 de Wardener et al: Plasma sodium and hypertension
of sodium chloride, but there are some indirect observa-
tions which suggest that plasma sodium is directly related
to the habitual intake. The first account [50] described
three studies: the first study was in 634 patients with es-
sential hypertension in whom there was a highly signifi-
cant positive correlation between 24-hour urine volume
and urinary sodium excretion (P < 0.001). The second
was in 1731 hypertensive patients and 8343 nonhyper-
tensive persons from 52 countries worldwide in the In-
tersalt Survey [51]. In within-sample analysis, 24-hour
urine volume was significantly related to 24-hour urinary
sodium excretion. Furthermore, this relationship was
similar between the hypertensive patients and normoten-
sive subjects; a reduction of 100 mmol/day in 24-hour
urine sodium predicted a reduction in 24-hour urine vol-
ume of 379 and 399 mL, respectively. The conclusion that
changes in urinary sodium excretion can control urine
volume was strengthened by the third study [50], in which
the sodium intake of 104 hypertensive patients was re-
duced from 350 mmol/day to 10 to 20 mmol/day. The re-
gression line of relationship between the difference in
urine volume and the decrease in urinary sodium excre-
tion in this group, when superimposed on the results from
the 2 previous studies, was similar.
As in normal circumstances, urinary sodium excre-
tion is equivalent to sodium intake, and urine volume
closely reflects fluid intake, these results show that di-
etary sodium intake controls fluid intake. But fluid intake
is regulated by the activity of the thirst center, which is
controlled by plasma osmolality and the blood volume.
Thirst is stimulated by a rise in plasma osmolality, and de-
pressed by an increase in blood volume [52]. Therefore,
the control of fluid intake by the habitual dietary intake
of sodium chloride appears to be due to the effect of the
salt intake on thirst due to its effect on plasma sodium
[53]. But hypertension is also related to a raised habitual
intake of salt. Accordingly, hypertension should be asso-
ciated with a rise in plasma sodium at least sufficient to
stimulate the thirst center. The threshold of thirst in a nor-
mal rat being infused with 1 mol/L NaCl is a rise in plasma
osmolality of 1.6 0.11% mmol/kg [54], equivalent to a
change of less than 1% in plasma sodium, which sug-
gests that even large changes in sodium intake are likely
to induce only minimal, and presumably, predominantly
transient, changes in plasma sodium. It is also relevant
that constant osmotic stimulation does not change the
sensitivity of the thirst center [55, 56].
There are few measurements on the relation of plasma
sodium to blood pressure in essential hypertension. There
are only 2 studies in which the sodium concentration
in the blood has been measured in a large number of
hypertensives and controls [57, 58]. Serum sodium was
measured in 3222 normotensive normal subjects and 741
hypertensive patients in Japan [57]. Serum sodium con-
centration differed between the 2 groups. The serum
2457
sodium concentration distribution curve in the pa-
tients with essential hypertension was shifted by about
2 mmol/L toward the higher values. The prevalence of
a serum sodium concentration greater than 147 mmol
in 24% to 27% of hypertensives, regardless of age, was
significantly greater than in the 4.6% of normotensive in-
dividuals in whom the sodium concentration increased
with age. The difference in serum sodium concentration
between the normotensive and hypertensive individuals
was not related to a difference in blood urea and plasma
creatinine. Some of this difference in serum sodium may
be explained if some of the individuals with hyperten-
sion had mild primary aldosteronism, but it is unlikely to
explain all of the difference.
Wannamethee et al [58] found a strong positive associ-
ation between serum sodium and systolic blood pressure
in 2297 hypertensives, and no relationship in 5393 nor-
motensive subjects. In the hypertensive group there was
also a slight, though not significant, tendency for the di-
astolic pressure to rise with increasing serum sodium. In
the normotensives, there was a weak but significant in-
verse association between serum sodium concentration
and diastolic pressure, but not in systolic blood pressure.
There is one study by Fang et al [59] on plasma sodium
of 9-week-old SHR and WKY on their normal basal
diet, which contained 0.6 mol/L NaCl. Plasma sodium
was measured at 1- to 2-hour intervals, and was about 1 to
3 mmol/kg greater in the SHR than in the WKY through-
out the 24 hours. There was a profound diurnal rhythm,
the pattern of which was similar in both strains. Plasma
sodium concentration was highest during daylight, when
the rats were asleep and blood pressure was at its lowest.
The pressor effect of plasma sodium on the brain,
the blood vessels, and tissue angiotensin II activity
A rise in plasma sodium may effect blood pressure by a
direct effect on the brain and the blood vessels, and it may
also enhance the activity of the renin-angiotensin system.
Brain
Sodium concentration in the brain and blood pressure.
Tobian and Ganguli found that the Na+ and K+ concen-
trations in the tissues surrounding the third ventricle of
Sprague-Dawley rats on 8% NaCl were greater than in
rats on a moderately low NaCl diet [60]. These observa-
tions suggest that a rise in plasma sodium may have an
exaggerated effect on the sodium concentration of those
areas surrounding the third ventricle, which control the
blood pressure [61]. In the Dahl S and R rats placed on a
high sodium diet, the rise in blood pressure in the Dahl S
rat is associated with a substantially greater accumulation
of 22 Na+ in the CSF and brain of the Dahl S rat [62].
Wang and Leenen [63] found that the cascade of
changes that take place in the hypothalamus of the Dahl
2458 de Wardener et al: Plasma sodium and hypertension
salt-sensitive rat on a high sodium diet, which leads to
a rise in arterial pressure, can be prevented by the in-
tracerebroventricular infusion of benzamil, which blocks
certain sodium channels. This confirms earlier observa-
tions that the third ventricle periventricular tissues, which
control the blood pressure, are particularly susceptible to
changes in plasma sodium, and that such changes have a
profound effect on the blood pressure [64]. In the adult
hypertensive SHR, however, brain% water content and
extracellular fluid 14 C sucrose volume of distribution are
not significantly different from the levels in the WKY rat
[65].
Increasing the concentration of CSF sodium by the
administration of hypertonic saline centrally raises the
blood pressure [6668]. Initial studies on the conscious
goat showed that infusions of solutions varying from 0.25
to 0.33 mol/L NaCl at 10 lL/min into the third ventricle
increased the blood pressure by 15 to 30 mm Hg within
60 minutes. Subsequently, in 5 studies in normal conscious
rats, the CSF NaCl concentration has been raised by the
continuous infusion of hypertonic NaCl, using 0.15 to
1.5 mol/L solution, into the third or lateral ventricle for
7 to 14 days at a pumping rate of 1 to 5 lL/hr [6973].
In one experiment in Sprague-Dawley rats with an infu-
sion of 0.8 mol/L NaCl [72], the systolic pressure did not
rise significantly until the ninth day. In another experi-
ment [73] in the same strain of rats on varying intakes
of salt, a lateral ventricle infusion with the same con-
centration of NaCl, in rats on a normal intake of salt,
increased the blood pressure on the 10th day, but if, in
addition, the intake of NaCl was also raised, the rise in
blood pressure occurred on the sixth day. In 3 other exper-
iments in which hypertonic saline was infused centrally,
the sodium concentration of the CSF obtained from the
cisterna magna was measured at the end of the exper-
iment [6972]. Kawano et al [70] infused 0.15 and 1.5
mol/L NaCl solutions at a rate of 5.5 lL/hr into the third
ventricle for 7 days; the CSF sodium concentrations on
the seventh day were 148.1 0.55 and 153.2 0.7 mmol/L,
respectively. During the infusion of the 0.15 mol/L NaCl
solution there was a progressive, though insignificant in-
crease in systolic pressure, which plateaued on the fifth
day. With the 1.5 mol/L NaCl solution there was a brisk
and significant rise in blood pressure on the first day.
Huang et al [69] infused either artificial CSF, 0.8 mol/L or
1.5 mol/L NaCl solution into the lateral ventricle at a rate
of 5.0 lL/hr for 14 days; the CSF sodium concentrations
at 14 days were 146 2, 152 2, and 160 3 mmol/L,
respectively. On the 14th day, there was a rise in blood
pressure with both the 0.8 and 1.5 mol/L Nacl solutions.
In a study by Katahira et al [71], though 0.15 mol/L, 0.8
mol/L, and 1.5 mol/L NaCl solutions were infused into
the lateral ventricle at a rate of 1 lL/hr for 12 days, the
CSF sodium concentrations on the 12th day were 153.4
9, 152.5 0.7, 153 0.4 mmol, respectively. Although
the CSF sodium did not appear to change, a sustained
rise in blood pressure occurred on the eighth day in the
rats receiving the 1.5 mol/L NaCl solution. Overall, these
experiments demonstrate that a rise in CSF sodium con-
centration raises blood pressure and suggest that the rate
of rise in pressure is directly related to the extent of the
increase in CSF sodium.
There is little information on the effect of increasing
dietary salt intake on CSF sodium and blood pressure
[41, 44, 74]. In one study [41] in the Dahl salt-sensitive
rat in which the CSF was only obtained during the day,
the rise in blood pressure occurred on the first day, while
CSF sodium rose on the fourth day. In another study [44]
in the SHR-S on a high dietary intake of NaCl, an initial
rise in CSF sodium for the first 3 days subsided to normal
at 7 days, though the rise in plasma sodium and blood
pressure continued thereafter [44]. It was concluded that
alterations in CSF sodium do not contribute to the in-
crease in arterial pressure induced by a high NaCl diet
in SHR-S. In 1K1 wrap Grollman kidney hypertension
given a diet rich in NaCl, CSF sodium only rose from the
third to the seventh day, while the blood pressure rose on
the sixth day and remained raised [74].
Sodium concentration, hypothalamic angiotensin II, and
blood pressure
Intervention in the activity of the hypothalamic an-
giotensin system in various forms of hypertensive rats
lowers blood pressure, but is without effect in the normal
rat [8895].
Andersson et al initially demonstrated that the pressor
effect of angiotensin II was much reduced when infused
centrally in a nonelectrolyte solution [66]. A quarter of a
century later, Qadri et al [96] demonstrated in conscious
rats that perfusion of the paraventricular nucleus by mi-
crodialysis with 0.3 mol/L and 0.6 mol/L NaCl elicited a
concentration dependent increase in the release of an-
giotensin II from the nucleus. Huang et als [69] studies
have demonstrated that the increase in hypothalamic an-
giotensin II activity, and the rise in blood pressure in-
duced by an increase in CSF sodium, is secondary to a
rise in the activity of an ouabain-like compound in the
hypothalamus, and can be prevented or reversed by the
intracerebroventricular administration of Fab fragments,
which bind such compounds. The pressor effect and the
increase in sympathetic activity induced by the central
administration of hypertonic saline can also be largely
prevented by the intracerebroventricular administration
of losartan [67, 69]. Similarly, in the rat, saralasin injected
into the third ventricle inhibits the response of paraven-
tricular neurosecretory cells to an intracarotid infusion
of 0.3 mol/L NaCl [97]. Chen et al [98] found that AT 1a
mRNA expression in the hypothalamus is significantly in-
creased by loading mice with 2% saline for 5 days. There
was no significant change in AT 1b mRNA.
 de Wardener et al: Plasma sodium and hypertension
Direct effect of sodium concentration on
neuronal function
The reduced hypothalamic sympathetic inhibition that
is responsible for the rise in arterial pressure when the
CSF sodium concentration rises may also be due in part
to the direct effect of plasma sodium on neuronal activity
for an increase in sodium concentration in neocortical
and hippocampal slices diminishes synaptic transmission
and neuronal excitability [99, 100], and a small rise in the
sodium concentration in the anterior hypothalamus of the
conscious rat reduces the local release of norepinephrine
[101].
VESSELS AND HEART
There is direct evidence that a rise in plasma sodium
in vivo can induce changes in the arteries which could
contribute to the associated rise in blood pressure, and
that, in vitro, a rise in sodium concentration can cause
intracellular changes in the vessels and the heart that are
similar to those found in vascular tissue from hyperten-
sive individuals or animals.
There is indirect evidence that, independent of the
blood pressure, a rise in plasma sodium in vivo induces
structural hypertensive changes in the vessels and the
heart, and that in both in vitro and in vivo, the vascu-
lar structural changes in hypertension may be due in part
to an increase in tissue angiotensin II activity of unknown
origin which, independent of the blood pressure, may be
due in part to a raised plasma sodium.
Direct in vivo evidence that an induced rise in plasma
sodium causes arterial changes that may contribute to
the associated rise in blood pressure
In Friedman et als peritoneal dialysis experiments in
rats with saline solutions of varying concentrations in
which the resulting changes in blood pressure were di-
rectly related to the induced changes in plasma sodium,
the transmembrane distribution of Na+ , K+ , and water
was measured in rapidly excised tail arteries [26]. The
intracellular sodium concentration was directly related
to the systolic and diastolic pressures [26]. A rise in in-
tracellular sodium increases muscle tone [102] due to the
resultant increase in intracellular free Ca2+ concentration
[103]. These studies were the first in vivo demonstration
that an acute rise in plasma sodium, not accompanied by
a rise in ECV, can raise blood pressure, and that such a
rise in blood pressure is associated with an increase in the
sodium concentration of smooth muscle.
Direct in vitro evidence that a rise in plasma sodium in-
duces multiple changes in vascular tissue similar to those
that occur in hypertension
The major structural changes in essential hypertension
are reduced vessel lumen diameter and medial thicken-
2459
ing due to hyperplasia, hypertrophy, reorganization of the
cells around the lumen of the artery, and an increase in
extracellular matrix and collagen [104]. In cultures of my-
ocardial myoblasts and vascular smooth muscle cells, Gu
et al [105] found that a change in sodium concentration
from 146 mmol/L to 152 mmol/L for 5 days increased cell
diameter, volume, and protein content of the cells. There
was also a decrease in protein degradation, but no hy-
perplasia. In another experiment, increasing the sodium
concentration by only 2 mmol/L above normal caused the
cellular protein content of cultured coronary artery
smooth muscle cells to increase by 84.5%. Similar results
were obtained in cultured umbilical vein endothelial cells
[106]. A 10 mmol/L increase in sodium concentration in-
duced a transient rise in c-fos proto-oncogenic mRNA ex-
pression, which began at 2 hours. After 3 days there was
an increased mRNA expression of many hypertrophy re-
lated factors, including endothelin, IGF, FGF, TGF, and
MIF. In isolated ventricular adult rat cardiomyocytes, in-
creasing the sodium concentration of the bath fluid from
128 to 139 and 179 mmol/L, by adding hypertonic saline
or increasing the osmolality by an equivalent amount
with sucrose for 30 minutes, induced a dose-dependent
increase in egr-l and c-fos levels mRNA up to 4- and 5-
fold, respectively [107]. Nickenig et al [108] found that
an increase in the concentration of NaCl by 10 mmol/L
in thoracic aorta and cultured rat vascular smooth mus-
cle cells caused a time-dependent rise in AT 1 receptor
mRNA levels that appeared at 12 hours, and was sus-
tained for 48 hours when the experiment was ended.
Indirect in vivo evidence that a rise in plasma sodium
is responsible in part for the increase in left ventricular
mass and arterial thickness and stiffness in hypertension
independent of blood pressure
Earlier it was pointed out that sodium intake, which,
in normal circumstances, is equivalent to sodium excre-
tion, is directly related to urine flow, and that urine flow
is directly related to thirst, which is controlled by plasma
sodium. Therefore, alterations in dietary sodium intake
appear to induce changes in plasma sodium. The follow-
ing studies, which demonstrate that sodium intake (mea-
sured as urinary sodium excretion) is directly related to
left ventricular mass and arterial thickening, therefore
suggest indirectly that these vascular changes are associ-
ated with changes in plasma sodium.
In normotensive subjects, left ventricular mass and
diastolic filling are positively correlated with urinary
sodium excretion [109, 110]. Normotensive rats on 1%
saline for several weeks develop an increase in heart
weight due to an increase in left ventricle mass, with-
out an increase in blood pressure [111, 112]. The increase
in left ventricular mass, which accompanies an increased
salt intake, is associated with an increase in noncollagen
protein and total collagen content [112, 113]. An increase
2460 de Wardener et al: Plasma sodium and hypertension
in sodium intake in both humans and experimental an-
imals increases the stiffness of conduit arteries and the
activity of resistance arteries, and both become hyper-
trophied, independent of blood pressure [114]. A high
salt intake in the rat induces structural alterations in the
cerebral and renal vessels, independent of blood pressure
[115], and in humans, an increase in salt intake increases
the stiffness and thickness of arterial walls, independent
of blood pressure [6].
In vivo and in vitro evidence that structural changes
in hypertension are due in part to an increase in
tissue angiotensin II activity in the vessels and the heart,
independent of blood pressure, and that these may be due
to an increase in plasma sodium
Epidemiologically, as the blood pressure rises with age
there is an inverse association between plasma renin ac-
tivity and systolic pressure [116], yet the administration
of angiotensin inhibitors to patients with essential hy-
pertension lowers their blood pressure, which suggests
that such patients have an increase in angiotensin activ-
ity in the tissues, due possibly to an increase in sensitivity
to angiotensin [117], perhaps related to dietary sodium.
Genetically manipulated mice that have no tissue-bound
angiotensin-converting enzyme (ACE), but a normal
plasma ACE, have a low blood pressure [118], which also
suggests that, in contrast to tissue angiotensin II, circulat-
ing angiotensin II plays only a minor role in the control
of the blood pressure.
Arterial and cardiac changes in hypertension that appear
to be due to increased angiotensin II activity. There is evi-
dence of increased angiotensin II activity in the vessels of
patients with essential hypertension. The gluteal muscle
of patients with essential hypertension has been studied
before, and after, one years treatment with either losar-
tan or atenolol. The fall in blood pressure in the 2 groups
was comparable, but the width-to-lumen ratio of the sub-
ject on losartan was significantly reduced, whereas there
was no change in those on atenolol [119]. The distensibil-
ity of the common carotid artery in 41 patients with es-
sential hypertension was enhanced by the administration
of an ACE inhibitor for 6 months, but it was not altered
by the administration of amiloride and hydrochlorazide,
though the fall in blood pressure was not significantly dif-
ferent [120]. The relatively acute vascular changes which
are associated with an infusion of angiotensin II do not
occur when the blood pressure is raised by some other
pressor agent, such as noradrenaline [121].
Experimental studies in the SHR have revealed evi-
dence of an increase in angiotensin II activity in the heart.
Ohta et al [122] found that left ventricular mRNA levels
for skeletal a-actin and for collagen types I and III in the
SHR were higher, and a-myosine heavy chain (MHC)
mRNA levels were lower than in the WKY. The admin-
istration of an ACE inhibitor attenuated the increase in
collagen types I and III mRNA, and raised the a-MHC
mRNA. These effects did not take place after the adminis-
tration of a calcium channel blocker or an a-1 adrenergic
blocker, although the reductions in blood pressure were
comparable. Thus, in the SHR, cardiac gene program-
ming can be attributed at least in part to angiotensin II.
Similarly, in the SHRSP rat, losartan induced regression
of left ventricular hypertrophy, and returned the altered
expression of a-MHC to normal, skeletal actin, TGF-
b 1 , and collagen type I and III to a greater extent than
amlodipine, despite comparable hypotensive effects [123,
124].
Possible role of plasma sodium in the apparent increase
in angiotensin II activity in vascular tissue in hypertension.
The increase in angiotensin II activity in the vessels in es-
sential hypertension, which appears to be due in part to
an increase in sensitivity to angiotensin II, may be due
in part to a raised plasma sodium. In cultures of vascular
smooth muscle, and of endothelial cells, a rise in sodium
concentration of the bath increases the number of AT 1
receptors [108] and TGF-b production [106, 125], and
the functional response of the cells to stimulation with
angiotensin II [108]. Touyz and Schiffrin suggest that the
increase in tissue angiotensin II activity in hypertension is
due to augmented angiotensin II signaling at the postre-
ceptor level [104].
DISCUSSION
It is probable that one of the principal reasons why it
took about 100 years for the connection between dietary
salt and hypertension to be generally accepted was the
absence of a satisfactory explanation. On a high salt in-
take a defect in the kidneys ability to excrete sodium will
give rise to a greater retention of sodium, and thereby, a
tendency for volume expansion. There are several hy-
potheses on the nature of the pressor mechanisms, which
are induced by the combined effect of an impaired abil-
ity to excrete salt, and a raised intake of dietary salt. All
incorporate the concept that this results in a tendency for
the extracellular volume to be increased. Based on exper-
iments in 70% nephrectomized dogs given large amounts
of saline intravenously daily for 2 weeks, Guyton [126]
suggested that volume expansion raises the blood pres-
sure by the autoregulatory effect on resistance vessels
of the increase in blood flow that accompanies the asso-
ciated persistent increase in cardiac output, even if this
slight increase in cardiac output is usually unmeasurable
[127]. But cardiac output in essential hypertension is nor-
mal, even when there is hypervolemia [128, 129]. Admit-
tedly, this does not exclude essential hypertension from
being caused by intermittent small increases in cardiac
output, but there are several observations that demon-
strate that cardiac output does not control blood pres-
sure. Dialysis patients loaded with saline develop a rise in
 de Wardener et al: Plasma sodium and hypertension
peripheral resistance without an increase in cardiac out-
put [130]; hypertension can occur in a patient with mitral
stenosis and a low cardiac output [131]; and after raising
the blood pressure of a dog for 6 weeks with metapy-
rone, there was no evidence of circulatory autoregula-
tion [131]. Others [132] have proposed that among the
multiple changes that counter the kidneys impaired abil-
ity to excrete sodium, and the resultant tendency to
volume expansion, there is an increase in the plasmas ca-
pacity to inhibit Na-K-ATPase, which not only increases
sodium excretion, but also raises blood pressure by in-
hibiting the sodium-calcium pump in vascular smooth
muscle [133]. This hypothesis was based on the demon-
stration that in normal dogs acute volume expansion in-
creases the plasmas capacity to inhibit Na-K-ATPase.
Such an increase is detectable in essential hypertension,
the SHR, and the Milan hypertensive rat. The nature
of the substance responsible for the Na-K-ATPase in-
hibition has been difficult to elucidate. One study in 27
untreated patients with essential hypertension has
demonstrated that plasma marinobufagenin immunore-
activity, which rises with acute volume expansion [134],
is raised in essential hypertension [135]. A variable in-
crease in plasma ouabain immunoreactivity [135], and
of ouabain extracted from plasma [136], has also been
reported in essential hypertension, although volume ex-
pansion does not raise plasma ouabain [136]. A third hy-
pothesis on the pressor mechanism induced by dietary
salt suggests that the tendency for an increase in extra-
cellular fluid volume is responsible for the documented
increase in right and left (wedge) pressures in the auricles.
It is proposed that the resultant increase in vagal afferent
stimulation is responsible for the observed hypothalamic
pressor changes [61].
In view of the impaired ability to excrete sodium
evident in the normotensive children of hypertensive
parents [137], and in young prehypertensive genetically
hypertensive rats [138], the premise that the increase
in blood pressure in these forms of hypertension is as-
sociated with some increase in the extracellular fluid
volume, however difficult to detect, is theoretically rea-
sonable. Studies of the extracellular volume, exchange-
able sodium, and of the natriuretic response to a rapid
infusion of saline, suggest that in hypertension there ex-
ists a state of continuous correction of a slightly expanded
extracellular fluid volume. Mullins [139] and Harrap [140]
found the extracellular volume and exchangeable sodium
in the SHR was significantly larger than in the WKY. In
humans, one group [141] found that in a total of 211 hyper-
tensive men there was a significant correlation between
exchangeable sodium, related to body surface and arte-
rial pressure, but not in women [142]. In hypertensive men
below the age of 35 years, however, exchangeable sodium
was significantly decreased. Simon et al [143] also found
that the extracellular volume in hypertension was not in-
2461
creased. Nevertheless, both groups [141, 143] found that
the extracellular fluid volume correlated with the blood
pressure. Subsequently, Berreta-Piccoli [144] reported
that exchangeable sodium was unrelated to arterial pres-
sure in both normotensive and hypertensives. A striking
functional signal of the existence of a controlled state of
volume expansion is the syndrome of accelerated natri-
uresis, which is elicited by a rapid infusion of saline. This
response occurs in primary hyperaldosteronism [145] in
normal subjects given aldosterone [146], even when, as
in essential hypertension, it may not be possible to detect
an increase in extracellular fluid volume. It is also elicited
in the SHR [147, 148], particularly those with a low plasma
renin, and in normotensive children of hypertensive par-
ents [21]. Other indications that hypertension is probably
associated with a tendency to volume expansion include
the reduced level of plasma renin [116], the raised lev-
els of atrial natriuretic hormone [137], and the increase
in the plasmas capacity to inhibit Na-K-ATPase [132].
There is agreement that plasma and total blood volume
in essential hypertension and hypertensive strains of rats
are either normal or decreased [129, 142, 143, 149151].
The possible role of prolonged small (<5 mmol)
changes in plasma sodium on blood pressure has not been
studied. The concentration of sodium in plasma is closely
and rapidly controlled by the movement of fluid between
the intra- and the extracellular fluid space, changes in
sodium excretion, and by the activity of the thirst cen-
ter, which, in the rat, is influenced by changes in plasma
sodium of under 1% [54]. Such small but still potent
changes in plasma sodium are technically difficult to de-
tect. Burtis and Ashwood [152] state that the coefficient
of variation for contemporary methods of detection of
sodium is less than 1.5%. The conclusion that, in essential
hypertension and the SHR, there is a small and persistent
rise in plasma sodium and osmolality, at least sufficient
to affect the hypothalamus, is consistent with the find-
ing that in both of these forms of hypertension, in which
there is evidence to suggest that there is a state of con-
tinuous correction of a slightly expanded extracellular
fluid volume [which would tend to reduce arginine vaso-
pressin secretion (AVP)], both plasma and urinary AVP
are raised [61].
In humans, we have not been able to find observations
on plasma sodium in large groups of normal or hyperten-
sive individuals, whose habitual intake of salt is known.
It would also be interesting to know if there are diurnal
changes in plasma sodium, and the effect of meals. Dogs
have a substantial transient postprandial rise in plasma
sodium [153]. The close relation that exists between di-
etary sodium and urine volume in normal and hyperten-
sive humans [50] suggests that the habitual dietary intake
of sodium controls plasma sodiumin other words, that
the raised thirst engendered by an habitually raised in-
take of sodium, which is evident as a raised 24-hour urine
2462 de Wardener et al: Plasma sodium and hypertension
volume, is due to stimulation of the thirst center by an
increase in plasma sodium. It follows that in essential hy-
pertension, the incidence of which is also related to a high
intake of salt, plasma sodium should be slightly raised.
In humans, there are only 2 relatively substantial stud-
ies in patients with essential hypertension in which plasma
sodium has been published [57, 58]. In both, the rise
in arterial pressure is significantly related to a small
(2 mmol) rise in plasma sodium. In the SHR, Fang
et al [59] found that on a normal intake of salt, plasma
sodium, measured at 1- to 2-hour intervals, was about 1
to 3 mmol/L greater throughout the 24 hours than in the
WKY rat. Because the pronounced and parallel diurnal
changes in plasma sodium in both strains were not syn-
chronous with the diurnal rhythm of the blood pressure,
Fang et al were reluctant to relate the hypertension to the
raised plasma sodium. But the plasma sodium concentra-
tion in the SHR was greater than in the WKY throughout
the 24 hours, as was blood pressure. In keeping with the
evidence discussed below, a small rise in plasma sodium
appears to be more likely to raise the blood pressure if
it is prolonged. Accordingly, the persistent small rise in
plasma sodium concentration in the SHR is likely to be
relevant to that strains persistently higher blood pres-
sure, whereas the short-term superimposed diurnal fluc-
tuations in plasma sodium in both the SHR and WKY are
unlikely to be responsible for diurnal changes in blood
pressure.
The evidence available suggests that the temporal re-
lation between a rise in sodium concentration and the
effect such a rise produces is such that small changes of
2 to 5 mmol/L take some days to have an effect, whereas
larger changes (e.g., of 15 mmol or more) may induce a
change within an hour. For instance, a rapid infusion of
hypertonic saline into the third ventricle increases blood
pressure within an hour [66], whereas a prolonged infu-
sion of a lower concentration of saline, which only raises
CSF sodium by 4 to 5 mmol/L, may take 6 to 10 days to
raise the blood pressure [73]. In essential hypertension
and the SHR, there appears to be a rise in CSF sodium
concentration that is less than 4 mmol/L [34, 43], so that
any effect such a rise would have on blood pressure might
take even longer. Similarly, in vivo, a rise of 15 mmol/L
in plasma sodium induces certain arterial changes and a
rise in blood pressure within hours [27], but, in vitro, a rise
of only 5 mmol/L takes 3 to 6 days to induce changes in
arterial segments [105, 106]. It is possible that the consid-
erable time it appears to take for a modest rise in sodium
concentration to affect the blood pressure is the reason
why the blood pressure did not rise in the study by Greene
et al [49] in rats which lasted 4 days, and in which the
weight of the rat was kept constant while plasma sodium
was raised from 143.5 to 152.4 mmol/L by a continuous in-
travenous infusion of salt solution. Accordingly, the pres-
sor response obtained within 4 days by a rise in plasma
sodium of 3.2 mmol/L by Qui et al [39], using a similar
protocol, but in which the input of salt was raised by in-
creasing the dietary salt intake, is anomalous.
It is interesting that in contrast to individuals over
30 years of age, a large increase in salt intake, including in-
travenous infusions of saline for 8 to 30 days in young men
below the age of 26 years, does not raise the blood pres-
sure, in spite of increases in plasma sodium, extracellular
fluid volume, blood volume, and exchangeable sodium. In
the young, therefore, none of those primary disturbances
that are induced by an increase in salt intake are effec-
tive in raising the blood pressure. Presumably, this is due
to the potency of counter mechanisms. Similarly, a fall in
pressure induced by a reduction in dietary salt appears to
be related to the extent of the compensatory change in
plasma renin activity and angiotensin II [36].
The evidence that the increase in angiotensin II activ-
ity in hypertensive vessels is in part secondary to a rise in
plasma sodium is suggested by the in vitro experiments
which demonstrate that an increase in sodium concentra-
tion of the bath solution increases the number and activity
of AT 1 receptors in vascular tissue [108], and promotes
metabolic changes which are similar to those induced by
angiotensin II [154]. These include increases in the size
and protein content, and a decrease in protein degrada-
tion, of cultured cardiac myoblasts and vascular smooth
muscle cells [104, 105]. This suggests that a rise in plasma
sodium could be responsible in part, not only for the rise
in arterial pressure, but also for the increase in ventric-
ular mass [5] and thickening of the arteries [7], both of
which are related to the intake of dietary salt and, in-
dependent of the blood pressure [3, 4], are responsible
for certain changes in the pressure, such as an increase in
pulse pressure. Furthermore, Gu et als [105] signal obser-
vation on the influence of sodium concentration on cell
metabolism may also explain some of the deleterious ef-
fects attributed to DOCA and aldosterone. Somers et al
[155] reported that rats given DOCA and water to drink
instead of 1% saline not only fail to develop hypertension,
but in contrast to rats given 1% saline, aortic superoxide
production and relaxation of vascular segments to acetyl
choline are unaffected.
CONCLUSION
Accumulating evidence suggests that for a given salt in-
take, those individuals who develop a rise in blood pres-
sure have a reduced ability to excrete sodium. This re-
sults in a barely perceptible rise in plasma sodium of 1 to
3 mmol/L, which is responsible for the tendency for an
increase in extracellular volume. Experimental increases
in plasma and CSF sodium concentrations greater than
5 mmol/L can increase the blood pressure independent
of the extracellular volume. In these studies, the time of
onset of the rise in arterial pressure appears to be related
 de Wardener et al: Plasma sodium and hypertension
Thirst ECV
Salt
PNa+ BP
intake
Brain and
vessels
Fig. 1. The greater rise in plasma sodium that occurs in hypertensive
prone subjects is due to a defect in the kidneys ability to excrete salt,
and is responsible for the rise in blood pressure.
to the extent of the increase in sodium concentration, so
that the delay may take several days. With 1 to 3 mmol/L
increases in sodium concentration that occur in hyper-
tension, but that have not been studied experimentally,
the delay is likely to be considerably longer. We suggest
that a small increase in plasma sodium (1 to 3 mmol/L)
not only tends to increase the extracellular fluid volume,
but may itself be a primary factor in the pressor effect
of dietary salt (Fig. 1). In other words, plasma sodium
drives the system. This hypothesis suggests the need for
well-controlled studies of careful measurement of plasma
sodium and urinary sodium excretion on normotensive
and hypertensive individuals on their habitual intake of
salt, and when salt intake is changed. In animals, much
longer studies should be carried out on the effect of pro-
longed 1 to 3 mmol/L increases of sodium concentration
on the blood pressure. There is also a need to study the
effect of prolonged similar increases in sodium concen-
tration on cultures of vascular tissue.
ACKNOWLEDGMENTS
We would like to thank Joy Lyall for her very valuable contributions
to the paper.
Reprint requests to Prof. G.A. MacGregor, Blood Pressure Unit, St.
Georges Hospital Medical Center, Cranmer Terrace, London SW17,
ORE
E-mail: g.macgregor@sghms.ac.uk
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