289
Clinical Science ( 1990) 79, 289-297
Editorial Review
The primary role of the kidney and salt intake in the aetiology
of essential hypertension: part I1
H. E. DE WARDENER
Research Laboratories,Charing Cross and Westminster Medical School, London
ESSENTIAL HYPERTENSION
The evidence that essential hypertension is related to salt
intake due probably t o a diminished capacity t o excrete
sodium comes from several sources.
Relation between normal dietary sodium intake and the
blood pressure in population studies
Rural oriental communities in which there are a wide
range of salt intake and each individual’s intake is
relatively constant have repeatedly shown a direct
relationship between 24 h urinary sodium excretion and
blood pressure [90-94]. In Western cultures, however, it
has been difficult, until recently, to detect a significant
relationship within populations. In addition, attempts to
correlate data from international sources was criticized in
that the various centres from which the data were
obtained used different criteria, and there was a failure to
take into account many confounding variables. Thus
cross-centre linear relationships between blood pressure
and sodium intake which were repeatedly demonstrated,
from data collected worldwide [95, 961, consistently failed
to be universally convincing.
The results of a massive international epidemiological
study (the lntersalt Study), which avoided the weaknesses
of previous investigations, have recently been published
[97]. It was carried out in 10079 men and women aged
20-59 years sampled from 52 centres around the world
using a standardized protocol, central training and a
central laboratory
After standardization for age, sex,
body mass index, alcohol intake and potassium excretion,
within-centre analyses showed that sodium excretion was
significantly related to systolic pressure in individuals, and
cross-centre analyses showed that sodium excretion is
[%I.
Correspondence: Professor H. E. de Wardener, Research
Laboratories, Charing Cross and Westminster Medical School.
Fulham Palace Road. London W6 8RF.
significantly related to the rise in systolic and diastolic
pressure with age. A conservative estimate of the size of
this effect is that, on average, a reduction in sodium intake
of 100 mmol/day between the ages of 25 and 55 years
corresponds to a 9 mmHg lower rise in systolic pressure.
This is likely to be an underestimate as only one 24 h
sample of urine was analysed for sodium excretion, but
within-individual variations in daily sodium excretion may
vary widely. In Western communities it is necessary to
sample five to 14 24 h samples in order to be able to
obtain a correct regression coefficient [99-1021. To try to
adjust for this variability in the lntersalt Study a
coefficient of reliability was calculated from the results of
t w o 24 h urine samples collected from 807 participants at
random.
Once again, the lntersalt Study demonstrated that in
geographically isolated centres which have urinary
sodium excretion rates below approximately 60 mmol/
day, of which there were four in the Intersalt Study, the
blood pressure does not rise with age and hypertension is
rare. In the past the applicability of such observations to
other, and particularly to Western, societies has tended to
be dismissed on the assumption that the general health
and daily life patterns of such isolated unacculturated
societies was probably more relevant to their low blood
pressure than to their intake of sodium [ 1031. It appears
that this assumption is unwarranted. The local organizers
at each of the four Intersalt centres with sodium intakes
below 60 mmol/day have reported that the participants
were physically active, appeared healthy and showed no
sign of malnutrition or protein deficiency [ 1041. And the
minor influence on the blood pressure of the daily life
patterns of these isolated communities, in contrast to their
intake of sodium, has been demonstrated in three further
studies. One was in six Solomon island communities with
similar life patterns [105]. The physical fitness of the
participants in all six islands was found to be ‘excellent’. In
three of the islands with sodium intakes below 30 mmol/
day the prevalence of hypertension was below 1%; in two
290
H. E. de Wardener
islands where the inhabitants added salt to the cooking so
that sodium intake varied between 50 and 130 mmol/day
the prevalence was 3.4 and 2.7%. and in the remaining
island where they cooked in 'copious amounts of sea
water' it was 7.8%. The second study was in two tribes
living on the shores of two adjoining southern tributaries
of the Amazon [ 1061. One tribe, which was under the care
of missionaries, regularly used table salt. In the men there
was a rising trend of arterial pressure with age; in the
women there was a similar, but statistically unimportant
rise. In the other tribe, who ate native low sodium food,
there was no rise in blood pressure with age in either sex.
The third study, which complements the others, was
undertakcn in an isolated nomadic tribe at a low level of
acculturation in southern Iran [ 1071. Throughout the
tribal area, which the tribe has inhabited for approximately 400 years, there are natural surface deposits of salt
which is used liberally in the baking of bread, cooking and
added at the table. The average urinary sodium excretion
was 186 mmol/day in the men and 141 mmol/day in the
women. The prevalence of hypertension, in those aged
over 30 years, was 12% and l8%, respectively, with no
tendency for weight to increase with age.
Effect of imposed changes in sodium intake on the blood
pressure of patients suffering from essential hypertension
The hypotensive effect of salt restriction in essential
hypertension was first described by Ambard & Beaujard
in 1904 [108]. In 1086 Morgan & Nowson [ l 0 0 ]
reviewed the results of 61 studies on the effect of salt
restriction on the blood pressure published after 1947.
The mean blood pressure was 105 mmHg or greater in
37. Sodium restriction reduced the blood pressure in
patients with severe hypertension, moderate hypertension
and mild hypertension. The studies that failed to show a
fall in blood pressure with a reduction in sodium intake
were usually in subjects with a blood pressure less than
130/90 mmHg. A regression line drawn through the
change in blood pressure and change in sodium intake in
the 61 studies demonstrated that the mean blood pressure
falls by about 10 mmHg for every 100 mmol/day reduction in sodium intake. Two subsequent trials have confirmed the hypotensive effect of reducing the salt intake of
patients with essential hypertension, and in addition have
shown that this is a long-term effect [ 110, 11 11.
An increase in sodium intake from 70 to 250 mmol/
day for 7 days, which caused no change in blood pressure
of 10 normotensive subjects with no family history of
hypertension, induced a significant rise in 23 subjects with
a family history of hypertension [ 1 121.
Acute changes in sodium status induced by a 2 litre
intravenous infusion of saline followed by sodium deprivation and frusemide administration was studied in 378
normotensive subjects and I98 patients with essential
hypertension [ 1 131. In both groups the resultant changes
in blood pressure were heterogeneous and showed a
Gaussian distribution. The blood pressure changes in the
hypertensive group, however, were significantly greater
than in the normotensive group. In other words the blood
pressure of more hypertensive patients was sensitive to
these acute changes in sodium status, i.e. were sodiumsensitive. Other studies in severely sodium-sensitive
patients has revealed that in such patients the rise in blood
pressure which occurs with an acute sodium infusion is
associated with a slower rate of urinary sodium excretion
[114, 11.51.
Volume changes. Plasma and blood volume in essential
hypertension are sometimes raised [ 1 161 but are usually
normal or low, tending to have an inverse correlation with
the blood pressure [117-1201. Such a distribution is
similar to that in primary aldosteronism [120] in which
the aldosterone undeniably imposes a persistent restraint
on urinary sodium excretion. The reduction in blood
volume at the higher pressures is due to an increased
transcapillary escape of albumin [ 12 I ] probably caused
by an increased filtration associated with the higher levels
of blood pressure [ 117, 1191. Nevertheless, because of
diminished venous compliance [ 122, 1231 and a redistribution of blood volume centrally [ 1241, the central venous
pressure in essential hypertension is raised [ 1251.
Extracellular fluid measured as the "Br, "Na or inulin
space has usually been found to be normal [ 116, 118,
1261 or low [127, 1281. Exchangeable sodium measured
at 6 h in 91 patients with hypertension was no different
from that of 121 normal subjects [129]. These large
numbers, however, revealed that the sodium space in the
hypertensive patients was significantly related to the
blood pressure, while it was not so related in the normal
subjects. In a sub-group of hypertensive patients aged 35
or less, the mean sodium space was below normal. It was
considered that these findings suggested that changes in
body sodium were more important in the later stages of
essential hypertension.
Plasma renin activity. Bianchi et ul. 11301 studied 56
normotensive children of hypertensive parents and 65
normotensive children of normotensive parents. The
blood pressure of both parents of each of the 12 1 subjects
was measured. Plasma renin activity of the children of
hypertensive parents was significantly lower ( P < 0.001).
In three other similar studies in which the number of
subjects in each group was much smaller, and one hypertensive parent was considered to be sufficient to allocate
the subject to the hypertensive group, plasma renin
activity was not significantly different, although in two of
the three studies the plasma renin activity tended to be
less in the offspring of hypertensive parents 113 I - 1331. In
line with the findings of Bianchi et a/. [ 1301, which suggest
that in essential hypertension there is a tendency to
volume expansion in pre-hypertensive subjects, there is
the epidemiological survey by Meade et a/. [ 1341 of men
aged 18-64 years and women aged 19-59 years. There
was a significant inverse relation between the systolic
pressure (range 90-220 mmHg) and plasma renin activity
in the 1282 men [ 1341. A similar trend in 488 women was
not significant.
Renal function. Renal blood flow and glomerular
filtration rate of normotensive children of two hypertensive parents are increased before they develop hypertension, although the cardiac output is not raised 1130,
Kidney, salt intake and hypertension: part I1
135I. This suggests a selective vasodilatation consistent
with the compensatory mechanism which comes into play
when there is a tendency for volume expansion. This
increase in blood flow persists in some patients after the
blood pressure has started to rise.
Attempts to obtain information on sodium reabsorption along selected areas of the tubule in hypertensive
patients have yielded inconsistent results. Using lithium
clearance as an index of proximal reabsorption, some
workers have concluded that hypertensive patients have
an increased reabsorption of sodium by the proximal
tubule [136, 1371. Others have not been able to repeat
these observations [ 138- 1401.
Kallikrein excretion. Urinary kallikrein originates in
the kidney. In essential hypertension [ 141, 1421 and in the
SHR rat (for explanation of abbreviations, see Part I )
[ 1431, the Milan hypertensive rat [ 1441 and the Dahl saltsensitive rat [ 1451, urinary kallikrein excretion is reduced
both before and after the onset of hypertension.
Presumably this lesion is inherited, as it is manifest before
the rise in pressure and it does not occur in other forms of
hypertension. There is a possibility that it may, in part, be
related to the diminished ability of the kidney to excrete
sodium in hereditary forms of hypertension. There is
direct evidence that kallikrein hydrolyses the amiloridesensitive sodium channels in the mucosa of the
mammalian bladder [ 1461, and indirect evidence that it
can hydrolyse sodium channels in the apical membranes
of distal and collecting duct renal tubules. A deficiency of
urinary kallikrein therefore might be associated with a
greater reabsorption of sodium.
Observations which demonstrate that increasing the
demand on the normal kidney to excrete sodium by
raising the intake of salt raises the blood pressure
Normal animals. The prolonged ingestion of increased
quantities of salt causes hypertension in the normal dog
[147, 1481, chicken [149], rabbit [150], baboon [33] and
rat [41, 42, 1511. The rate of rise in pressure depends on
the amount ingested. Hypertension usually comes on
within a few weeks, is sustained thereafter and is
proportional to the intake. The effect is more marked in
animals exposed just after birth [33,411 and in males [33,
1521. In the baboon 1331 the blood pressure returns to
normal when the high salt intake is stopped after 1.5
years.
Normal man. A rise in sodium intake to less than a total
of 420 mmol/day for 4 days to 4 weeks in young or
middle-aged ( < 47 years) normotensive subjects did not
cause a rise in arterial pressure in four of five studies
[ 153-157].
In another report [ 1581 the administration of 640
mmol of sodium/day for 23 days to one young adult
normal male subject, in addition to the salt contained in
food taken at meals, caused a progressive rise in blood
pressure from I10/75 to 135/88 mmHg. In an extreme
example of salt loading, Murray et al. [ 1591 increased the
oral intake of sodium to six normal young men from 10 to
300 and then to 800 mmol/day over only 9 days. For 3
29 1
further days the 800 mmol of sodium by mouth was
supplemented each day by an additional 700 mmol of
sodium intravenously. There was a rise in mean blood
pressure from 80 to 103 mmHg, the relationship between
systolic, diastolic and mean blood pressures and sodium
excretion being highly significant ( P <0.001). In another
study [ 1601 by the same group intravenous saline was not
used, the oral intake of sodium being raised to 1200
mmol/day. In black subjects, an increase up to 600-800
mmol/day caused a rise in arterial pressure within 9 days.
In Caucasian subjects the sodium intake had to rise to
1200 mmol/day before a rise in pressure was detectable
within the 9 day period of study.
A most dramatic spontaneous demonstration of the
effect of a high salt intake on a young normotensive
individual, although admittedly not a normal subject,
occurred in a boy suffering from diabetes with a craving
for salt [ 161, 1621. On a sustained intake of 850 mmol/
day he had severe hypertension. When switched to normal intake of 80 mmol/day the pressure rapidly returned
to normal. This phenomenon was confirmed in four other
diabetic children and one normal child (aged between 13
and I 5 years) by intentionally increasing sodium intake
up to about 600 mmol/day for 2 weeks. In the normal boy
the blood pressure rose from 120/70 to 145/100 mmHg.
There do not appear to be any studies, comparable
with those made in animals, of the effect of a prolonged
modest increase in salt intake on the blood pressure of
young normal subjects. In older subjects ( > 50 years) in
whom it is normal for renal function to deteriorate [ 1631,
an impaired ability to excrete sodium becomes detectable
and plasma renin falls [ 1341; an increase in salt intake up
to 340 mmol/day for 4 weeks has been shown to cause a
rise in arterial pressure 1164, 1651.
In view of the evidence that essential hypertension is a
hereditary condition, study of the changes in urinary
sodium excretion which occur with acute changes in
sodium status in 37 pairs of monozygotic and 18 pairs of
dizogotic normotensive twins is of interest. The twins
were given 2 litres of saline intravenously in 4 h followed
immediately by 120 mg of frusemide and a low sodium
diet. The results demonstrated that the induced changes
in urinary sodium excretion were influenced by hereditary
factors [ 1661.
Observations which demonstrate that diminishing the
demand on the normal kidney to excrete sodium by
reducing the intake of salt lowers the arterial pressure
The effect of a reduction in salt intake on the arterial
pressure of normal subjects has been studied in neonates,
school children and adults. The blood pressure in normal
newborn babies was found to be particularly sensitive to a
prolonged small reduction in sodium intake. Hofman er
a/. 11671 allocated 476 babies into two groups, one of
which had a normal sodium intake and the other a lower
intake for 6 months. The normal intake was three times
greater than the lower. There was a progressive and
increasing difference in systolic pressure between the two
groups, so that the mean systolic pressure at 6 weeks was
292
H. E. de Wardener
significantly higher in those o n the higher sodium intake.
In four studies in children the significance of the results
was greatly influenced by the number of participants. In
one study with a total of only 80 children a reduction in
sodium intake of 30 mmol/day to an intake of 56 mmol/
day had no effect on the blood pressure at the end of 1
year [ 1681. In the second study with a total of 124 participants, a reduction in sodium intake of 65 mmol/day to an
intake of 45 mmol/day for 24 days induced a non-significant fall in blood pressure [ 1691. In a third group of 149
subjects a reduction in sodium intake of 55 mmol/day to
an intake of 50 mmol/day induced a significant fall in
blood pressure after 12 weeks but only after adjustment
for age and weight 11701. With a total group of 750 children, however, a reduction in sodium intake of 39 mmol/
day to an intake of 127 mmol/day induced a significant
fall in blood pressure at 24 weeks j17 11.
In one study in 32 adults (aged around 40 years) a
mean reduction in urinary sodium excretion from 153 to
70 mmol/day induced a significant fall in blood pressure
at 12 weeks, the fall in pressure being correlated with the
fall in urinary sodium excretion [ 1721.
COMMENTS
In interpreting the results of the experiments in which a
renal graft from a hypertensive-strain donor rat is placed
into a normotensive-strain recipient it is possible that the
outcome is determined by the state of the graft at the time
of the transplantation. It could be proposed that when the
kidney comes from a 10-20-week-old hypertensive
hypertensive-strain donor, the rise in pressure induced in
the normotensive-strain recipient is due to irreversible
occlusive hypertensive vascular lesions in the graft. When,
howevever, the hypertensive-strain graft comes from a
6-week-old normotensive rat, or a 20-week-old rat that
has had its blood pressure kept within normal limits until
the kidney is transplanted, the rise in arterial pressure in
the normotensive-strain recipient is unlikely to be due to.
acquired vascular changes. Admittedly at 6 weeks the
blood pressure in hereditary hypertensive strains of rats is
marginally higher than in the control strains. Nevertheless
it is improbable that any vascular changes induced by
such a small rise in pressure for so short a time would not
be reversed when the kidney after transplantation is
perfused at a normal pressure with normal blood in a
denervated environment. But more importantly, Wilson
& Byrom [173], who were the first to observe that in a
two-kidney one-clamp form of Goldblatt hypertension
the presence of hypertensive vascular lesions in the
undamped kidney could perpetuate the hypertension,
noted that such hypertensive vascular lesions had to be
very obvious on light microscopy. The light microscopy
appearance of a kidney obtained from a 7-week-old SHR
rat are not distinguishable from that of the kidney of a
WKY rat [174].
O n the other hand, interpretation of the experiments in
which a kidney from a normotensive-strain rat is transplanted into a hypertensive-strain rat depends on the age
of the recipient. Normotensive-strain kidneys, when
placed into adult hypertensive hypertensive-strain
recipents, induce a sustained fall in pressure and when
placed into young 5-6-week-old normotensive hypertensive-strain recipients prevent a rise in blood pressure.
Two disconcerting but logical conclusions emerge from
the cross-transplantation experiments in rats. The first is
that in hereditary strains of hypertension the rise in
arterial pressure stems from a genetic abnormality of the
kidney. It does not follow that the genetic fault which
leads to the functional hypertensinogenic renal
disturbance is only present in the kidney. There is much
evidence that in hereditary hypertension, in both rats and
man, there are generalized membrane abnormalities
[175-1771, including an increase in the density of padrenoceptors [178]. Nor does it follow that the same
genetic abnormality is responsible for all forms of
hereditary hypertension. The theoretical notion that
hereditary hypertension originates in the kidney has been
repeatedly proposed over the past 80 years. It originated
with Fahr in 19 19 [ 1791, was resurrected by Borst in 1940
[ 1801 and more recently reaffirmed for differing reasons
by Guyton et a/. [ 1811 and Bianchi et a/. [ 1821. It is in line
with the multiple demonstrations that most forms of
experimental hypertension are induced by interfering with
the kidney.
A second conclusion emerges from the cross-transplantation experiments. It is that genetic abnormalities in
vascular smooth muscle, the brain or sympathetic system
in hereditary forms of hypertension, d o not per se cause
hypertension, for the blood pressure of a hypertensivestrain rat does not rise in the presence of a normal kidney.
Conversely, an imposed surgical procedure on a kidney
can induce hypertension in an animal with no genetic
abnormalities of its vascular smooth muscle or nervous
system.
The observed arterial pressure changes after renal
transplantation in man are in keeping with the notion that
the initiating cause of essential hypertension resides in the
kidney, but they are not as impressive as in the hypertensive strains of rats. The finding, however, that in six
individuals suffering from long-standing severe essential
hypertension the blood pressure fell and remained normal
after a renal transplant forcefully supports the conclusion
that hereditary abnormalities associated with essential
hypertension which are situated outside the kidneys d o
not give rise to hypertension.
Identification of the functional limitation or abnormality in the kidney in hereditary hypertension, which causes
the blood pressure to rise, has to be distinguished from
renal abnormalities which are induced either by the
hypertension (e.g. changes in glomerular ultrafiltration
coefficient [ 183]), or by a tendency to volume expansion
(e.g. the accelerated natriuresis which can be induced by
rapid volume expansion), and by inbred abnormalities
which are not hypertensinogenic. When the ability of the
normal kidney to excrete sodium is stressed by increasing
the intake of sodium, it is self-evident that the principal
hypertensinogenic problem is the limited ability of the
kidney to excrete sodium. In acquired forms of hyper-
Kidney, salt intake and hypertension: part 11
tension the blood pressure rises when the intake of
sodium is normal, although it will rise to higher levels if
the intake is raised. That the experimental procedures or
the renal disease responsible for acquired hypertension
reduce the ability of the kidney to excrete sodium is inherent in the procedure or the disease, e.g. the effect of
DOCA and aldosterone, a fall in perfusion pressure and a
reduction in renal mass, is well documented. In the saltsensitive Dahl rat, the onset of hypertension is dependent
on the diminished capacity of the kidney to excrete
sodium and perhaps an abnormal cardiovascular
response to the ensuing increase in blood volume. In the
Milan hypertensive rat and SHR rat, the suggestion that
there is an impaired ability to excrete sodium is based on
the observation that as the blood pressure is rising there is
a transient fall in urinary sodium excretion associated
with a positive sodium balance, which persists thereafter
in the SHR rat. These changes are associated with a fall in
plasma renin activity which is transient in the Milw
hypertensive-strain rat but appears to be more prolonged
in the SHR rat. Moreover, experiments with micropuncture techniques and brush-border membrane vesicles in
both the Milan hypertensive rat and the SHR rat reveal
abnormalities compatible with there being an increased
sodium reabsorption by the proximal tubule of the intact
kidney. In man the close association between hypertension and salt intake, conhrmed by the Intersalt Study,
including the repeated finding that an intake of less than
60 mmol/day is not associated with a rise in blood pressure with age, the hypotensive effect of reducing salt
intake to patients with essential hypertension, the
impaired ability of a substantial proportion of patients to
excrete an acute sodium load, and the negative correlation
between the blood pressure and plasma renin activity,
suggests that in essential hypertension there is also an
impaired ability to excrete sodium.
The hypertensinogenic effect of stressing the capacity
of the normal kidney to excrete sodium by raising the
intake appears to be analogous to the hypertensinogenic
effect of a normal sodium intake on an impaired ability to
excrete sodium. How stressing or relaxing the demand on
the ability of the kidney to excrete sodium causes the
blood pressure to rise or fall is not clear. The disturbances
induced when the demand on the ability of the kidney to
excrete sodium is altered must stimulate volumecontrolled mechanisms. In acquired forms of hypertension, in spite of the imposed persistent restraint on the
ability of the kidney to excrete sodium (e.g. the continued
administration of DOCA, the loss of nephrons or the fall
in perfusion pressure), an initial fall in sodium excretion is
followed by a rise and the animal comes into sodium
balance. After such initial adjustments it is often difficult,
if not impossible, to detect any alteration in plasma
volume or extracellular fluid volume. It does not follow
that at such times volume-controlled mechanisms are not
persistently mobilized to restrain the persistent tendency
to volume expansion. It seems reasonable to propose that
a sustained restraint on sodium excretion stimulates a sustained activity of volume control systems in the hypothalamus which in turn cause the blood pressure to rise.
293
In both acquired [ 184-1901 and inherited [ 187-1921
hypertension in the rat the hypothalamus manifests
certain changes in catecholaminergic, and an increase in
cholinergic, activity which, although not identical in the
two forms of hypertension, appear to be responsible
for sympathetic and non-sympathetic hypertensive
mechanisms [ 193-1981. In both forms of hypertension the
intraventricular administration of 6-hydroxydopamine,
which destroys catecholaminergic neurons, prevents the
onset of hypertension but has no effect on established
hypertension [ 199-2021. The administration, by the same
route, of hemicholinium, which blocks the transfer of
choline across the neuron membrane and thus inhibits the
synthesis of acetylcholine, prevents the onset of
hypertension and also reversibly lowers the blood
pressure to normal when the hypertension is established
[203-2041. Hemicholinium has no effect on the blood
pressure of the normal rat [205]. It appears therefore that
the rise in blood pressure in both acquired and inherited
hypertension in animals stems from increased hypothalamic cholinergic activity both during and after the
initial increase in peripheral sympathetic activity.
How a sustained stimulation of hypothalamic volume
control centres might initiate a local disturbance in
cholinergic activity is a matter for conjecture. In both
acquired and inherited hypertension the plasma contains
increased quantities of digitalis-like substance/s, the
concentration of which also rises with an increase in salt
intake [2O6-2 121. There is evidence which suggests that
such a substance originates in the hypothalamus
[2 13-2 161 and that its concentration at this site rises with
an increase in sodium intake [212, 2161 and in acquired
and inherited hypertension [ 212, 2 171. It has been
proposed that the raised plasma concentration may
have a direct peripheral vasoconstrictive effect [2181
and that the raised hypothalamic concentration may have
a central hypertensinogenic effect [2161. Possibly therefore the rise in the concentration of a digitalis-like
substance in the plasma and hypothalamus, provoked by
an increased demand on the capacity of the kidney to
excrete sodium, may raise the blood pressure by a direct
peripheral effect and by interfering with neuronal
cholinergic metabolism in the hypothalamus.
It is not known how 'stressing' the capacity of the kidney
to excrete sodium is perceived. Lee et a!. [219] have
provided experimental evidence consistent with their
proposal that the afferent signal is a swelling of the tissues
surrounding the third ventricle. Friedman and co-workers
[220, 2211 have shown that a change in plasma sodium
induces parallel fall in intracellular sodium and blood
pressure, irrespective of associated changes in extracellular volume or plasma osmolality. Ackerman [222] and
Ackerman & Pearce [223] reported that with acute
volume expansion the afferent stimulus which controls the
increase in sodium excretion is more closely related to the
central venous pressure than to the intravascular volume
or the extravascular fluid volume, a proposal first put
forward by Gauer eta!. [224]. A dissociation between the
rise in exchangeable sodium and the blood pressure in F,
hybrids of SHR/WKY rats has been claimed to provide
294
H. E. d e Wardener
evidence against a causal relationship between salt retention and hypertension in the SHR rat [65]. In the light of
the close causal relation between salt intake and hypertension in non-genetic forms of hypertension and the
apparent lack of relation between the extracellular fluid
and volume control mechanisms, it is probably incorrect
t o assume that the hypertensinogenic stimulus associated
with an impaired ability to excrete sodium is an increase
in extracellular fluid volume.
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