193
Clinical Science ( 1990) 79, 193-200
Editorial Review
The primary role of the kidney and salt intake in the aetiology
of essential hypertension: part I
H. E.DE WARDENER
Research Laboratories, Charing Cross and Westminster Medical School, London
INTRODUCTION
In 1967 Page put forward an hypothesis entitled “The
mosaic theory of arterial hypertension” [ 11. He had long
held the view that “even the simplest hypertension is a
mosaic in which many mechanisms are to a greater or
lesser extent involved” [2] and he came to the conclusion
that “in any closed system in equilibrium, such as depicted
by the hypertensive mosaic, there is no need for a single
triggering mechanism. Any one of its many regulatory
facets, or degrees of freedom as Willard Gibbs called
them, or more likely several of them, act in concert to
alter equilibria which in turn alter the blood pressure ...”
[3].Lack of a perceived need is not a compelling reason to
exclude a potential phenomenon; neveriheless, the mosaic
theory continues to attract much intuitive support such as
Laraghs [4] that “... my everyday experience in observing
and treating patients with high blood pressure has made it
strongly apparent to me that cases of so-called hypertension are not all alike”, or Frolichs [2] that “.... multifactorial problems must have multifactorial answers”. But
or from
patients suffering from hypothyroidism
meningococcal septicaemia are not all alike, and why
should one triggering abnormality not lead to multiple
abnormalities? The mosaic theory has encouraged work
on the many mechanisms which control the normal blood
pressure, but it has inevitably tended to stifle the exploration of a possible triggering mechanism for essential
hypertension.
The following account reviews briefly a body of data
which substantiates a particular aspect of an hypothesis
first put forward in 1980 [ 5 ] .It is proposed that in most
forms of hypertension, including essential hypertension,
there is one common initiating factor, the presence of an
Correspondence: Professor H. E. de Wardener, Research
Laboratories, Charing Cross and Westminster Medical School,
Fulham Palace Road, London W6 8RE
abnormal kidney, the functional hypertensinogenic
expression of which is a diminished ability to excrete
sodium. In essential hypertension and hereditary forms of
hypertension in the rat the abnormal kidney is inherited
whereas in the other forms of hypertension a normal
kidney becomes hypertensinogenic through disease or
some imposed experimental manoeuvre. Most of the
findings described here have come to light since this
concept was first advanced.
THE RENAL ORIGIN OF HYPERTENSION
Acquired hypertension
In most models of acquired hypertension it is selfevident that the kidney initiates the hypertensive process.
Most forms of experimental hypertension either involve
some surgical interference to the kidney or its vascular
supply, or the administration of agents, the hypertensinogenic activity of which are entirely related to their effect
on the kidney. In man the association of renal failure and
hypertension is well documented.
Hereditary hypertension
The evidence that in hereditary hypertension the initial
hypertensive trigger resides in the kidney has been
obtained by renal transplantation.
Rats. Cross-transplantation experiments have been
performed between hypertensive-strain rats and their
normotensive controls, the recipients having been
bilaterally nephrectomized. The results demonstrate that
the blood pressure of the recipient follows that of the
donor. Variations on this experiment, which were first
performed in 1966 [6], have been carried out by five
different groups in four different strains of hypertensive
rats.
194
H. E. de Wardener
Dahl rats are exposed to a diet containing 8% (w/v)salt
(equivalent to about 700 mmol/day for a 70 kg man). One
strain develops hypertension and is referred to as saltsensitive; the other, the salt-resistant strain, remains
normotensive. Two groups performed cross-transplantation experiments on bilaterally nephrectomized Dahl saltsensitive and salt-resistant strains of young rats
6-8-weeks-old [ 7, 8,9]. Because some Dahl salt-sensitivestrain rats may develop a rise in blood pressure, even
when salt intake is less than Soh, many of the experiments
were performed on Dahl strain animals given foods containing a normal content of salt (0.3-0.5%). When the
recipient and the donor of the renal graft came from the
same strain the arterial pressure of a recipient on a normal
salt intake was unaffected, but when they came from different strains the blood pressure of the recipient was
altered. Thus a salt-resistant rat on a normal intake of
sodium given a kidney from a salt-sensitive-strain rat
developed hypertension, and a salt-sensitive recipient on
the same salt intake given a kidney from a salt-resistant
donor did not develop hypertension. Dahl’s group also
demonstrated that kidneys from 8-9-week-old normotensive salt-resistant-strain rats, when transplanted into
adult hypertensive salt-sensitive-strain rats on a normal
sodium intake [lo],induced a profound fall in blood pressure. Conversely, when a kidney from an 8-9-week-old
salt-sensitive-strain rat, which had been hypertensive for
about 3 weeks, was transplanted into a normotensive saltresistant-strain rat, there was a sustained rise in blood
pressure.
In another set of experiments, which were also
performed in bilaterally nephrectomized animals, the diet
of the recipient was switched to the high sodium intake
(So/, salt) 4 weeks after the cross-transplantation procedure [8, 91. The high sodium diet increased the blood
pressure considerably in all the rats that received a graft,
including the salt-sensitive-strain rat that had received a
kidney from a salt-resistant-strain rat. This suggested that
a single kidney from a salt-resistant rat did not have the
capacity to easily excrete the sodium contained in an 8”/0
sodium diet. Nevertheless, in other experiments it was
observed that a uninephrectomized salt-resistant rat
which had not received a graft remained normotensive on
a high salt intake and that a salt-resistant-strain rat on a
high salt intake which received a kidney from another
salt-resistant-strain rat did not develop hypertension [9].
Thus the salt-resistant-strain donor kidney’s capacity to
control the blood pressure depends in part on the host
into which it is placed. Possibly extrarenal natriuretic
mechanisms are less developed in the salt-sensitive-strain
rat than in the salt-resistant-strain rat. In addition, Greene
et al. [ l l ] , in acute experiments, have observed that a
sudden striking increase in salt intake from 1 to 20 mmol/
day was associated, in the first 96 h, with the same rise in
body weight and blood volume in the two strains of rats.
But although there was a substantial increase in blood
pressure in the salt-sensitive-strain rat the blood pressure
of the salt-resistant-strain rat fell slightly, demonstrating
that under these conditions the salt-sensitive rat has an
accelerated hypertensive response to volume expansion.
Bianchi et al. [ 121 performed cross-transplantation
experiments in Milan hypertensive and normotensive
strains of rats. When kidneys from 6-week-old normotensive hypertensive-strain rats, were transplanted into
bilaterally nephrectomized normotensive-strain rats, the
normotensive-strain rats developed hypertension. On the
other hand, kidneys from 5-week-old normotensive-strain
rats, transplanted into normotensive bilaterally nephrectomized rats, did not cause a rise in blood pressure. In a
second set of experiments kidneys obtained from adult
( 15-week-old) normotensive-strain rats transplanted into
adult bilaterally nephrectomized hypertensive hypertensive-strain rats induced a sustained fall in arterial
pressure [ 131. And after an initial transient fall, the blood
pressure of adult bilaterally nephrectomized hypertensive-strain rats remained raised after receiving a renal
graft from 15-week-old hypertensive strain rats.
Kawabe et al. [ 141 cross-transplanted kidneys from
either 10- or 20-week-old spontaneously hypertensive
(SHR) rats or from normotensive control (Wistar-Kyoto,
WKY ) rats into F, hybrids of the two strains. The modest
hypertension of the F, hybrid fell to normal whether it
received either an F, kidney from another F, animal or a
kidney from a normotensive strain rat. Thus the antihypertensive action of a kidney from a normotensive
animal, which was demonstrated unequivocally when
transplanted into Dahl and Milan hypertensive hypertensive-strains was not distinguishable in an SHR F,
hybrid from the effect of transplantation itself, possibly
because the pre-operative arterial pressure of the hybrid
was only 130 mmHg. A kidney from a 10- or 20-week
SHR rat transplanted into an F, hybrid, however, did
cause a rise in blood pressure, a finding recently
confirmed by Rettig et a/. [ 151 in the stroke-prone SHR
(SPSHR) rat and the normotensive WKY control rat.
Thus kidneys from 20-week-old SPSHR rats (blood
pressure approximately 186 mmHg) transplanted into F,
hybrids (blood pressure approximately 136 mmHg)
caused an increasing rise in blood pressure to 239 mmHg
8 weeks later. There was no significant change in blood
pressure in F, hybrid recipients of WKY rat kidneys.
More importantly, Rettig et al. [ 161 have since found that
the blood pressure of a 20-week-old bilaterally nephrectomized F, SHR/WKY hybrid recipient will rise even if
the transplanted kidney is obtained from a 20-week-old
SHR rat that has had its blood pressure kept within
normal limits from the age of 4 weeks with a converting
enzyme inhibitor. In these experiments the blood pressure
rise, after cross-transplantation, plateaued at approximately 180 mmHg. Kidneys from WKY rats did not
induce hypertension.
Man. The nearest equivalent to the cross-transplantation experiments in animals is the relationship of the
recipient’s blood pressure, after renal transplantation, to
the blood pressure of the donor or the donor’s parents
[ 17-20]. Collectively, the results are consistent with the
notion that it is the kidney which initiates the rise in blood
pressure in essential hypertension.
Standgaard & Hansen (201 compared the incidence of
hypertension in recipients of kidneys from donors dying
Kidney, salt intake and hypertension: part 1
either from subarachnoid haemorrhage or from head
injury and cerebral tumours. The weight of the heart of
the donors who had died of subarachnoid haemorrhage
was significantly greater than that of the other donors, a
difference attributed to the probable presence of preexisting hypertension. After a 6 year follow-up, the blood
pressure of the recipients was analysed by one of the
authors who was unaware of the findings of the postmortems carried out on the donors. There were 23
recipients with normal or near-normal graft function.
Twelve patients who had received kidneys from donors
dying of subarachnoid haemorrhages had consistently
higher systolic blood pressures ( P< 0.004) and needed
more anti-hypertensive treatment ( P < 0.0004) than the
11 recipients of kidneys from donors who had died from
head injury or cerebral tumour
Guidi et al. [ 191 reported the results of a 2 year retrospective study in 50 selected patients who were the
recipients of cadaver kidneys. One of the criteria for
selection was that the blood pressure of both the parents
of the donor and both the parents of the recipient should
have been measured by the investigators. Recipients from
normotensive families who received a kidney from a
donor from a hypertensive family needed significantly
more antihypertensive therapy (at 1 year P <0.05, and at
2 years P< 0.01) than those who received a kidney from a
normotensive family. N o difference was apparent when
the recipients came from hypertensive families.
In a complementary study, Curtis et al. [21] reported
that the blood pressure of six hypertensive black patients
with terminal renal failure due to severe essential hypertension, fell to normal and remained normal without the
need of antihypertensive treatment after receiving a
kidney from young normotensive donors (two living
related and four cadaveric). The average follow-up was
4.5 years (range 1.3-8.0 years). The recipient’s own
kidneys were removed before the transplantation. All six
patients had been observed to have hypertension before
the onset of renal failure, with only mild proteinuria, and
each patient had a family history of hypertension. The
light microscopy appearances of the kidneys removed at
operation did not reveal evidence of any renal disease
other than nephrosclerosis. This was confirmed by an
electron microscopy examination of three glomeruli from
each patient.
OBSERVATIONS WHICH SUGGEST THAT THE
RENAL ABNORMALITY WHICH CAUSES THE
BLOOD PRESSURE TO RISE IN ACQUIRED AND
INHERITED HYPERTENSION IS A DIMINISHED
CAPACITY TO EXCRETE SODIUM
Acquired hypertension
In most forms of experimental hypertension the rise in
arterial pressure is either dependent on, or its severity
strongly influenced by, the intake of sodium. In the GoldMatt form of hypertension, in which one renal artery is
partially stenosed with a clip, the prolonged and sustained
rise in arterial pressure which ensues is not due to the
195
initial transient rise in plasma renin, or renal afferent
nerve stimulation, but to the acquired persistent difficulty
in excreting sodium [22-241 which is inherent in having
lowered the perfusion pressure to the kidney [25, 261.
When deoxycorticosterone acetate (DOCA)is used as an
hypertensive agent, it is always administered with a high
salt intake, and usually accompanied by a unilateral
nephrectomy, presumably to accentuate the salt-retaining
effects of DOCA. That DOCA per se is not hypertensinogenic has repeatedly been demonstrated [27-3 11.
In the reduced renal mass rat (80% of the total renal mass
is removed) the presence of hypertension is determined
by the intake of sodium [32]. Similarly, the hypertension
provoked in a normal baboon by a high salt intake is more
severe after uninephrectomy [33].A high sodium intake in
man causes a rise in blood pressure in chronic renal
disease, during maintenance haemodialysis and after renal
transplantation.
Hereditary hypertension
Dahl salt-sensitive and salt-resistant rat. That the
kidney of the salt-sensitive strain has less capacity to
excrete the massive intake of sodium than the saltresistant strain has been demonstrated both in whole
animals and in isolated kidney preparations. Whole-anima1 studies were performed in groups of normotensive
conscious salt-sensitive and salt-resistant rats on a restricted sodium intake. After an acute infusion of saline the
rise in urinary sodium excretion and glomerular filtration
rate in the salt-resistant strain was greater than in the saltsensitive strain [34]. Changes in blood pressure and
volume expansion were the same in both groups. Fractional excretion of lithium was also greater in the saltresistant strain, suggesting that the lower capacity for
sodium excretion of the salt-sensitive rats may be partially
due to the volume expansion having induced a less pronounced fall in sodium reabsorption in the proximal
tubule of the salt-sensitive rat.
Three isolated kidney studies have been performed
[35-371. In all three the kidneys were obtained from saltsensitive and salt-resistant rats which had been fed a low
sodium diet for 8-14 weeks after weaning. In all three
studies the blood pressure in the salt-sensitive and saltresistant rats was therefore normal, although the arterial
pressure of the salt-sensitive rats was significantly greater
than that of the salt-resistant rats. In the first series the
isolated kidneys were connected to the circulation of
normal rats and were thus perfused with normal rat blood
[ 3 5 ] .Kidneys from salt-sensitive rats required a higher
perfusion pressure than kidneys from salt-resistant rats to
excrete an equivalent amount of sodium. In the other two
isolated kidney studies the kidney was perfused with
specially prepared media [36, 371. In both, bovine serum
albumin was used. One study again demonstrated that
kidneys from salt-sensitive rats required higher perfusion
pressures to excrete sodium, whereas the other did not.
The difference between the two studies may be attributable to the albumin in the first study having been dialysed
before use. which would remove vasodilatory substances.
196
H. E. de Wardener
In line with the findings on the isolated kidney that
suggest that the kidney of the salt-sensitive rat has an
inferior ability to excrete sodium, the plasma renin activity of the salt-sensitive rat is low [38] and its plasma
volume is raised [38]. The extracellular fluid volume,
however, is not raised [39].
In some Dahl salt-sensitive-strain rats the hypertension
is self-sustaining in that hypertension persists when the
high sodium intake is withdrawn [40]. The age at which
the high sodium chloride diet is begun influences the
outcome. If it is started at weaning, fulminating hypertension occurs with a high mortality [41].
In view of the observation by Meneely et al. [42] that
normal stock rats exposed to an 8% sodium intake for 1
year all eventually develop hypertension, the uniform
normality of the arterial pressure of the Dahl salt-resistant
rats on an 8% sodium intake suggests that resistant rats
have a supra-normal capacity to excrete sodium. This
conclusion is supported by the report by Tobian et al. [35]
that the urinary sodium excretion of isolated kidneys of
sodium-resistant rats perfused at 130 mmHg was
approximately twice that of kidneys from either normal
rats or WKY rats.
Milan hypertensive rat. The rise in blood pressure to
hypertensive levels in this strain develops during the
second, third and fourth week after weaning (at 24 days),
at which time a slight, but statistically significant, retention
of sodium occurs associated with a transient fall in urinary
fractional excretion of sodium. Although this is
accompanied by an increased faecal content of sodium,
which compensates in part for the lower urinary sodium
excretion, an average of about 2.5 mmol more sodium is
retained. Plasma renin activity in the Milan hypertensive
strain rat at weaning is significantly lower and remains less
until the third week after weaning when the plasma renin
activity of the normotensive control falls to the same level
as that of the hypertensive rat [43].Exchangeable sodium
has only been measured at 24 days and at 18 weeks of
age, at which times the results in the hypertensive rats
were not significantly different from those in the normotensive rats [43].
Gloinerular filtration rate, single nephron filtration rate
and renal interstitial pressure in the kidneys of 26-30day-old pre-hypertensive rats are higher than in the
normotensive controls [44], and at this age no tubular
glomerular feedback activity could be detected [44]. It
was suggested that these findings and the low plasma
renin activity mentioned earlier were compatible with the
pre-hypertensive Milan hypertensive rat being in a state of
'slight volume expansion'. From 35 to 49 days when the
blood pressure was rising however, glomerular filtration
rate and single-nephron filtration rate, instead of rising
normally with age, fell substantially, whereas interstitial
pressure returned to normal. The tubuloglomerular feedback mechanism now became extremely active and
remained active in the face of an intravenous infusion of
saline [44].
Perfused isolated kidney studies have only been
performed with cell-free albumin solution [45] and not
whole blood. In kidneys obtained from 4-week-old hyper-
tensive-strain rats the pressure/natriuresis curve was no
different from that of the kidney of control normotensive
rats. In kidneys removed from 10-week-old hypertensive
rats the pressure/natriuresis curve was shifted slightly, but
significantly, to the right.
Finally, Parenti et al. [46] and Hanozet et al. [47] have
found that proximal tubule brush-border membrane
vesicles of pre-hypertensive rats ( 4 weeks old) have a
higher sodium uptake than vesicles from normotensive
controls, whereas a number of other vesicle functions are
the same.
SHR rat. The kidney of the SHR rat demonstrates
several differences from that of the WKY rat which are
consistent with there being a restraint on its ability to
excrete sodium. These observations have to be
interpreted with some care in that although SHR rat
stocks from various sources appear to be biologically
identical, DNA fingerprinting has revealed genetic
heterogeneity between different WKY rat stocks [48].
Multiple confirmation of experimental findings is
therefore more important than usual.
The effect of sudden changes in arterial pressure
(within the autoregulatory range 100- 160 mmHg) on
urinary sodium excretion of kidneys in situ of 3-5-weekold SHR and WKY rats has been studied by Roman [49].
The blood pressure of the SHR rats was Y8f5 mmHg
and that of the WKY rats was 8 1 f 6 mmHg. Differences
in neural and endocrine background were minimized by
renal denervation and by maintaining plasma vasopressin,
aldosterone, corticosterone and noradrenaline constant
with intravenous infusions. At 3-5 weeks of age the slope
of the relationship between sodium excretion and renal
perfusion pressure was the same in SHR rat and WKY rat
kidneys, but the slope of the SHR rat kidney was significantly shifted to the right (by about 15 mmHg), i.e. a
greater pressure was needed to excrete the same amount
of sodium. The renal blood flow and glomerular filtration
rate of the SHR rat and WKY rat kidneys were not significantly different. In contrast, the perfusion pressure/
urinary sodium excretion relationship in an isolated
kidney, obtained from 17-week-old SHR rats, when
perfused in vitro with blood from a normal rat was no
different from that of kidneys obtained from WKY rats
[50]. In another study isolated kidneys from SHR and
WKY rats of various ages were perfused with cell-free
albumin solution [511. At 4 weeks the pressure/natriuresis
curve in the SHR rat kidney was shifted significantly to
the left (sic)of the WKY rat kidney, whereas at 30 weeks
it was shifted substantially to the right.
With the exception of one strain [52], raising the intake
of sodium of the SHR rat, particularly when it is young,
raises the blood pressure [53-561. Lowering the intake
has little effect on the blood pressure [57] until the intake
falls below that necessary for normal growth (22 pmol/g)
[58, 591, and at an intake of 9 pmol/g the blood pressure
of SHR and WKY rats was not significantly different [59].
With lower intakes ( 5 pmol/g [60] and 1.5 pmol/g [61]),
however, the blood pressure of the SHR rat, although
lower than on a normal sodium intake, was substantially
greater than that of the WKY rat. This phenomenon is
Kidney, salt intake and hypertension: part I
similar to the hypertensive response which occurs i n
normal rats on exceptionally low sodium intakes [62].
The finding that arachidonic acid-induced thromboxane release from isolated perfused kidneys from 6-weekold SHR rats is much greater than from WKY rat kidneys,
is perhaps another intrinsic renal abnormality [63]. This
phenomenon does not occur in kidneys obtained from
hypertensive DOCA-salt-uninephrectomized rats. The
increased tendency to release thromboxane is no longer
detectable at 18 weeks. It has been suggested that this
phenomenon may be related to the transient reduction in
renal blood flow and glomerular filtration rate in the
6-week-old rat.
Studies of sodium excretion during the development of
hypertension have been performed by three groups
[64-661. In two [64, 661 in which SHR rats were
compared with control WKY rats, the sodium excretion
of the SHR rats was significantly less than that of the
WKY rats between the fourth and sixth weeks of age
when the blood pressure was rising. In one study (641 the
fraction excreted in the urine of the SHR rat, as a proportion of the amount ingested, was less than that of the
WKY rat. As there was no difference in faecal sodium
excretion measured over a 3 week period, there was thus
a positive sodium balance. Faecal sodium was not
mentioned in the second study [66], in which after 8
weeks the urinary excretion of sodium rose and was no
longer different from that of the WKY rats. In the third
study, a sodium balance determination was performed
during the seventh week and SHR rats were compared
with ordinary Wistar rats 1651. In agreement with the first
two studies, urinary sodium excretion (as a percentage of
intake) in the SHR rat was significantly less than in the
Wistar rats. However, faecal sodium excretion in the SHR
rat was significantly greater, suggesting that sodium
balance had not been disturbed. It is unfortunate that this
third group of investigators did not use WKY rats for
their control studies and that the faecal collection
measurement covered only a period of 1 week. The
transient fall in urinary sodium excretion which occurred
as the blood pressure was rising in these three studies in
the SHR rat is similar to what occurs in the Milan hypertensive-strain rat.
Using 12-day-old SHR and WKY rats, Mullins [67]
found that the extracellular fluid volume (NaZ3%O,space)
of the SHR rat was significantly larger than that of the
WKY rat, whereas the plasma volumes were not different.
Harrap [68] also reported that the SHR rat has a consistently higher exchangeable sodium level than the WKY
rat, with a period of relative sodium retention during the
development phase of hypertension. Leehen et al. [69]
found that plasma volume increased at 4 weeks but subsequently it became lower than normal; changes in blood
volume demonstrated a similar pattern, returning to
control levels at 12 and 16 weeks. Sodium space was
slightly increased at 6 weeks but this was no longer
detectable at 8 and 16 weeks.
In contrast to the multiple evidence indicating a
tendency to volume expansion, there are the findings from
workers in Sweden [70] that the plasma volume of the
197
SHR rat is slightly less than that of normal Wistar rats
throughout the phase or rapid increase in blood pressure
(the third to the tenth week) with no difference in extracellular fluid volume.
Micropuncture studies have revealed certain
differences at 6 weeks which at 14- 16 weeks are either no
longer present or less pronounced 1711. At 6 weeks, the
renal blood flow, whole glomerular filtration rate and
single-nephron filtration rate in the SHR rat were
25-30% lower than in the WKY rat. A tendency for a
higher proximal tubular fractional reabsorption in the
SHR rat was not significant, yet due to the low singlenephron glomerular filtration rate less fluid was delivered
from the proximal tubule into the distal tubule. At 12-16
weeks, however, the single-nephron glomerular filtration
rate was either the same in the two strains or reduced in
the SHR rat by only 11% [71-731. In rats aged 12-15
weeks undergoing an infusion of saline (3% and 0.9%
NaCI), the single-nephron glomerular filtration rate of the
SHR and WKY rats was the same, but the urinary sodium
excretion of the SHR rat was significantly less than that of
the WKY rat [73, 741. In one set of experiments the
recovery rate in the urine of ZZNainjected into the
proximal tubule of the SHR rat kidney was less than when
injected into the proximal tubule of the WKY rat kidney
[74]. Thus during a saline infusion the amount of sodium
reabsorbed by the proximal tubule of the SHR rat kidney
was greater than that reabsorbed by the proximal tubule of
the WKY rat kidney. Recovery rate of 22Nainjected into
the distal tubule was the same in the SHR and WKY rats.
These micropuncture studies demonstrate a number of
abnormalities which would restrain sodium excretion.
They are supported by three additional findings which are
consistent with an increased sodium reabsorption by the
proximal tubule: (a) brush-border membrane vesicles
from 6-week-old SHR rats have an intrinsic derangement
of sodium transport characterized by an increased
Na+-H+ antiport activity [75], (b) microdissected
proximal tubules have an increased Na -K -adenosine
triphosphatase activity [76], and (c) isolated SHR rat
kidneys from 6-10 month old animals, when perfused
with artificial media containing albumin, have a reduced
fractional lithium excretion, glomerular filtration rate,
urinary sodium excretion and fractional sodium excretion
i771.
In keeping with these findings which overall intimate
that the kidney of SHR rats has a difficulty excreting
sodium, there is some evidence which suggests that there
is an accompanying low plasma renin activity and low
plasma aldosterone level. In about half the numerous
reports plasma renin activity of SHR rats up to 15 weeks
of age has been found to be significantly lower [78-831
than in control normotensive animals, whereas in the
other reports it has not been significantly different
[84-891. Low plasma renin activity appears to be more
frequent when blood is obtained by decapitation or under
light ether anaesthesia rather than when it is sampled from
a conscious restrained animal via a previously inserted
indwelling catheter or by cutting the tip of the tail. This
suggests that the higher (normal) plasma renin activity
+
+
198
H. E. d e Wardener
levels may be due to increased sympathetic and
behavioural response to environmental stress of the SHR
rat. The conclusion that the true plasma renin activity in
the SHR rat is low is supported by the following
additional observations: (a) basal renin release from
kidney slices obtained from SHR rats is less than from
slices obtained from WKY rats [82], (b) the isolated
perfused SHR rat kidney releases significantly less renin
at all levels of perfusion pressure [50], and (c) plasma
renin levels fail to rise after volume contraction [80].
Plasma and urinary aldosterone levels in SHR rats aged 7
and 16 weeks respectively are low [78,81].
This Review will be concluded in the next issue of Clinical
Science.
REFERENCES
1. Page, I.H. The mosaic theory of arterial hypertension - its
interpretation. Perspect. Biol. Med. 1967; 10,325-33.
2. Frolich, E.D. The first lrvine H. Page Lecture. The mosaic
of hypertension: past, present and future. J. Hypertens.
1988; 6 (SUPPI.4), S2- 1 1 .
3. Page, I.H. Hypertension mechanisms. Orlando, FL: Grune
andstratton, 1987: 910-16.
4. Laragh, J.H. Personal views on the mechanisms of hypertension. In: Genest, J., Kuchel, O., Hamet, P. & Cantin, M.,
eds. Hypertension. New York: McGraw Hill Book
Company, 1983: 6 15-3 I .
5. de Wardener, H.E. & MacGregor, G.A. Dahl’s hypothesis
that a saluretic substance may be responsible for a sustained
rise in arterial pressure. Its possible role in essential hypertension. Kidney Int. 1980; 18, 1-9.
6. Tobian, L., Coffee, K., McCrea, P. & Dahl, L. A comparison
of the antihypertensive potency of kidneys from one strain
of rats susceptible to salt hypertension and kidneys from
another strain resistant to it. J. Clin. Invest. 1966; 45, 1080.
7. Dahl, L.K., Heine, M. & Thompson, K. Genetic influence of
renal homografts on the blood pressure of rats from
different strains (36566). Proc. SOC.Biol. Med. 1972; 140,
852-6.
8. Dahl, L.K., Heine, M. & Thompson, K. Genetic influence of
the kidneys on blood pressure. Circ. Res. 1974; 34, 94- 1 0 1 .
9 Morgan, D.A., DiBona, G.F. & Mark, A.L. Effects of interstrain renal transplantation on NaC1-induced hypertension
in Dahl rats. Hypertension 1990; 15,436-42.
10. Dahl, L.K. & Heine, M. Primary role of renal homografts in
setting chronic blood pressure levels in rats. Circ. Res.
1975; 36,692-6.
1 1 . Greene, A.S., Yuan Yu, Z., Roman, R.J. & Cowley, A.W.
Role of blood volume expansion in Dahl rat model of hypertension. Am. J. Physiol. 1990; 258, H508-14.
12. Bianchi, G., Fox, U., Di Francesco, G.F., Bardi, U. & Radice,
M. The hypertensive role of the kidney in spontaneously
hypertensive rats. Clin. Sci. 1973; 45, 135s-9s.
13. Bianchi, G., Fox, U., Di Francesco, G.F., Giovanetti, A.M. &
Pagetti, D. Blood pressure changes produced by kidney
cross-transplantation between spontaneously hypertensive
rats and normotensive rats. Clin. Sci. 1974; 47,435-48.
14. Kawabe, K., Watanabe, T.X., Shionos, K. & Sokabe, H.
Influence on blood pressure of renal isografts between
spontaneously hypertensive and normotensive rats, utilizing
the F, hybrids. Jpn. Heart J. 1979; 20,886-94.
15 Rettig, R., Stauss, H., Folberth, C., Ganten, D., Waldherr, R.
& Unger, T. Hypertension transmitted by kidneys from
stroke-prone spontaneously hypertensive rats. Am. J.
Physiol. 1989; 257, F197-203.
16. Rettig, R., Folberth, C., Stauss, H., Kopf, D., Waldherr, R. &
Unger, T. Role of the kidney in primary hyptertension. A
renal transplantation study in rats. Am. J. Physiol. 1990;
258, F606- 1 1.
17. Merino, G.E., Kjellstrand, C.M., Simmons, R.L. & Najarian,
J.S. Late hypertension in renal transplant recipients:
possible role of the donor in late primary hypertension.
Proc. Dialysis Trans. Forum 1976; 6, 145-53.
18. Guidi, E., Bianchi, G., Dallosta, V. et al. Influence of familial
hypertension of the donor on the blood pressure and antihypertensive therapy of kidney graft recipients. Nephron
1982; 30,318-23.
19. Guidi, E., Bianchi, G., Rivolta, E. et al. Hypertension in man
with a kidney transplant: role of familial versus other
factors. Nephron 1985; 41, 14-21.
20. Strandgaard, S. & Hansen, U. Hypertension in renal
allograft recipients may be conveyed by cadaveric kidneys
from donors with subarachnoid haemorrhage. Br. Med. J.
1986; 292,104 1-4.
21. Curtis, J.J., Luke, R.G., Dustan, H.P. et al. Remission of
essential hypertension after renal transplantation. N. Engl. J.
Med. 1983;309,1009-15.
22. MacDonald, G.J., Boyd, G.W. & Peart, W.S. Effect of the
angiotensin I1 blocker 1-Sar-8-Ala-angiotensin I1 on renal
artery clip hypertension in the rat. Circ. Res. 1975; 37,
640-6.
23. Gavras, H., Brunner, H.R., Vaughan, E.D. & Laragh, J.H.
Angiotensin-sodium
interaction in blood pressure
maintenance of renal hypertension and normotensive rats.
Science 1973; 180, 1369-71.
24. Ploth, D.W. Angiotensin-dependent renal mechanisms in
two kidney one clip renal vascular hypertension. Am. J.
Physiol. 1983; 245, F131-41.
25. Selkurt, E.E., Effect of pulse pressure and mean arterial
pressure modification on renal haemodynamics and electrolyte and water excretion. Circulation 195 1; 4, 541-5 1 .
26. McDonald, S.J. & de Wardener, H.E. The relationship
between the renal arterial perfusion pressure and the
increase in sodium excretion which occurs during an
infusion of saline. Nephron 1965; 2, 1 - 14.
27. de Champlain, J., Krakoff. L.R. & Axelrod, J. Relationship
between sodium intake and norepinephrine storage during
the development of experimental hypertension. Circ. Res.
1968; 23,479-91.
28. Nakamura, K., Gerold, M. & Thoenen, H. Experimental
hypertension of the rat: reciprocal changes of norepinephrine turnover in heart and brainstem. NaunynSchmiedebergs Arch. Pharmakol. 1971; 268, 125-39.
29. Reid, J.L., Zivin, J.A. & Kopin, I.J. Central and peripheral
adrenergic mechanisms in the development of deoxycorticosterone-saline hypertension in rats. Circ. Res. 1975; 37,
569-79.
30. Berecek, K.H., Murray, R.D. & Gross, F. Significance of
sodium, sympathetic innervation and central adrenergic
strictures on renal vascular responsiveness in DOCAtreated animals. Circ. Res. 1980; 47,675-83.
31. Bruner. C.A., Mangiapane, M.L., Fink, G.D. & Clinton
Webb, R. Area postrema ablation and vascular reactivity in
deoxycorticosterone-salt-treated rats. Hypertension 1 988;
11,668-73.
32. Huot, S.J., Pamnani, M.B., Clough, D.L. et al.
Sodium-potassium pump activity in reduced renal mass
hypertension. Hypertension 1983; 5 (Suppl. I), 194- 100
33. Cherchovich, G.M., Capek, K., Jefremova, Z . , Pohlova, I. &
Jelinek, J. High salt intake and blood pressure in lower
primates (Papio hamadryas). J. Appl. Physiol. 1976; 40,
601 -4.
34. Ross, J.C., Kirchner, K.A., Abernethy, J.D. & Langford,
H.G. Differential effect of salt loading on sodium and
lithum excretion in Dahl salt-resistant and -sensitive rats.
Hypertension 1984; 6,420-4.
35. Tobian, L., Lange, J., Azar, S . et al. Reduction of natriuretic
capacity and renin release in isolated, blood-perfused
kidneys of Dahl hypertensive-prone rats. Circ. Res. 1978;
4 3 ( S ~ p p lI),
. 192-98.
36. Maude, D.L. & Kao-Lo, G. Salt excretion and vascular
resistance of perfused kidneys of Dahl rats. Hypertension
1982; 4,532-7.
Kidney, salt intake and hypertension: part I
37. Girardin, E., Caverzasio, J., Iwai, J., Bonjour, J.-P., Muller;.
A. & Grandchamp. A. Pressure natriuresis in isolated
kidneys from hypertension-prone and hypertensionresistant rats (Dahl rats). Kidney Int. 1980; 18, 10-9.
38. Iwai, J., Dahl, L.K. & Knudsen, K.D. Genetic influence on
the renin angiotensin system. Circ. Res. 1973; 32,678-84.
39. Genain, C.P., Reddy, S.R., Ott, C.E., Van Loon, G.R. &
Kotchen, T.A. Failure of salt loading to inhibit tissue
norepinephrine turnover in pre-hypertensive Dahl saltsensitive rats. Hypertension 1988; 12,568-73.
40. Dahl, L.K. Effects of chronic excess salt feeding. Induction
of self-sustaining hypertension in rats. J. Exp. Med. 196 1;
114,231-6.
41. Dahl, L.K., Knudsen, K.D., Heine, M.A. & Leitl, G.J.
Effects of chronic excess salt ingestion. Modification of
experimental hypertension in the rat by variations in the
diet. Circ. Res. 1968; 22, 11-8.
42. Meneely, G.R., Tucker, R.G., Darby, W.J. & Auerbach, S.H.
Chronic sodium chloride toxicity: hypertension, renal and
vascular lesions. Ann. Int. Med. 1953; 39,991-8.
43. Bianchi, G., Baer, P.G., Fox, U., Duzzi, L., Pagebti, D. &
Giovannetti, A.M. Changes in renin, water balance and
sodium balance during development of high blood pressure
in genetically hypertensive rats. Circ. Res. 1975; 1 6 & 37
(SUPPI.I), 1153-161.
44. Boberg, U. & Person, E.G. Increased tubuloglomerular
feedback activity in Milan hypertensive rats. Am. J. Physiol.
1986; 250, F967-74.
45. Salvati, P., Pinciroli, G.P. & Bianchi, G. Renal function of
isolated perfused kidneys from hypertensive (MHS) and
normotensive (MNS) rats of the Milan strain at different
ages. J. Hypertens. 1984; 2 (Suppl. 3), 35 1-3.
46. Parenti, P., Hanozet, G.M. & Bianchi, G. Sodium and
glucose transport across renal brush border membranes of
Milan hypertensive rats. Hypertension 1986; 8,932-9.
47. Hanozet, G.M., Parenti, P. & Salvati, P. Preseqce of a
potential-sensitive Na transport across renal brush-border
membrane vesicles from rats of the Milan hypertensive
strain. Biochim. Biophys. Acta 1985; 819, 179-86.
48. Samani, N.J., Swales, J.D., Jeffries, A.J. et al. DNA finger
printing of spontaneously hypertensive and Wistar-Kyoto
rats: implications for hypertension research. J. Hypertens.
1989; 7,809-16.
49. Roman, R.J., Altered pressure-natriuresis relationship in
young spontaneously hypertensive rats. Hypertension 1987;
9 ( S ~ p p lIII),
. 111-1 30-6.
50. Tobian, L., Johnson, M.A., Lange, L. & Magraw, S. Effect of
varying perfusion pressures on the output of sodium and
renin and the vascular resistance in kidneys of rats with
‘post-salt’ hypertension and Kyoto spontaneous hypertension. Circ. Res. 1975; 36 & 37,1162-70.
5 1. Salvati, P., Ferrario, R.G. & Bianchi, G. Natriuretic capacity
in isolated kidneys of rats of the Milan strain and after
development of hypertension: comparison with spontaneously hypertensive rats. J. Hypertens. 1987; 5 (Suppl.
S ) , 235-7.
52. Oparil, S., Chen, Y.-F., Meng, Q.C., Yang, R.-H., Honkui, J.
& Wyss, J.M. The neural basis of salt sensitivity in the rat:
altered hyperthalamic function. Am. J. Med. Sci. 1988; 295,
360-9.
53. Chrysant, S.G., Walsh, G.M., Kem, D.C. & Frolich, E.D.
Hemodynamic and metabolic evidence of salt sensitivity in
spontaneously hypertensive rats. Kidney Int. 1979; 15,
33-7.
54. Yamori, Y., Kihara, M., Nara, Y . & Horie, R. Salt and hypertension: importance of genetic pre-disposition and balance
with othernutrients. Magnesium 1982; 1, 163-71.
55. Winternitz, S.R. & Oparil, S. Sodium-neural interactions in
the development of spontaneous hypertension. Clin. Exp.
Hypertens. Part A 1982; 4,751-60.
56. Dietz, R., Schomig, A., Rascher, W., Strasser, R. & Kubler,
W. Enhanced sympathetic activity caused by salt loading in
spontaneously hypertensive rats. Clin. Sci. 1980; 59,
171s-3s.
199
57. Aoki, K., Yamori, Y., Ooshima, A. & Okamoto, K. Effects of
high or low sodium intake in spontaneously hypertensive
rats. Jpn. Circ. J. 1972; 36, 539-45.
58. Grunert, R.R., Meyer, J.H. & Phillips, P.H. The sodium and
potassium requirements of the rat for growth. J. Nutr. 1950;
42,609- 18.
59. Toal, C.B. & Leenen, F.H.H. Dietary sodium restriction and
development of hypertension in spontaneously hypertensive
rats. Am. J. Physiol. 1983; 245, H1081-4.
60. Louis, W.J., Tabei, R. & Spector, S. Effects of sodium intake
on inherited hypertension in the rat. Lancet 1971; ii,
1283-6.
61. Ely, D.L., Fribergm, P., Nilsson, H. & Folkow, B. Blood
pressure and heart rate responses to mental stress in
spontaneously hypertensive (SHR) and normotensive
(WKY) rats on various sodium diets. Acta Physiol. Scand.
1985; 123,159-69.
62. Seymour, A.A. Hypertension produced by sodium depletion and unilateral nephrectomy; a new experimental model.
Hypertension 1980.2, 125-9.
63. Shibouta, Y., Terashita, Z.-I., Inada, Y., Nishikawa, K. &
Kikuchi, S. Enhanced thromboxane A2 biosynthesis in the
kidney of spontaneously hypertensive rats during development of hypertension. Eur. J. Pharmacol. 1981; 70,247-56.
64. Beierwaltes, W.H., Arendshorst, W.J. & Kremmer, P.J.
Electrolyte and water balance in young spontaneously
hypertensive rats. Hypertension 1982; 4,908-1 5.
65. Lundin, S., Herlitz, H., Hallback-Norlander, M.A.,
Rickstein, S.E., Gothberg, G. & Berglund, G. Sodium
balance during development of hypertension in the spontaneously hypertensive rat (SHR). Acta Physiol. Scand.
1982; 115,317-23.
66. Thomas, D., Salvi, D., Stein, J. & Lau, K. Mechanism for
increased sodium retention by pre-hypertensive spontaneously hypertensive rats (SHR): role of aldosteroneindependent tubular reabsorption. Kidney Int. 1986; 29,
260.
67. Mullins, M.M. Body fluid volumes in pre-hypertensive
spontaneously hypertensive rats. Am. J. Physiol. 1983; 244,
H652-5.
68. Harrap, S.B. Genetic analysis of blood pressure and sodium
balance in spontaneously hypertensive rats. Hypertension
1986; 8,572-82.
69. Leehen, F.H.H., Cooper, S.M. & Toal, C.B. Body fluid
volumes during development of hypertension in SHR.
Kidney Int. 1982; 2 1, 190.
70. Rippe, B., Lundin, S. & Folkow, B. Plasma volume, blood
volume and transcapillary escape rate (TER) of albumin in
young spontaneously hypertensive rats (SHR) as compared
with normal controls (NCR). Clin. Exp. Hypertens. Part A.
1978; 1,39-50.
7 1 . Dilley, J.R., Stier, C.T. & Arendshorst, W.J. Abnormalities
in glomerular function in rats developing spontaneous
hypertension. Am. J. Physiol. 1984; 246, F12-20.
72. Azar, S., Johnson, M.A., Scheinman, J., Bruno, L. & Tobian,
L. Regulation of glomerular capillary pressure and filtration
rate in young Kyoto hypertensive rats. Clin. Sci. 1979; 56,
203-9.
73. DiBona, G.F. & Rios, L.L. Mechanism of exaggerated
diuresis in spontaneously hypertensive rats. Am. J. Physiol.
1978; 235, F409- 16.
74. Kato, S., Miyamoto, M., Kato, M. et al. Renal sodium
metabolism in spontaneously hypertensive rats: renal micropuncture study of the rate of 12Na recovery by the microinjection method. J. Hypertens. 1986; 4 (Suppl. 3), 255-6.
75. Morduchowicz, G.A., Sheik-Hamad, D., Ok, D.J., Nord,
E.P., Lee, D.B.N. & Yahagawa, N. Increased Na/H antiport
activity in the renal brush border membrane of SHR.
Kidney Int. 1989; 36,576-8 I.
76. Garg, L.C., Narang, N. & McArdle, S. Na-K-ATPase in
nephron segments of rats developing spontaneous hypertension. Am. Physiol. 1985; 249, F863-9.
77. Firth, J.D., Raine, A.E.G. & Ledingham, J.G.G. Sodium and
lithium handling in the isolated hypertensive rat kidney.
200
H. E. de Wardener
Clin. Sci. 1989: 76, 335-41.
78. Freeman, R.H., Davis, J.O., Varsano-Aharon, N., Ulick, S. &
Weinberger, M.H. Control of aldosterone secretion in the
spontaneously hypertensive rat. Circ. Res. 1975; 37,66-7 1.
79. Shiono, K. & Sokabe, H. Renin-angiotensin system in
spontaneously hypertensive rats. Am. J. Physiol. 1976; 231,
1295-9.
80. Cangiano, J.L., Rodriguez-Sargent, C., Nascimento, L. &
Martinez-Maldonado, M. Renin response to volume contraction and indomethocin in spontaneously hypertensive
rats. Clin. Sci. 198 1; 60,479-82.
81. Herlitz, H., Lundin, S., Henning, M., Karlberg, B.E. &
Berglund, G. Hormonal pattern during development of
hypertension in spontaneously hypertensive rats (SHR).
Clin. Exp. Hypertens. Part A 1982; 4,915-35.
82. Watanabe, M., Nishikawa, T., Takagi, T., Kamiyama, Y.,
Tamura, Y. & Kumagai, A. Mechanism of suppressed
renin-angiotensin system in spontaneously hypertensive rat.
Clin. Exp. Hypertens. Part A 1983; 5,49-70.
83. Knardah, S. & Murison, R. Plasma corticosterone and renin
activity during two-way active avoidance learning in
spontaneously hypertensive and Wistar-Kyoto rats. Behav.
Neurol. Biol. 1989; 51, 389-400.
84. Bagby, S.P., McDonald, W.J. & Mass, R.D. Serial
renin-angiotensin studies in spontaneously hypertensive
and Wistar-Kyoto normotensive rats. Hypertension 1979;
1,347-54.
85. Kawashima, K., Shiono, K. & Sokabe, H. Variation of
plasma and kidney renin activities among substances of
spontaneously hypertensive rats. Clin. Exp. Hypertens. Part
A 1980; 2,229-45.
86. Kawashima, K., Miwa, Y. & Fujimoto, K. Possible involvement of an impaired baroreflex mechanism but not the
renin-angiotensin system and vasopressin in the enhanced
pressor responsiveness to physostigmine in spontaneously
hypertensive rats. Gen. Pharmacol. 1989; 18,327-30.
87. Kitami, Y., Hiwada, K. & Kokubu, T. l d n e y renin gene
expression in spontaneously hypertensive rats. J. Hypertens.
1989; 7,727-3 1.
88. Leehen, F.H. & Toal, C.B. Dietary sodium restriction and
the renin-angiotensin system in young spontaneously
hypertensive rats. J. Hypertens. 1989; 7, 57-6 1.
89. Mesenger, E.A., Stonier, C. & Aber, G.M. Influence of age
on glomerular binding of angiotensin I1 in normotensive and
spontaneously hypertensive rats. Clin. Sci. 1989; 76,
6 19-23.