Original Articles
Dahl Salt-Susceptible and Salt-Resistant Rats
A Review
JOHN
P. RAPP, D.V.M., PH.D.
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(Hypertension 4: 753-763, 1982)
T
HE purpose of this article is to review comprehensively the data available on the strains of
rats that were selectively bred by Dr. Lewis K.
Dahl for susceptibility (S strain) or resistance (R
strain)* to the hypertensive effect of high salt diet. In
this review "salt" will always mean NaCl.t
From the Departments of Medicine and Pathology, Medical College of Ohio, Toledo, Ohio.
Supported by Grant HL 20176 from the National Institutes of
Health.
Address for reprints: Dr. John P. Rapp, Department of Medicine,
Medical College of Ohio, C.S. 10008, Toledo, Ohio 43699.
Received for publication January 20, 1982: revision accepted
June 21, 1982.
Dedication: This review is dedicated to Lewis K Dahl. M.D..
for his brilliant and innovative work in hypertension research.
Selective Breeding
In the 1950s, Meneely and coworkers studied the
effects of high salt diet on the blood pressure of rats.
Meneely and Ball5 reviewed the work, showing that for
a large group of rats the average blood pressure of the
group was positively and linearly related to the percentage of NaCl in the diet between 0 and 10% NaCl.
Moreover, they remarked that "there was quite a
marked degree of individual variation" in the response
of blood pressure to salt. This work was carried out on
Sprague-Dawley rats that were presumably randombred.
•A nomenclature committee of the International Society of Hypertension has stated that Dahl salt-sensitive (or salt-susceptible)
rats should be designated DS and Dahl salt-resistant rats should be
designated DR (see ref. I). This nomenclature is specifically not
used in this review, and its use. except as noted below, is discouraged. In DahTs original work in 1962 and for 14 years until his
death. Dr. Dahl called the strains S and R. There is no need to
replace that historic precedent. The nomenclature committee specifically states that they were naming "hypertensive rat strains with
stable hypertension which had been inbred (brother-sister mating)
for at least 20 generations" (ref. \>. Apparently they were naming
inbred strains under development at Brookhavcn National Laboratory since Dr. Dahl's death in November, 1975. No fully inbred rats
were supplied to investigators from the Brookhaven colony because
they do not exist (yet). What was supplied were rats from colonies
of S and R rats separate from the inbreeding program and maintained as Dahl had done for many years by selective breeding,
avoiding inbreeding where possible. Thus, the use of DS and DR
implies the use of specific inbred strains which do not exist. If and
when such strains from Brookhavcn become available, these specific strains of inbred S and R rats can be referred to as DS and DR.
tSodium in the diet is expressed in two ways in the literature,
either as % Na+ or % NaCl The latter assumes that all the Na+ is
present as NaCl, % NaCl means grams of NaCl per 100 grams of
food. In most of the literature reviewed, sodium was expressed as %
NaCl, and so this will be used throughout the review. Where the
original article gave data in % N a + . this will be given followed by
the % NaCl so that diets can always be compared on the same basis
(% NaCl = 2.54 times % Na + ).
A survey of commercial rat chows shows that they contain close
to 1% NaCl, and so "normal salt diet" will refer to l%NaCl in the
food. Two diets were introduced by Dahl during his work with S
and R rats: 8% NaCl diet referred to as "high salt diet"; and 0.3 to
0.4% NaCl diet referred to as "low salt diet." Note that with this
arbitrary nomenclature, low salt diet has only somewhat less than
half the salt content of normal diet. Where a diet was fed that
contained insufficient salt for optimum growth, this will be called
sodium-deficient diet. The minimum dietary requirement of sodium
for optimum growth in the rat is 0.05% Na+ (0.13% NaCl) (see ref.
2) and this is also an adequate minimum for reproduction (see ref.
3). On diets containing 2.8% NaCl and higher, rats grow slower
than the optimum (see ref. 4).
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FIGURE 1.
VOL 4, No 6, NOVEMBER-DECEMBER 1982
Lewis K. Dalit, M.D.. 1914-1975
During the 1950s, Dr. Lewis K. Dahl (fig. 1) had
worked largely with the effects of salt on blood pressure in humans. In the early 1960s, he turned his attention to studies in the rat, in which he, like Meneely et
al., showed that chronic excess salt ingestion leads to
sustained hypertension.6 Taking advantage of the observation that not all rats responded to salt with similar
changes in blood pressure and cognizant of the data
suggesting genetic influences on blood pressure in humans, Dahl et al. 7 - s were able to selectively breed rats
for susceptibility (S rats) or resistance (R rats) to the
hypertensive effects of high salt (8% NaCl) diet. After
only three generations of selective breeding, the S and
R lines were clearly separated. The blood pressures of
R rats were essentially similar on control or high salt
diets, but S rats responded to salt with a pronounced
increase in blood pressure. Thus, the two strains yielded an interesting model for the interaction of an environmental factor (salt) with genotype.
Blood pressure is a polygenic trait, meaning that
there are multiple genetic loci with effects on blood
pressure. When starting from a genetically heterogenous base population, the technique of selective breeding acted to concentrate in the salt-susceptible or saltresistant strains, respectively, the alleles with effects to
increase or decrease blood pressure response to salt.
Although it is often recognized that the extreme sensitivity of the S to salt is unique, the extreme resistance
of the R rat is equally unique. R rats should not be
considered a "normal" control strain equivalent to
random-bred, unselected rats. In this context it is well
to recognize that it is the whole spectrum of blood
pressure, from high to low, that is genetically regulated and that hypertension in the genetic context is a
rather arbitrary, albeit very convenient, designation.
It was estimated using quantitative genetic techniques that approximately 2—4 loci were involved in
controlling the blood pressure response to salt in S and
R rats.9 The theoretical formulas from which such estimates were calculated were based on genetic assumptions that in practice are less than perfectly met.10
Thus, the result of 2-A loci influencing salt susceptibility in S and R rats is approximate. To date only one of
these loci has been definitively described in biochemical genetic terms" (see below under Endocrine Factors). There is no evidence for sex-linked genes.9
In the original selective breeding experiments to
produce S and R rats, brother-sister matings (i.e., inbreeding) were made for the first few generations.8
Subsequently, selection was continued but purposeful
THE SALT-SUSCEPTIBLE RAT/Rapp
inbreeding was avoided (Dahl, personal communication). As of 1975, the S and R rats in the Brookhaven
colony were not inbred strains, although they were
sometimes referred to as such in the literature. An
inbred strain is one for which brother-sister matings
have been made for 20 or more generations. This theoretically leads to homozygosity at almost 100% of genetic loci, thus fixing the characteristics of the strain.
Since 1975, inbreeding programs with S and R rats
have been initiated at Brookhaven and in my
laboratory.
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General Characteristics of the Strains
When S rats were placed on a high salt (8% NaCl)
diet at weaning (21-23 days of age), they rapidly developed hypertension and all died by the 16th week of
salt feeding. With similarly treated R rats, blood pressure remained in the normotensive range, and 80% of
the animals survived to the 48th week on high salt.9
The age at which high salt diet was started partly determined the magnitude of the blood pressure response in
S rats. When given high salt at weaning, S rats developed fulminating hypertension (above 200 mm Hg)
within 6 weeks. If high salt feeding was delayed until 3
months of age, the hypertension developed less rapidly
and blood pressure went to about 185 mm Hg by 16—20
weeks.12
Studies by Meneely et al. using regular laboratory
rats showed that supplemental potassium prolonged
survival rate in rats on high salt diets. 5 - l3 Using S rats,
Dahl et al.14 found that for diets with the same amount
of NaCl blood pressure was reduced by increasing
potassium content. On diets with different absolute
concentrations of NaCl and KC1, but with identical
Na + /K + molar (M) ratios, animals on the higher absolute NaCl intake had higher blood pressures. Thus,
both the Na + /K + M ratios and the absolute amount of
Na + in the diet are important determinants of the final
blood pressure.
There is a widespread misconception that S rats become hypertensive only when placed on high NaCl
diets. In fact, on normal rat chow that contains 1%
NaCl S rats become markedly hypertensive, but it just
takes a longer time (months instead of weeks)." Moreover, on low salt (0.3 to 0.4% NaCl) diets, S rats often
have pressures 15-20 mm Hg higher than R.
There was no marked retention of sodium in S vs R
rats as measured by whole carcass sodium, or half-life
of 22Na. There was also no depletion of carcass potassium in S rats. Serum sodium and potassium were
similar for S and R.16 Skeletal muscle sodium and
potassium were similar for the two strains, and muscle
electrolytes responded similarly in S and R to treatment with deoxycorticosterone.17 Thus, there is no evidence that S rats become hypertensive because of gross
sodium retention.
The usual practice with S and R rats is to vary the
NaCl content of the food and provide water ad libitum.
Both strains eat the same amount of food on either high
(8% NaCl) or low (0.4% NaCl) diets.18-19 If, however,
the rats are provided with both water and saline solu-
755
tions to drink, the S rats will consume significantly less
saline.20
In an interesting demonstraton of the high salt content of processed baby food, Dahletal. 21 showed that S
rats fed such food developed hypertension and died.
Control S rats on 0.4% NaCl rat chow had relatively
normal blood pressures and lived significantly longer.
Sensitivity of S Rats to Other Forms of
Experimental Hypertension
The S rat is more sensitive than the R rat to hypertension induced by several experimental procedures.
These include deoxycorticosterone plus 7.3% NaCl in
food,22 adrenal regeneration plus 1% NaCl to drink,
and cortisone given to adrenalectomized rats drinking
0.85% saline.23 Obviously, with these techniques the
excess salt feeding included in the protocols confounds
the claim that salt-sensitive rats are more prone to
steroid-induced forms of hypertension. But, in fact, if
deoxycorticosterone is administered without excess
salt, S rats do show significantly increased blood pressure while R rats do not.17 The S rats are also more
prone than R to develop hypertension in experiments
that omit excess salt but that involve clipping of the
renal artery,22 injection of cadmium,24-25 or psychological stress.26 In early studies on "stress," electric
shocks were administered independent of the rats' behavior and no elevations in blood pressure occurred.27
However, with the appropriate conflict between the
necessity to obtain food and to avoid electric shock, S
rats did respond with increased blood pressure,28-29 and
this response was greater in S than R.26
Kidney
The kidney has been the focus of considerable attention in S and R rats. This interest largely arises from
the renal cross-transplantation experiments of Dahl et
al. If the kidney from an S rat is transplanted into an R
rat from which both original kidneys have been removed, the R rat develops higher blood pressure than
R rats with transplanted R kidneys or R rats with unilateral nephrectomy. Conversely, an R kidney transplanted into an S rat ameliorates the blood pressure rise
seen in S rats with transplanted S kidneys or S rats with
unilateral nephrectomy.30"32
Early attempts to identify some abnormality of renal
function between S and R rats were unsuccessful.
Using clearance methods on unanesthetized rats, BenIshay et al.33 found that the glomerular filtration rate
and renal plasma flow were similar in S and R. The
natriuretic and diuretic response to a hypertonic saline
load was also equal in the two strains.34 In contrast,
when the saline load was given as an isotonic solution,
S rats excreted significantly more sodium and water
than R rats.35 This difference was present in young rats
before the development of markedly increased blood
pressure in S rats.
It has been reported3* that S rats have 15% fewer
glomeruli than R. Following 20-30 days of high salt to
induce mild hypertension in the S rats, the S compared
to R showed increased single nephron blood flow,
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increased single nephron glomerular filtration rate,
and decreased resistance at the afferent and efferent
arteriolar segments.37 These data were interpreted as
adaptive changes to the reduced number of glomeruli.
Recently it was found that S rats responded to acute
administration of dexamethasone with a markedly
greater diuresis and proteinuria than R.38 Since glucocorticoids act by increasing glomerular plasma flow
rate, this result implies differences in glomerular function between S and R.
Using an autoperfused kidney preparation, Fink et
al.39 found that the renal vascular resistance of rats on a
low salt diet was less in S than R rats. Following 4
weeks of 8% NaCl diet fed to 8- to 10-week-old animals, R rats had decreased renal vascular resistance
and an increased slope of their pressure-renal blood
flow curves (i.e., a greater change in blood flow for a
given change in pressure) compared to R rats on a
0.4% NaCl diet. In contrast, the S rats did not change
their renal vascular resistance or renal pressure-flow
curves in response to salt. This was interpreted to mean
that S rats did not decrease renal vascular resistance in
response to high salt intake and therefore S renal vascular resistance was inappropriately high on high salt
intake. Another interpretation, also discussed by the
authors,39 is that the S renal vasculature was already
dilated on a low salt diet and could not respond further
to salt. The latter interpretation is more compatible
with the micropuncture studies.37
Tobian et al.40 have studied Na + and water excretion
using isolated perfused kidney preparations from S and
R rats raised for 8 weeks on 0.06% Na + (equivalent to
0.15% NaCl). Kidneys were perfused with blood from
normal Sprague-Dawley rats. At any given renal perfusion pressure, R kidneys excreted more urine and
sodium than S. Thus, in S rats, the pressure-natriuresis
curve was shifted to the right relative to R. Girardin et
al.41 performed similar experiments with S and R rats
before and after high salt (8% NaCl) diet. They concluded that there was no preset abnormality of the
pressure natriuresis curve in S rats until after S-rat
kidneys had been exposed to high blood pressure for 7
weeks. This suggests than an abnormal pressure-natriuresis curve may result from the significant vascular
lesions that are known to occur in S rats with elevated
pressure (see below). The point is not settled, however, because Tobian et al. were careful to compare S and
R rats with similar blood pressures and still found
differences in pressure-natriuresis curves.
In any case, it is important to know what lesions
have been described in S and R kidneys. Jaff6 et al.42
reported that, as S rats develop hypertension, they
develop focal tubular collapse, focal tubular dilation,
glomerular scarring, and proliferation of musculoelastic tissue at arteriolar branch pads. As hypertension
progressed, the lesions progressed in distribution and
severity with larger areas of tubular collapse or dilation, and protein casts. Glomerular scarring and proliferative lesions at the branch pads became severe, and
degenerative changes in arterioles were seen.42 The
severity of the lesions correlated well with blood pres-
VOL. 4, No 6, NOVEMBER-DECEMBER 1982
sure, and discernible lesions were seen even with only
mild elevations of blood pressure in the S rats in the
range 130-150 mm Hg (fig. 9 of ref. 43). In my own
experience, significant renal lesions are seen with
blood pressures in the 150-160 mm Hg range. There
are significant correlations among blood pressure,
renal lesions, and urinary protein excretion even in
mildly hypertensive S rats.17 Control R rats in these
experiments uniformly lacked significant renal
pathology. 174243
It is worth emphasizing that lesions at the renal
vascular branch pads are evident in S rats even with
modest elevation in blood pressure.42 Branch pads are
valve-like structures in the normal rat which in the
kidney are present only where the interlobular arteries
give rise to afferent arterioles that supply the juxtamedullary glomeruli.44 The efferent vessels from juxtamedullary glomeruli of course supply the renal medulla. It
is interesting that mildly and moderately hypertensive
S rats have a reduced renal papillary plasma flow compared to R.45 Whether this is a physiologic effect or a
pathologic effect due to branch pad thickening has not
been investigated.
Urinary kallikrein excretion has been uniformly reported to be lower in S than R rats. 4 " 9 Urinary kallikrein is known to be stimulated by mineralocorticoids.
S rats have a net mineralocorticoid excess due to increased production of 18-hydroxy-11 -deoxycorticosterone (see Endocrine Factors below). Low urinary
kallikrein at first appears inconsistent with the higher
mineralocortocoid status. It was found,17 however,
that urinary kallikrein excretion of S rats did not increase in response to exogenous mineralocorticoid.
The mineralocortocoid treatment did of course increase blood pressure, and in this short-term experiment, the S rats developed mild renal lesions and proteinuria. S rat urinary kallikrein did increase normally
in response to a sodium-deficient diet, a situation
where increases in blood pressure and renal damage
would be minimized. Thus, low urinary kallikrein in
the S rat might be secondary to renal damage. The
developmental pattern for urinary kallikrein excretion
is compatible with this suggestion. There was no difference in urinary kallikrein excretion between young
S and R rats (6 weeks old). Differences in urinary
kallikrein between S and R developed concomitantly
with increased blood pressure and increased urinary
protein excretion in S over R rats.15 Moreover, it has
been found that S rats early in the development of
hypertension and concomitant with the developent of
proteinuria excrete in their urine a kallikrein-binding
protein. Initial evidence suggests that this binding protein could be a kallikrein inhibitor originating from the
plasma.50
Urinary prostaglandin E, excretion" and in vitro
renomedullary synthesis of prostaglandin E251 are lower in S than R. These changes are difficult to interpret
because in most species prostaglandin E2 is a renal
vasodilator but in the rat it may be a vasoconstrictor.52 53 If so, lower vasoconstrictor activity in the S-rat
kidney should not to potentiate hypertension.
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The S rats have unequivocally lower plasma renin
activity,4*-M-55 lower renal renin activity,54 and lower
juxtaglomerular granularity4' than R rats. Plasma and
renal renin activity in both strains respond appropriately to changes in NaCl intake, but a difference between
S and R remains regardless of diet.54'55 The strain
difference in plasma renin activity was present as early
as 39 to 42 days of age; small differences in blood
pressure were also present at this young age, S pressures being higher than R.56 Perfused S kidneys also
released less renin than perfused R kidneys.4" A possible inhibitory action of S-rat plasma on hog renin in
vitro has been reported. R-rat plasma had no such
activity.57 The substance(s) responsible for this have
never been pursued. The pH profile of plasma renin
activity has also been shown to differ in S and R rats.56
Although the pH optima were the same, the slope of
the pH curves above pH 7.0 were different. It was
possible to type individual rats as either S or R on the
basis of the pH profile of their plasma renin activity,
and this characteristic was independent of changes in
plasma renin induced by alteration of salt intake. The
cause of this phenomenon is unknown, but could involve molecular differences in renin or renin substrate.
Renal (Na + ,K + )-ATPase has been measured in
renal microsomes. In young S and R rats with minimal
changes in blood pressure, there was no difference
between strains in renal microsomal (Na + ,K + )ATPase activity. In 6-month-old rats fed a normal 1%
NaCl diet, S rats had long-standing hypertension and
also reduced renal microsomal (Na + ,K + )-ATPase activity which was attributed to possible renal damage.5*
No evidence for a mutation in the (Na + ,K + )-ATPase
molecule was found in comparing the enzyme from S
and R rats.58 In another study,55 renal microsomal
(Na + ,K + )-ATPase was less in hypertensive S rats than
in R rats, and this difference persisted when the rats
were placed on a sodium-deficient diet (0.01% Na +
equivalent to 0.025% NaCl).
Yamori and Okamoto59 have described a genetically
controlled electrophoretic polymorphism of a renal
medullary esterase in the Japanese spontaneously hypertensive rat (SHR). The enzyme pattern in both S
and R rats was not like that in the SHR, but was like
that in normotensive Wistar control rats.60
Unidentified Humoral Factors
Studies by Dahl et al.61"64 using parabiosis in combination with renal artery clipping or nephrectomy provided evidence that the S kidney may be the origin of a
hypertensinogenic agent that can cross the parabiotic
junction. The nature of the putative agent is obscure.
In later studies involving renal homografts, 3132 the
data were interpreted to suggest that "genetically controlled factors acting through the kidney can chemically modify blood pressure up or down. " 32 The potential
blood-pressure-lowering ability of the R vs the S kidney may reflect the increased number and increased
granularity of the renomedulary interstitial cells in the
R rat.65 These cells are known to contain lipids that can
decrease blood pressure.66
757
Using an isolated perfused kidney preparation, Tobian et al.67-68 have provided evidence for a sodiumretaining humoral agent in S rats. Kidneys of normal
Sprague-Dawley rats were perfused with blood from S
or R rats that had been adrenalectomized and nephrectomized 1 hour prior to use. Perfusion with S-rat blood
resulted in Na + excretion equal to only one-half that
obtained by perfusion with R-rat blood. Since kidney
perfusions with blood from normal Sprague-Dawley
rats resulted in a high Na + excretion similar to perfusions with R-rat blood, these results were interpreted to
mean that S-rat blood contained more of a Na + -retaining substance(s) than R-rat blood. The nature of such a
substance is obscure.
Endocrine Glands
It has been shown that adrenalectomy in S rats prevents the development of hypertension induced by
high salt diet.69 This shows that adrenal function is
necessary for salt-induced hypertension, but by itself
does not establish that abnormal adrenal function in S
rats causes the hypertension. But, in fact, the pattern of
steroids secreted by S and R adrenal glands are markedly different. S adrenals show increased 18-hydroxylation of deoxycorticosterone (DOC) to form 18-hydroxy11-deoxycorticosterone (18OH-DOC) compared to R
adrenals. This higher 18-hydroxylation per unit weight
of the S adrenal was exactly offset by a lower 11 /3hydroxylation of DOC to form corticosterone (B) in S
compared to R. Total utilization of DOC percursor was
identical between the strains, it was just the proportion
going to 18OH-DOC or corticosterone that was altered. This gave rise to characteristic ratios of 18OHDOC/B for S and R rats, which allowed unambiguous
separation of S and R strains on the basis of the in vitro
incubation of the adrenal. Salt feeding had no effect on
these characteristic steroid patterns.70-7I
Genetic studies have shown that the characteristic
steroid patterns of S and R rats are controlled by a
single genetic locus with two alleles inherited by
codominance." The locus was eventually named Hyp/ for hypertension locus number 1 for reasons given
below.
Initially, the genetic data on the Hyp-l locus presented an enigma. The increment in 18-hydroxylation
in S compared to R was equal to the decrement in 11 /3hydroxylation. Thus, equal and opposite effects were
apparently produced on the two enzymes, 18-hydroxylase and 11 )3-hydroxylase, by a single gene. Detailed
biochemical studies show that the assumption that 18hydroxylation and 11 /3-hydroxylation are catalyzed
by separate enzymes is wrong. The S-rat cytochrome
P-450 for 18-hydroxylation had an identical Warburg's partition constant to that of S-rat cytochrome P450 for 11 /3-hydroxylation, implying that the two
reactions were catalyzed by the same enzyme. Similarly, the partition constant of R-rat P-450 for 18-hydroxylation was identical to the partition constant of R-rat
P-450 for 11 /3-hydroxylation, again implying one enzyme for the two hydroxylations. The S and R partition
constants differed drastically, however, implying the
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existence of a mutant form of a single cytochrome P450 for 18- and 11 /3-hydroxylation between the two
strains. Moreover, the S and R genotypes at Hyp-1
segregated with the characteristic S and R partition
constants for the enzyme.72 This constitutes genetic
proof that the same enzyme catalyzes both 18- and 11
/3-hydroxylation of DOC. Subsequently, pure cytochrome P-450 for 11 /3-hydroxylation was isolated
from bovine adrenals; this enzyme also catalyzed 18hydroxylation.73 The obvious rationalization for the
equal and opposite effects in the S and R rats for 18and 11 /3-hydroxylations is that, when a given form of
P-450 (S or R) binds a DOC molecule, the molecule is
hydroxylated at either the 18- or the 11 /3-position. If a
molecule of DOC is 18-hydroxylated, it detaches from
the enzyme and is not 11 /3-hydroxylated or vice versa.
Therefore, a genetically mutated P-450 with increased
18-hydroxylase activity (S rats) necessarily has a complementary reduction in 11 /3-hydroxylase activity.
Alleles at the Hyp-1 locus were shown to segregate
with an increment in blood pressure in salt-fed F2 rats
derived from an S x R cross. This is powerful genetic
evidence that the Hyp-1 locus causes differences in
blood pressure. It was concluded from the genetic experiments that the Hyp-1 locus accounted for a blood
pressure difference of about 16 mm Hg between S and
R rats in the environment of a high salt diet." Since
blood pressure in the S and R model is known to be
under polygenic control,9 the remaining difference in
blood pressure between the strains is obviously due to
the other (unidentified) genetic loci.
Because of the effects of the Hyp-1 locus, S rats
have 2 to 3 times higher peripheral plasma levels of
18OH-DOC than R rats, but the plasma concentrations
of corticosterone and DOC are not different between
the strains. 4870 Adrenals of S rats are about 15% to
20% heavier in S than R.70 This situation probably
arises as a consequence of corticosterone levels being
regulated by the pituitary. ACTH-induced compensatory hypertrophy of the S adrenals presumably occurs
to make up for their less efficient production of corticosterone per unit weight of adrenal. This, of course,
can only exacerbate the total overproduction of 18OHDOC which occurs at a higher rate per unit weight of
adrenal in the S rat. Corticosterone, but not 18OHDOC, causes feedback regulation of ACTH.74 " Since
there is no underutilization of DOC precursor, excess
DOC secretion does not occur.
Plasma aldosterone is significantly lower in S than
R, 48 -" possibly as the consequence of the mineralocorticoid activity of 18OH-DOC causing suppression of
the renin-angiotensin system. Aldosterone in S and R
rats responds normally to a sodium-deficient diet55
and, more important, aldosterone secretion is suppressed by excess salt intake in S as well as in R
rats. 76 -" It has been argued77 that on low salt intakes the
net mineralocorticoid status of the rat is dominated by
aldosterone. As aldosterone is suppressed by salt,
however, the net mineralocorticoid activity is more
and more dominated by steroids from the inner adrenocortical zones, which are secreted independently of
VOL 4, No 6, NOVEMBER-DECEMBER 1982
salt intake. Since these include 180H-DOC, which is
higher in S than R, the net mineralocorticoid activity
calculated for S on high salt approaches 1.5 times that
calculated for R on a high salt diet.77 Thus, there is
some rationale for an interaction between the Hyp-I
locus and salt on blood pressure. Injections of 18OHDOC into unilaterally nephrectomized rats drinking
1% saline caused a modest (15-20 mm Hg) increase in
blood pressure after 3 weeks of administration.78"80
Mineralocorticoid receptors in the kidneys of S and
R rats have been studied. The concentration of receptors and their affinities for aldosterone or 18OH-DOC
were the same for the two strains.81 Although blood
pressure responses to exogenous mineralocorticoid are
greater in S than R, 1 7 ~ this is probably not due to an
increased effect of the mineralocorticoid on S rats at
the level of the kidney because distal tubular hypertrophy and skeletal muscle potassium depletion were
equivalent in S and R rats.17
There is no evidence for sex linkage of the genetic
effects on blood pressure,9 meaning that none of the
genetic loci controlling blood pressure is located on
the X chromosome. Sex steroids do, however, exert
effects. Intact S females respond to 8% NaCl diet with
a slower increase in blood pressure than S males, although both sexes eventually reach the same high level. Castration in S males has no effect on blood pressure response to salt, but castration of S females
altered their blood pressure response so that it was like
that of S males.82 Contraceptive steroids given to female S rats had complex interactive effects with salt.
On 0.38% NaCl diet, contraceptive steroids significantly lowered blood pressure, but on 4% NaCl diet
contraceptive steroids significantly increased blood
pressure.83
About 85% of the R rats from Dahl's original stock
(Brookhaven colony) had a curious anatomical change
in their pituitary glands. This consisted of marked accumulation of a proteinaceous fluid (histologically referred to as colloid) in the pituitary cleft (Rathke's
cleft). This characteristic was rarely seen in S-rat pituitaries.84 Gel electrophoresis of the proteins in the pituitary colloid showed a pattern similar to serum proteins
but with the addition of four proteins that were unique
to the colloid.84-85 Two of these proteins (MW 52,000
and 63,000) were isolated and shown to cross-react
immunologically with rat albumin. Peptide mapping
of one of these showed strong homology with rat albumin, suggesting that it was a fragment of albumin.86
Pituitaries of R rats showed much greater protease
(esteropeptidase) activity than pituitaries of S rats. 8687
This proteolytic activity may account for the unique
colloid proteins that are probably proteolytic fragments of plasma proteins.
The accumulation of pituitary colloid was shown to
be an inherited trait, but the genes involved had not
been fixed by selection for blood pressure response to
salt in the Brookhaven colony. Following inbreeding
of R rats, two sublines were obtained, one with and
one without pituitary colloid accumulation. Genetic
studies showed that accumulation of one of the unique
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pituitary colloid proteins was largely controlled by a
single genetic locus (Pc for pituitary colloid).88 Although inverse correlations between blood pressure
and colloid accumulation were seen in segregating F2
populations derived from crosses of S and R rats in two
separate experiments, 8485 definitive associations of
blood pressure and the Pc locus were not obtained.88
Lacking in these experiments is any knowledge of a
molecule with an effect on blood pressure. In retrospect, it seems possible that the data obtained on pituitary colloid accumulation may have arisen as a consequence of loose linkage of the Pc locus to another locus
actually involved in blood pressure regulation.
The secretion and pressor effects of antidiuretic hormone (ADH) have been studied in S and R rats. On low
salt intake, urinary excretion of ADH and plasma ADH
concentrations are similar for S and R. On high salt
intakes, urinary ADH excretion and plasma ADH increase significantly more in S than R.l8-8l) Matsuguchi
et al.18 concluded that this increased plasima ADH did
not contribute to hypertension in salt-fed S rats because
treatment with a compound that selectively blocks the
pressor effect of ADH had no effect on blood pressure.
If the renin-angiotensin system is blocked with captopril, than a specific inhibitor of the pressor effect of
ADH does lower blood pressure significantly more in
S than R rats.89 Whether this should be interpreted to
mean that ADH participates in elevating blood pressure in the S rat is a moot point.
Serum thyroxine and triiodothyronine are the same
in S and R rats. Both hormones are suppressed by
feeding 8% NaCl diet and both are suppressed equally
in S and R.58 Therefore, no role for the thyroid in the
hypertension of the S rat is evident.
Nervous System
If S rats are treated with either guanethidine90 or 6hydroxydopamine91-92 to destroy the sympathetic nervous system, then salt-induced hypertension is reduced or fails to occur. Ganglionic blockade abolished
the blood pressure difference between S and R rats fed
high salt diet for 4 weeks.93 Lesions of the paraventricular nuclei,92 paraventricular nuclei plus suprachiasmatic nuclei,94 or the anteroventral third ventricle
(AV3V) region95 reduced or prevented the rise in blood
pressure of S rats fed a high salt diet. Lesions of the
suprachiasmatic nuclei enhanced the blood pressure
response of S rats to salt.92
Results of ablation or blocking experiments that reduce blood pressure do not necessarily mean that overactivity of the nervous components that are blocked are
causally involved in salt-induced hypertension in the S
rat. Such experiments may mean only that normal activity of the nervous components involved are required
for blood pressure responses to develop, that is, the
particular nervous component may be permissive.
Other work, however, suggests more than a permissive
role for the nervous system. Takeshita and Mark19
studied a perfused hindlimb preparation in which they
were able to demonstrate an increased neurogenic
759
component to vascular resistance in S compared to R
rats. Sympathetic denervation caused a significant decrease in vascular perfusion pressure in S rats on high
salt (8% NaCl), but not in S rats on low salt (0.4%
NaCl), or R rats on either salt intake. Sympathetic
nerve stimulation increased perfusion pressure more in
S rats on a high salt diet than in S rats on low salt or in
R rats on either salt intake. These results were probably not due to structural changes in blood vessels
since perfusion pressures of hindlimbs during maximal
vasodilation with papaverine were similar for S and R
rats on both high and low salt diets.
It has been reported96 97 that the pressor responses of
S rats were slightly greater than R in response to intracerebroventricular administration of angiotensin II or
hypertonic saline. It was suggested97 that this difference was not due to structural changes in blood vessels
because the rats were fed low salt (0.3% NaCl), although the S rats had significantly higher pressures
than R (approximately 130 vs 115 mm Hg). This suggestion appears justified, at least for the hindlimb
blood vessels, where a similar difference in pressure
apparently generated no structural changes.19 Increasing the potassium content of the diet decreased the
pressor responses to intracerebroventricularly administered angiotensin II or hypertonic saline by about 5
mm Hg without altering the basal blood pressure levels
on the low salt (0.3% NaCl) diet. Thus, the claim was
made97 that the beneficial effect of high potassium diet
in the presence of high sodium may have a central
nervous system component, although no tests were
made on high NaCl diets.
There is an abnormality of baroreflex control of the
heart rate in S compared to R rats. Gordon et al.93 gave
bolus injections of phenylephrine and determined the
slope of the lines relating blood pressure and pulse
interval (heart rate). The slope of these plots (baroreflex slope) was greater for R than S, that is, for any
change in blood pressure the heart rate changed more
in R than S. This difference was present with rats on a
low salt diet where basal blood pressure differences
were minimal, suggesting that the difference in baroreflex slopes was not a response to hypertension. Feeding high salt had no apparent effect on the difference in
baroreflex slopes between strains, but it did "reset"
the reflex in S rats by shifting the line for S rats to the
right, that is, a higher pressure was now required in S
rats to cause a given pulse interval (heart rate). Gordon
et al.93 favored an interpretation of their results relating
the "defect" in baroreflex sensitivity of S rats to a
neural component rather than, for example, to a difference in the arterial distensibility.
Pettinger et al.98 have studied the properties of areceptors in S and R rats. Renal a,- and a2-receptor
densities were higher in S than R. High salt diet caused
an increase in renal a2-receptors in S but not in R rats.
Renal a,-receptor density was unchanged by salt feeding. The higher renal a2-receptor densities were not a
result of hypertension per se because renal a2-receptor
density was not increased by DOCA-salt or renal hypertension in normal rats. Whether increased a-recep-
760
HYPERTENSION
tor density is a genetically mediated cause of salt sensitivity in the S rats remains to be determined by genetic
analysis.
R rats show more exploratory behavior" and greater
aggressive behavior100 than S rats. The relationship of
this behavior to blood pressure is obscure, and the
difference could have arisen from genetic drift (i.e.,
chance selection of behavior patterns).
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Cardiovascular System
Ganguli et al.101 have described the early changes in
some hemodynamic parameters when rats were placed
on a high salt (8% NaCl) diet. After 3 days on high
salt, R rats showed an 18% increase in cardiac output,
a 14% decrease in peripheral resistance, and no change
in blood pressure. At 7 days of salt feeding, the cardiac
output and peripheral resistance in R rats were back to
the levels seen in control rats on a 0.3% NaCl diet, and
blood pressure remained unchanged. S rats responded
very differently, with a 10% increase in cardiac output,
a 10% increase in peripheral resistance, and a 20%
increase in blood pressure after 3 days on a high salt
diet. At 7 days on high salt, cardiac output had returned to the control value but blood pressure and
peripheral resistance remained elevated.
When pressor agonists are given intravenously, S
rats respond with a greater increment in blood pressure
than R. This is true with angiotensin,102 norepineph93
and vasopressin.18-102 In
r j n e is. 102 phenylephrine,
these experiments, this difference in pressor response
was seen with rats on low salt (0.4% NaCl) diets,
where differences in blood pressure between strains
were minimal and thus structural adaptations of the
vasculature (smaller arteriolar lumens) and subsequent
hyperresponsiveness on this basis would be minimal.
Whether there was always complete absence of structural adaptation is a moot point. In the case of Gordon
et al., 93 the strain difference in response to phenylephrine was abolished by ganglionic blockade. Such
blockade also abolished the baroreceptor reflex, and so
the authors suggested that hyperresponsiveness to
pressor agents could be due to the altered baroreceptor
reflex in S rats.
In vitro studies have shown no differences in responses of the tail arteries from S and R rats to norepinephrine or serotonin. Membrane potentials of tailartery smooth muscle were also similar for the two
strains, as were smooth-muscle intracellular potassium, sodium, and chloride concentrations.l03 A genetic locus controlling vascular smooth muscle responsiveness to cobalt (CO2*) has been described in
spontaneously hypertensive rats (SHR), but this locus
was not polymorphic in S and R rats.104 Aortic rings
from S rats do, however, respond with a greater contraction than those from R in response to vanadate
anion.105 Although vanadate is a known potent inhibitor of Na + ,K + -ATPase in vitro, it can be shown that:
1) the contraction of the aortic rings by vanadate is not
due to inhibition of the Na + ,K + -pump activity; and 2)
vanadate action is blocked by a specific inhibitor of
anion transport, suggesting that vanadate works from
VOL 4, No 6, NOVEMBER-DECEMBER 1982
inside the cell. In these experiments, aortic rings from
the two strains contracted similarly to depolarizing
concentrations of K + , and S contracted with less force
than R in response to norepinephrine.
An interesting hypothesis106"108 is that Na + ,K + pump
activity may be decreased in volume-expanded hypertension due to a (somewhat tenuous) "natriuretic hormone" (see refs. 109 and 110 for reviews). Although a
natriuretic hormone might inhibit Na + ,K + -ATPase in
the kidney and cause natriuresis, it has been suggested
that in cardiovascular tissue it would inhibit Na + ,K + ATPase, leading to vascular smooth muscle contraction by either depolarizing the membrane and opening
voltage dependent Ca2+ channels, with a subsequent
rise in intracellular Ca 2+ , or by allowing intracellular
Na + to accumulate followed by Na + -Ca 2+ exchange
withCa 2+ moving into the cells. In spite of the fact that
S rats fed a high salt diet show increased blood volume, 1 " Na + ,K + -pump activities as measured by ouabain-sensitive 86rubidium uptake were increased in the
tail artery and aorta." 1 " 2 Also, cardiac microsomal
Na + ,K + -ATPase activity per milligram of microsomal
protein was increased.58 These changes in cardiovascular tissues are opposite to those predicted by the hypothesis involving natriuretic hormone in the pathogenesis of hypertension in this genetic model. It is
possible, however, that with these in vitro tests any
endogenous, reversible inhibitor of Na + ,K + -ATPase
may have dissociated and been lost from the tissue
prior to evaluating the Na + ,K + -ATPase activity.
Aortic prostaglandin I2 synthesis was significantly
increased by salt feeding in S but not R rats. This
was interpreted to be a secondary response to
hypertension."
Exercise
Forced treadmill running has a pronounced effect on
the blood pressure of salt-fed S rats. If running is
started soon after weaning, concomitant with salt feeding, the onset of hypertension was delayed 8 weeks
and the mortality rate was reduced. This beneficial
effect of exercise was less effective when exercise was
started at a later age." 3
Drug Treatment
A thiazide diuretic was not at all effective in preventing an initial marked rise of blood pressure in 6week-old S rats where treatment was started concomitant with feeding 8% NaCl diet. Continued thiazide
treatment of the salt-fed rats did, however, eventually
normalize the blood pressure." 4 In another experiment, thiazide diuretic was started at weaning and continued for 14 weeks on 0.3% NaCl diet. When the rats
were then switched to a 8% NaCl diet with continued
thiazide treatment, the marked rise in blood pressure
occurring in the nonthiazide-treated S-rat controls was
prevented in the thiazide-treated group.67 Thus, there
appears to be a complex interaction between the age at
which thiazide and salt are started and blood pressure
response.
THE SALT-SUSCEPTIBLE RAT/Rapp
The calcium antagonist nifedipine, when administered to hypertensive S rats on high salt, lowered
blood pressure into the normal range and maintained it
there for 12 weeks, in spite of continued high salt
intake." 5 If nifedipine treatment was started with the
high salt diet, the development of hypertension was
prevented." 6 In contrast, the converting enzyme antagonist captopril had no effect on salt-induced hypertension in S rats.89
15.
16.
17.
18.
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Conclusions
The blood pressure response to salt (NaCl) in Dahl
salt-susceptible (S) and salt-resistant (R) rats is inherited as a polygenic trait. The genetic loci involved not
only alter the blood pressure response to salt but also
alter blood pressure responses to other experimentally
induced forms of hypertension. Experimental evidence
indicates important roles for the kidney, adrenal cortex, nervous system, and unidentified humoral factors
in regulating blood pressure in S and R rats. Only in the
adrenal cortex has a genetic locus, which is involved in
regulating blood pressure, been identified.
19.
20.
21.
22.
23.
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Hypertension. 1982;4:753-763
doi: 10.1161/01.HYP.4.6.753
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