Effect of Dietary Salt on Hemodynamics of
Established Renal Hypertension in the Rabbit
Implications for the Autoregulation Theory of Hypertension
P A U L I. KORNER, M.D.,
JUDITH R. OLIVER, B . S C , AND D A V I D J. CASLEY, M S . A P P . S C .
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SUMMARY Two groups of 10 rabbits were subjected to renal cellophane wrapping and sham operation.
Their initial mean arterial pressures (MAP) were similar, 92 ± 1.5 and 90 ± 2.9 mm Hg. Six weeks later
three experimental periods began, each of 2 weeks' duration, on low, normal, and high salt (1,9, and 50 mmole
Na/100 g food) diets. Each group had two subgroups: rabbits with both kidneys, and rabbits with only one
kidney and previous nephrectomy. The hemodynamic findings were similar in each group. After sham operation, the range of dietary salt produced no significant circulatory changes. After wrapping, MAP was reduced
on low compared with normal and high salt diets (122 TS 132 and 136 mm Hg;p = 0.01). This was entirely due
to lowering of cardiac output (CO) on low salt; on normal and high salt CO was higher than in sham-operated
rabbits. Total peripheral resistance (TPR) in the wrapped animals was unaffected by diet, i.e., 21.4,20.5, and
21.2 units on low, normal, and high salt — about 35% above values of sham-operated rabbits. Volume-related
CO changes therefore produce long-term changes in MAP without alteration in TPR, which is not in conformity with the autoregulation theory of hypertension. Evidence of impaired capacity of wrapped compared with
sham-operated rabbits to handle salt included diet-related bematocrit changes, lower creatinine clearance, and
some differences in renin responses to salt. Giving saralasin reduced TPR while the rabbits were on low salt;
the fall was twice as great in wrapped compared with sham-operated rabbits.
(Hypertension 2: 794-801, 1980)
KEY WORDS • autoregulation theory • blood pressure • cardiac output
• renin • salt • saralasin • vascular resistance • volume
E
• hypertension
In some of the studies above, animals were placed
on different regimes before and during development of
hypertension (when the kidney's capacity to handle
salt may itself change) rather then during stable established hypertension (when the quantitative effects
of different salt loads might be easier to assess). The
hemodynamic mechanisms involved in the possible
long-term effects of salt and fluid loads are also unclear. In some of the experiments with large salt loads
or renal impairment, rises in cardiac output (CO) have
sometimes preceded elevation of total peripheral
resistance (TPR). 1 8 '" This has been explained by the
autoregulation theory of the pathogenesis of hypertension20"" as a transformation of "volume" factors
(influencing CO) into increased resistance. However,
the initial complex sequence of CO and TPR changes
has not been uniformly observed, and recently some
doubts have been expressed about how far a phase of
elevated CO is important in the development of
hypertension.18'19' 2S"M
The purpose of the present investigation has been to
study the effects of moderate increases and decreases
in dietary salt on the mean arterial pressure (MAP),
CO, and TPR in rabbits with established cellophanewrapped hypertension and in sham-operated rabbits.
This has provided a further test of the predictions of
the autoregulation theory.
PIDEMIOLOGICAL analysis has suggested a
strong association between the average salt
intake in different countries and the incidence
of hypertension. 1 ' However, evidence for such an
association has been less striking with data from certain countries (e.g., Dawber et al.4). Similarly, in
many types of experimental hypertension, altering the
salt intake has produced only small effects on blood
pressure. Increasing the salt intake in one-kidney
renovascular hypertension, perinephritis hypertension,
and several types of genetic hypertension produced
either small or no rise in blood pressure, 610 except
with very high salt loads, dietary protein deficiency, or
after markedly reducing the renal mass. Decreasing
the level of salt in these models produced only slight, if
any, lowering of the blood pressure except if the salt
intake was almost zero and the diet was also low in
protein."'T-14-17
From the Baker Medical Research Institute, Melbourne,
Australia.
Supported by a grant from the National Health and Medical
Research Council of Australia.
Address for reprints: Professor P. I. Korner, Baker Medical
Research Institute, Commercial Road, Prahran, Victoria 3181,
Australia.
Received January 14, 1980; revision accepted May 16, 1980.
794
SALT AND ESTABLISHED
Methods
Animals and Operations
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Female rabbits bred from a colony developed from
several multicolored English strains underwent renal
cellophane wrapping or sham operation under
halothane anesthesia after induction with propanidid.*3 A thermistor catheter (for measuring CO) was
inserted into the descending abdominal aorta through
the iliolumbar artery, with its tip about 5 mm below
the renal artery; in this location there are no detectable losses of thermal indicator injected at room
temperature into the right atrium."• M Perivascular
balloons had also been placed around the descending
aorta and inferior vena cava for studying the properties of the baroreceptor-heart rate reflex, unrelated to
the present experiments.™ Each group of rabbits had
two subgroups: one in which both kidneys were either
wrapped in cellophane or merely exposed through the
same type of flank incision during sham operation;23
and one in which one kidney was removed and the second either wrapped or exposed. The rabbits were
studied on 3 experimental days, when minor operative
procedures (e.g., catheterization of the central ear
artery and vein) were performed under local 0.5%
lidocaine anesthesia.™
Measurements
Ear artery pressure, right artery pressure (RAP),
and heart rate were recorded as described previously."
Cardiac output was determined by thermodilution
after rapid injection of a known volume (about 0.4 ml)
of 5.5% dextrose into the right atrium using the injection apparatus and computer for determining the area
of the primary curve described previously.18
Urine was collected through a funnel and mesh
from the animal's metabolic cage into a glass cylinder
containing a known amount of HC1 and a small quantity of mineral oil. The urine volume was measured,
the urine further acidified to dissolve urates and
sodium, and the potassium concentrations determined
by flame photometry. Creatinine was determined by
autoanalyzer.
On the day of the experiment, fresh arterial blood
was collected for microhematocrit estimation, for
measuring plasma sodium, potassium, and creatinine
concentration, and for determining plasma renin activity (PRA) and plasma renin concentration (PRC).
The latter was measured by radioimmunoassay into
0.1 ml cold BAL/EDTA solution and immediately
centrifuged cold; 100 /xl aliquots were frozen and
stored for subsequent radioimmunoassay.*0-J1
Plan of Experiment
The rabbits remained in individual metabolic cages
from the time before the operation throughout the
study. For the first 6 weeks after operation, they were
given their ordinary pellet diet of normal sodium composition. The main part of the experiment then began
in three periods, each of 2 weeks, in which the rabbits
received pellets of either low, normal, or high salt
HYPERTENSION/KO/TW
et al.
795
composition plus tap water ad libitum. A Latin
Square experimental design was used to eliminate bias
in the order of their administration."
The sodium and potassium concentrations of the
pellets were as follows: low salt = Na 1.1, K 25.6
mmoles/100 g pellets; normal salt = Na 8.9, K 25.2
mmoles/100 g; and high salt = Na 50, K 26.4
mmoles/100 g. Their composition was otherwise the
same, i.e., approximately 20% protein, 4% fat, 65%
carbohydrate (starch), 10% fiber, plus vitamins and
salt-free minerals; the energy value was about 260 k
cal/100 g.
Urine was collected for the last 4 days of each 2week period on each diet. Collections were made over
Days 3 and 4 and Days 1 and 2 before the
hemodynamic study. In each group there were no
significant differences in urine volume, sodium,
potassium, and creatinine excretions over the two
collection periods, suggesting that the animals were in
a stable state of fluid balance. The results reported
here refer to Days 1 and 2 before the hemodynamic
study. Blood samples for creatinine (and other) estimations were taken only at the time of the latter
study to avoid excessive sampling in the rabbit, and we
have used this value and the urinary excretion data to
estimate creatinine clearance.
On the day of the experiment, the rabbit rested for
30 minutes in its box after completion of the minor
operative procedures. An arterial blood sample of
about 2.5 ml was then taken followed by another 20minute rest period. Five sets of measurements of
MAP, RAP, and CO were then obtained at 2-minute
intervals, and TPR was calculated as (MAP — RAP,
mm Hg)/(CO, ml/min) units; the average of each
variable was taken as the animal's value for that part
of the experiment. About 30 minutes later (following
tests of baroreceptor-heart rate reflex function not
relevant to this paper) a second 1.3 ml sample of
arterial blood was taken for a second set of PRA and
PRC determinations. The animals then received an infusion of saralasin (sarcosine1 — alanine* — angiotensin II) 6 ^g/kg/min i.v. This produced an approximately 100-fold shift to the right in the angiotensin II
(A II) — MAP dose response curve to bolus injections
of synthetic valine A II (Hypertensin, Ciba) and completely blocked the pressor effect of a bolus of 0.25
fig/kg/i.v. of A II. Saralasin was infused for 60
minutes before obtaining another five sets of
hemodynamic measurements as before.
After the last experiment the animals were killed
with an overdose of sodium pentobarbital and the
organs rapidly removed, drained of blood, and
weighed after washing in saline. Kidney and heart
were also examined histologically after fixation in 10%
formalin-saline.
Statistical Analysis
Significance of differences within rabbits was
assessed by two-way analysis of variance, with
orthogonal partitioning of the "between salt diets"
sums of squares into individual degrees of freedom."
796
HYPERTENSION
VOL 2, No 6, NOVEMBER-DECEMBER 1980
WRAP
SHAM
For estimating the significance of differences of PRA,
PRC, and urinary sodium excretion, logarithmic
transformation of the data was employed. Comparison of CO values between normotensive and
hypertensive animals and the different weights were
assessed by unpaired t test and by the Mann-Whitney
U test."
l40 r
120
MAP
100
.-
mmHg
Results
80
Hemodynamic Findings
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The preoperative MAP levels and body weights
were similar in rabbits subsequently subjected to renal
wrapping (MAP = 91.5 ± 1.45 (SEM) mm Hg;
2.59 ± 0.11 kg; n = 10) and sham operation
(89.6 ± 2.88 mm Hg; 2.51 ± 0.08 kg; n = 10). In both
groups, body weight had altered little from initial
values during the main part of the experiment from 6
to 12 weeks postoperatively, and there was no effect
due to dietary salt (table 1).
In sham-operated rabbits, MAP also remained
close to the preoperative value on all three levels of
salt (fig. 1). In this group the different diets had no
700
CO
600
ml/min
500
20
TPR
15
FIGURE 1. Average values of mean arterial pressure
(MAP), cardiac output (CO), total peripheral resistance
(TPR), and hemalocrit (H'CRIT) in 10 sham-operated and
10 renal-wrapped rabbits using pooled data of rabbits with
two kidneys and with only one kidney. Each animal was
studied after 2 weeks on low (L), normal (N), and high (H)
salt. Horizontal interrupted line is preoperative MAP.
Asterisk denotes significant change (p < 0.05) within
animals from the value on normal salt. Standard error of
mean (within animals) of each column is SD (from table
units
10
40
H'CRIT
30
20L
L
N H
L N H
TABLE 1. Average Hemodynamic, Hematocrit and Body Weight Values on Txrw, Normal, and High Sail Diets in Sham-Opcratetl
and Renal-Wrapped Rabbits with both Kidneyt (£K) and with only one Kidrun/ phis Nephrcctomy (IK)
Measure
Mean arterial pressure
(mm Hg)
Cardiac output
(ml/min)
Right atrial pressure
(mm Hg)
Heart rate
(beats/min)
Low
2K
87.6
89
89.8
IK
86.6
89.0
89.5
SD
IJOW
Ren al-wrapped
Hiffh
Normal
126
133
137.6
118.2
131.8
135.2
614
*
569
712
766
699
709
-1.8
-2.1
-12
-1.7
-1.0
-1.6
269
259
276
226
240
262
(±5.0)
2K
660
688
579
(±84.4)
IK
517
573
569
2K
-0.7
-1.6
-2.5
IK
-2.0
-2.7
-1.7
2K
271
268
274
(*1.D
2K
249
2.69
262
2.71
275
2.69
(±104.2)
(±0.9)
(±33.3)
2.55
2.53
2.59
2.51
2.58
2.58
(±0.12)
IK
2.38
2.43
2.37
SD
(±11.0)
(±28.7)
IK
Body weight
(kg)
Sham-operated
High
Normal
Rabbit
(±0.11)
n = 5 each subgroup; Low, Normal, High refer to dietary salt Figures in parentheses are SD obtained from analysis of
variance as (error mean square)^.
*Low compared with average of normal + high salt, p < 0.05, using pooled data of both subgroups.
SALT AND ESTABLISHED HYPERTENSION/Ko/vier et al.
797
Effect of Saralasin
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significant effects on CO, TPR, and heart rate, and the
findings were similar in the two subgroups of rabbits
with two and only one kidney (table 1).
In the two subgroups of renal hypertensive rabbits,
the findings were again closely similar (table 1). After
pooling the results (fig. 1) MAP was not significantly
different on normal and high salt diets (means 132.4
and 136.4 mm Hg respectively) but was reduced on
low salt (122 mm Hg;/> within animals = 0.01). This
fall in MAP was entirely accounted for by reduction in
CO on low salt (p < 0.05). The TPR remained closely
similar on low, normal, and high salt, with values of
21.4, 20.5, and 21.2 units respectively.
In the hypertensive rabbits, the CO values on normal (705 ml/min) and high (738 ml/min) salt diets
were above the average value (601 ml/min) and range
observed in sham-operated rabbits (p < 0.05 by
Mann-Whitney U test) (fig. 1). Heart rates were
variable and not significantly different on the three
diets (table 1). Stroke volumes were higher in the
wrapped rabbits on normal and high salt (2.8 ± 0.21
ml) than in sham-operated rabbits on the same diet
(2.26 ± 0.11 ml;p = 0.05). Low salt brought the CO
of the wrapped rabbits (604 ml/min) into the range of
the sham-operated animals, but had a less pronounced
effect on stroke volume (2.53 ± 0.21 ml).
Hematocrit did not alter significantly in shamoperated rabbits on low, normal, and high salt (34.8,
35.3, and 34.8% respectively). By contrast, in the
renal-wrapped group, the hematocrit on low sodium
(32.8%) was 2.3% ± 0.7% (p < 0.01) greater than the
average on normal (31.5%) and high (29.6%) salt; on
high salt it was significantly less than on normal salt
(SED ± 0.86; p < 0.05) (fig. 1, table 1).
In sham-operated rabbits, 1 hour of saralasin infusion reduced MAP in animals on low and normal salt,
but not on high salt (table 2). However, it was only on
low salt that the fall in MAP was consistently
associated with reduction in TPR. In the renalwrapped group, saralasin infusion was associated with
a fall in MAP on all three diets, but again it was only
on low salt that TPR was also reduced, a reduction
about twice as great as that in sham-operated rabbits
(table 2). In the hypertensive animals, the fall in TPR
was associated with an increase of about 10% in CO
(table 2). Saralasin produced no significant changes in
heart rate in either group on low and normal salt, but
on high salt there was a small reduction in beats/min
of 14.4 ± 5.3 (wrapped) and 14.9 ± 6.1 (sham)
(p = 0.05). In both sham-operated and renal-wrapped
rabbits, the changes in RAP after saralasin were
variable on all diets and were not significant.
After All blockade, the pattern of absolute "Allindependent" values of MAP, CO, and TPR on the
different diets differed from that observed before
blockade (table 2). In sham-operated rabbits, the
difference in MAP between low and high salt was
slightly greater than before saralasin (0.1 > p >
0.05), while TPR was about 7% greater on high
salt than on the other diets (p = 0.05). In the
renal-wrapped rabbits, the absolute MAP values after
saralasin were somewhat lower than before blockade
on all diets, but the difference between low salt on the
one hand and normal and high on the other was the
same as before (table 2). However, the more marked
reduction in MAP on low salt was now no longer
solely accounted for by reduction in CO, which had in-
TABLE 2. Pooled Hemodynamic Data on Different Dietary Salt in 10 Sham-Operated and 10 Renal-Wrapped Rabbits Before and
During Infusion of Saralasin
Low
Measure
B
S
Mean arterial pressure
(mm Hg)
A
"±" 8BD
Cardiac output
(ml/min)
±
B
S
592
A
17
SED
B
S
Total peripheral
resistance (units)
A
±
86.6
76.7
-9.9
±2.0*
BED
609
±16.4
15.3
13.6
-1.7
±0.6*
vSham-operated
High
Normal
89.9
80.0
-9.9
±3.0*
636
604
-32
±35.1
15.5
14.4
-1.1
±0.7
8 EM
89.5
85.6
-3.9
±2.7*
(±1.6)
(±3.2)
574
580
(±26.7)
(±33.3)
+6
±24.0
16.3
15.9§
-0.4
±0.9
(±0.76)
(±0.75)
Low
Renal-wrapped
High
Normal
SEM
136.6
126.0
-10.4
±3.3*
(±3.4)
-12
±4.6*
132.4
125.4
-7.0
±3.0*
604f
665
61
±29.6*
705
704
-1
±2.6
737
(±44.3)
(±54.8)
21.4
17.9
-3.5
±0.6*
20.5
19.4
-1.1
±0.9
122ft
nott
718
(±6.8)
-19
±25.0
21.2
19.6
-1.6
±1.4
(±1.7)
(±1.9)
B = before saralasin; S = during saralasin; values in parentheses are standard error of mean (SEM) from analysis of variance.
A is (S —B); ± SED is standard error of difference within rabbits; *p < 0.05 for change after saralasin.
fp < 0.05 for within animal difference low compared with average of normal + high salt,
jp < 0.01 for within animal difference of low compared with average of normal + high salt
§p < 0.05 high compared with average of normal and low salt
798
HYPERTENSION
creased in this group after saralasin. Thus, in the
hypertensive animals on low salt, CO levels were not
brought as effectively into the range of CO values of
normotensive rabbits as before giving the All antagonist (table 2).
Plasma Renin
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Both PRA and PRC increased on low compared
with normal salt intake and fell slightly on high salt
(table 3). For each diet the difference in average values
of PRA and PRC between sham-operated and renalwrapped groups was not statistically significant.
However, in the wrapped group, PRA and PRC
values tended to be somewhat higher on low sodium
and somewhat lower on high sodium than in shamoperated rabbits, so that the difference in logarithmically transformed renin values on these two
diets was greater than in sham-operated animals
(table 3; p = 0.05).
Plasma and Urine Sodium and Creatinine
In sham-operated rabbits, urinary sodium excretion
was least on low salt and greatest on high salt, but
plasma sodium concentration did not change (table 4).
Plasma and urinary creatinine did not alter with salt
intake (table 4). Urinary sodium and creatinine excretion was the same in both subgroups of rabbits, but in
rabbits with only one kidney plasma creatinine was
about 50% higher than in those with both kidneys, i.e.,
their creatinine clearance was lower.
In renal-wrapped rabbits the daily sodium excretion
on normal and high salt was less than in shamoperated rabbits (table 4; p = 0.05; see Discussion).
Another difference was that in the hypertensive rabbits on low salt the plasma sodium was about 2
mmoles/liter lower than in those on normal and high
salt (p = 0.05), while in sham-operated rabbits it did
not change (table 4). In addition, in each subgroup of
hypertensive rabbits plasma creatinine levels were
significantly higher than in the corresponding subgroup of sham-operated normotensive animals (table
4). Urinary creatinine excretion did not alter with the
different levels of salt in each group. However, it was
slightly smaller in the wrapped rabbits, so that the estimated creatinine clearance was about 30% lower
than in the sham-operated group.
VOL 2, No 6, NOVEMBER-DECEMBER 1980
Organ Weight
Heart and left ventricular weights were about 50%
higher in the wrapped rabbits (7.92 ± 0.65, 5.0 ± 0.33
g respectively) than in sham-operated animals
(5.50 ±0.18,3.30 ± 0.16 g). There were no significant
differences between the renal parenchymal weights
(after removing the capsule) of the two groups. The
fibrous capsule of the hypertensive animals weighed
approximately 25-30% of the weight of the renal
parenchyma. In rabbits with only one kidney there
was little evidence of "compensatory" hypertrophy
following removal of the other kidney, so that in uninephrectomized rabbits renal weight was about 50% of
that of rabbits with two kidneys.
Discussion
Moderate increases and decreases of dietary salt
produced no circulatory changes in sham-operated
rabbits. However, in rabbits with established
hypertension, low salt reduced MAP by about 12 mm
Hg; i.e., by 25% of the rise in blood pressure in rabbits
on normal salt after cellophane wrapping. In the
wrapped rabbits, TPR was about 34% above the value
of sham-operated rabbits but did not alter with dietary
salt intake. The lowering of MAP on low salt was entirely due to reduction in CO, which was brought from
its elevated value on the other diets into the "normal"
range of sham-operated rabbits. The probable
mechanisms by which CO fell in hypertensive rabbits
on low salt included 1) reduction in blood volume, estimated from the hematocrit changes (see below), and
2) the peripheral constrictor action of All assessed
from the saralasin experiments (table 2).
The conclusion, based on hematocrit changes, that
in the hypertensive rabbits blood volume decreased on
low salt and increased on high salt must be interpreted
with caution." We have regarded them as directional
indicators (but not quantitative") of changes in blood
volume. They only occurred in hypertensive rabbits,
but not in sham-operated animals subjected to the
same protocol. The relatively higher stroke volumes in
the former group and the somewhat greater renin suppression on the high salt diet both favor the conclusion
of an elevated central blood volume."-" However,
TABLE 3. Average Values of Plasma Renin Activity (PRA) and Plasma Renin Concentration (PRC)
Low
Sham-operated (n = 10)
Normal
High
BE
Low
Renal-wrapped (n = 10)
Normal
High
8E
PRA
(ng/ml/hr)
2.91
(0.445)*
2.21
(0.339)
1.90
(0.240)*
(0.041)
4.45
(0.548)*
2.37
(0.309)
1.51
(0.114)*
(0.082)
PRC
(ng/ml/hr)
7.10
(0.826)*
5.38
(0.714)
4.29
(0.593)*
(0.044)
8.07
(0.84O)*
4.47
(0.617)
3.22
(0.458)*
(0.068)
Analysis of logarithmic transformation of data shown in brackets.
'Significantly different from normal salt value.
SALT AND ESTABLISHED HYPERTENSION/ATorner el al.
799
TABLE 4. Average Values of UrineVolume, Sodium, and Crealinine Excretion and of Plasma Sodium, and Creatinine Concentmiions
Measure
Rabbit
Urine volume
(ml/min)
Plasma sodium
(mmole/liter)
Urine sodium
(mmole/day)
Ave
2K
IK
Plasma creatinine
(mmole/liter)
Ave
2K
IK
Urine creatinine
(mmole/day)
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Ave
2K
IK
Low
Sham-operated
High
Normal
8E
92
119
168*
12.6
139
140
139
1.3
0.36*
(0.47)
(0.26)
7.0
(6.1)
(7.9)
37.2*
(40.4)
(34.5)
0.10
(0.080)
C0.120)
0.10
(0.080)
(0.118)
0.90
(0.98)
(0.83)
1.03
(1.02)
(1.03)
Low
96
Renal-wrapped
Normal
High
84
129*
141.4
137.6*
142.1
t
0.61*
(0.8)
(0.39)
3.76
(4.53)
(2.80)
24.4*
(25.3)
(23.4)
0.104
(0.080)
(0.124)
0 0036
0.123
(0.094)
(0.152)
0.119
(0.110)
(0.130)
0.110
(0.094)
(0.130)
0.92
(0.90)
(0.94)
0.056
0.81
(0.86)
(0.74)
0.87
(0.85)
(0.90)
0.79
(0.80)
(0.79)
SE
14.9
1.53
± 0.0082
± 0.075
"Significantly different from normal salt value p < 0.01.
2K, IK = subgroups with both kidneys and with only one kidney.
fSignificanee assessed after logarithmic transformation.
diet-related changes in osmolality (e.g., related to the
fall in plasma sodium on low salt) could have contributed to the changes in hematocrit.
In wrapped rabbits, PRA (and PRC) increased
slightly more on low salt and decreased slightly more
on high salt than in sham-operated animals. The work
of Swales and colleagues14 suggests that in these rabbits there may have been a greater change in body
sodium on altering diets than in sham-operated rabbits which probably maintained normal sodium on all
diets." The fall in plasma sodium, the diet-induced
changes in hematocrit, and somewhat exaggerated
renin responses of the wrapped animals are consistent
with this view. It should be noted that on normal and
high salt the PRA (and PRC) levels of rabbits of both
groups were distinctly higher than in resting conscious
dogs on their normal, relatively high, sodium intakes
as determined in our laboratory by the same assay.11
This may be a factor in the apparent difficulty of renal
hypertensive rabbits of maintaining body fluid
volumes with relatively modest dietary salt loads.
Saralasin lowered the MAP in rabbits not only on
low salt but also on some of the other diets. Only on
low salt was there consistent blockade of Allmediated vascular constriction since this diet alone
was associated with significant reduction in TPR. The
fall in TPR was about twice as great in hypertensive as
in normotensive rabbits, similar to the previously
observed difference in constrictor sensitivity of the
hindlimb vessels to norepinephrine, All, and
vasopressin between the groups.37'" Therefore, the
difference of the constrictor sensitivity to endogenous
All in wrapped and sham-operated rabbits on low salt
in the present study was probably nonspecific and
mainly determined by structural changes in the
hypertensive resistance vessels." This seems more
likely to account for the twofold difference in TPR
response than the small differences in PRA and PRC
between the hypertensive and normotensive rabbits on
low salt. The significant rise in CO after giving
saralasin to hypertensive rabbits on low salt differs
from findings in man where CO either does not change
or falls.40 The small degree of bradycardia that
developed on saralasin in both wrapped and shamoperated rabbits on high salt is similar to that recently
reported with Sar1, Thr'-AII in the dog;41 its
significance is uncertain.
In the two subgroups of wrapped rabbits the
creatinine clearance was about 30% less than in the
corresponding subgroup of sham-operated animals.
The work of Brace and colleagues" suggests that it is
the increase in renal tissue pressure that occurs after
cellophane wrapping that is the major factor in altering renal function. They found that in dogs the
pressure that developed 4 weeks after cellophane
wrapping was 30 mm Hg. This could have been even
greater in the present experiments because of their
longer duration. The intrarenal mechanisms contributing to greater salt and fluid retention were not
examined in our study; they were clearly not just a
reduction in renal mass since the hemodynamic and
blood volume changes were similar in the wrapped
subgroups with one and two kidneys.
In our study only urine volume and sodium output
were measured, and not intake. In each group urinary
output values were stable over the last 4 of the 14 days
on each diet (see Methods). This suggests that the
animals were in a stable state of fluid and sodium
balance at that time. Hence the smaller daily sodium
output on normal and high salt of the hypertensive
compared with sham-operated groups probably
reflected a difference in their intakes, or greater loss
800
HYPERTENSION
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by the fecal route. Both would tend to make less apparent the true degree of impairment of sodium
homeostasis in the hypertensive animals.
Our finding that MAP in the wrapped rabbits on
normal and high salt was raised entirely through an increase in CO is at variance with the predictions of the
autoregulation theory of the pathogenesis of hypertension. According to these, one would have expected
that after 2 weeks on each diet there would be little
difference in the CO values but an increasing TPR
with increased salt intake.21' Mi " We did not measure
hemodynamics at an earlier stage of each dietary
period, and there may have been even larger changes
in CO at that time."1 M However, if long-term
"autoregulatory" processes were at work there should
have been a demonstrable salt-related difference in
TPR after 2 weeks on the different diets.
Our results suggest that CO can exert prolonged
effects on MAP independently of TPR. This has also
been observed by Bravo et al.*4 in steroid hypertension
in the dog where in about half their animals MAP was
raised for several weeks entirely through elevation of
CO.
We have previously studied the development of
renal-wrap hypertension in another strain of rabbits.13
Comparison of the time course of hemodynamic
changes in wrapped and sham-operated rabbits maintained throughout on the same normal salt diet
suggested that hypertension was entirely TPRmediated from the beginning; an early rise in CO occurred in both groups and was considered to be a nonspecific accompaniment of surgery unrelated to the
subsequent development of hypertension.2*
These two studies suggest that in the pathogenesis
of renal-wrap hypertension "volume" and "constrictor" factors play a causally independent role and are
not interrelated as envisaged by the transformation of
CO to TPR postulated by the autoregulation theory.
We cannot be certain that the independence of these
two factors also applies to other models of experimental hypertension or to different types of human
hypertension. However, we believe that to regard
them as independent is at present a better working
hypothesis than to regard them as closely interrelated,
as implied in the concept of long-term autoregulation,
and is probably more useful in the search for different
pathogenetic causes of hypertension. In many of the
earlier studies, the experimental designs would
generally not have permitted a distinction as to
whether "volume" or "constrictor" factors were independent or interrelated. Many of the studies were
performed during development of hypertension, and
early CO changes could appear to become
transformed into TPR changes even if volume and
constrictor factors were altered independently but at
different rates. To date, most of the autoregulatory
processes described have been fairly rapid processes,
of several minutes' duration, ones that play an important role in adjusting tissue blood flow to local requirements." Their importance in moment-tomoment control is recognized in both normotensive
VOL 2, No 6, NOVEMBER-DECEMBER 1980
and hypertensive circulations. However, there is at
present no firm experimental evidence for a special
process of long-term autoregulation envisaged by the
autoregulation theory of hypertension.
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P I Korner, J R Oliver and D J Casley
Hypertension. 1980;2:794-801
doi: 10.1161/01.HYP.2.6.794
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