Comparable Effect of Isotonic Infusions on
Blood Pressure in the Anephric Rat
H O L U S D. KLEINERT, P H . D . , BRUCE R. LESLIE, M.D.,
E. DARRACOTT VAUGHAN, J R . , M.D.,
JOHN H. LARAGH,
M.D.,
AND JEAN E. SEALEY, D . S C .
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SUMMARY Whether and to what extent sodium chloride infusions elevate blood pressure acutely
were examined in conscious, normotensive, and spontaneously hypertensive (SHR) anephric rats. All
animals were bilaterally nephrectomized 18 hours before study.
Normotensive Wistar rats, allowed no food or water post nephrectomy (Groups I-IV), received
either no infusion (Group I, control) or intravenous infusion of isotonic solutions of either NaCI,
mannitol, or dextrose at a rate of 0.018 ml/min for 2 hours. Mean arterial pressure (MAP) measurements were determined directly by arterial catheter for control (C), 1 hour, and 2 hours. Blood
pressure was increased above control in all groups at 1 hour and 2 hours (p < 0.05). The increase in
MAP with NaCI was similar to that with no infusion or infusion of mannitol or dextrose. Normotensive
Wistar rats (Groups V-VI) and SHR (Group VII) were allowed free access to food and water post
nephrectomy and received either no infusion (Group V, control) or infusion of isotonic saline at a rate
of 0.037 ml/min for 2 hours. MAP was elevated above control in all groups (V-VII) at 1 and 2 hours (p
< 0.05). The magnitude of the rise was similar among all groups. Food and water accessibility post
nephrectomy did not alter results. In both sets of experiments when saline was infused we were unable
to identify any increase in blood pressure greater than control at either infusion rate. In fact, we
continued the saline infusion in Group VI, until 100 ml of saline was infused without any elevation in
blood pressure above control. We conclude that during the 2 hours of observations neither sodium nor
chloride ions exert an independent eifect on MAP in normotensive or hypertensive anephric rats when
compared to no infusion or isotonic isovolemic infusions of mannitol or dextrose during the same time
period. (Hypertension 5: 421-426, 1983)
KEY WORDS • sodium chloride • mannitol • dextrose • Wistar Kyoto rats
spontaneously hypertensive rats • acute infusions
C
HRONIC dietary administration of sodium
chloride may elevate blood pressure under a
variety of specific conditions.'"3 It has been
assumed that this action is mediated indirectly because
of accompanying fluid retention and the resultant increase in intravascular volume. 4 Although the volume
theory is widely accepted, other mechanisms such as
release of a slow pressor substance have been suggested5' 6 as an alternate means by which sodium chloride
indirectly induces an elevation in blood pressure.
Although there exists a large body of literature on
chronic sodium administration and blood pressure,
there are few studies dealing with the effects of acute
sodium administration on blood pressure. In 1980,
Hatzinikolaou et al., 7 found higher blood pressures in
normotensive anephric rats receiving acute infusions
of hypertonic saline than in those receiving hypertonic
mannitol. The pressor action of hypertonic saline was
not completely inhibited by a vasopressin antagonist,
and the difference between the blood pressure after
vasopressin (AVP) blockade, and control was greater
in the saline group. We inferred that the hypertensive
effect following hypertonic saline infusion and AVP
blockade could have been due to a direct pressor action
of sodium chloride, above the osmotic stimulation of
vasopressin. If this is correct, then one might expect
that the acute infusion of isotonic sodium chloride
should result in a greater pressor activity than infusion
of other isotonic solutions, which may even lower
blood pressure by dilution. Isotonic, rather than hypertonic solutions, have the advantage of not stimulating
the osmoreceptors, and thus avoid the pressor effect of
the resultant vasopressin release. It should be recognized that such a series of experiments should be able
to address the question of whether isotonic saline has a
From the Cardiovascular-Hypertension Center, and Department
of Surgery (Urology), New York Hospital-Cornell University
Medical College, 525 East 68th Street, New York, New York.
Supported in part by the James Buchanan Brady Foundation and
Grants NHLBI-18323-SCR and HL-07379 from the National Institutes of Health.
Address for reprints: Dr. Hollis D. Kleinert, Cardiovascular Center, New York Hospital-Cornell University Medical College, 525
East 68th Street, New York, N.Y. 10021.
Received April 14, 1982; revision accepted December 8, 1982.
421
HYPERTENSION
422
pressor action acutely, and answer whether the sodium
ion plays a physiologically active or passive role. It
leaves open the question of whether concentrations of
sodium ions above the normal range are pressor.
Therefore, the present study was undertaken to determine whether isotonic sodium chloride acts acutely
as a pressor agent by testing its effect in conscious
anephric normotensive and spontaneously hypertensive rats. The anephric preparation was selected because acute administration of sodium chloride to animals with kidneys results in rapid natriuresis.8 Further,
since the level of sodium sensed at the macula densa is
inversely related to renin-angiotensin activity,9 a pressor effect might be masked by a concurrent fall in
circulating angiotensin II. Since pressor sensitivity to
sodium chloride may vary according to the preexisting
level of blood pressure,10 both normotensive and hypertensive rats were studied.
VOL 5,
No
4, JULY-AUGUST
1983
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sion, solutions were determined to be isotonic by Osmette Osmometer (Precision Systems, Inc., Sudbury,
Massachusetts) and delivered through the venous catheter using a Harvard Infusion Pump (Harvard Instruments, Millis, Massachusetts).
At time zero, 18 hours after nephrectomy, control
measurements of blood pressure and HR were recorded. The procedure then differed in accordance with
each particular series. Groups I—IV had no access to
food or water following nephrectomy. Group I served
as control (no infusion). Groups II—IV received infusions at a rate of 0.018 ml/min fora period of 2 hours.
The total volume infused was 2.2 ml. Group II received 0.9% NaCl solution; Group III received 5%
mannitol solution, and Group IV received 5% dextrose
solution.
Groups V-VII were allowed free access to food and
water following nephrectomy. Group V served as control (no infusion). Groups VI and VII received infusions at a rate of 0.037 ml/min for 2 hours totaling 4.4
ml. Group VI received 0.9% NaCl solution. In Group
VI, after the standard 2-hour period, the infusion rate
was increased to 1 ml/min, until a total volume of 100
ml had been infused. Group VII, the only group of
SHR, was infused with 0.9% NaCl.
Statistical analysis of the data was performed using
paired or unpaired Student t test. Significance was
accepted at p < 0.05.
Methods
Male normotensive Wistar rats and Okamoto-Aoki
spontaneously hypertensive rats (SHR), weighing between 225-300 g were maintained on normal Purina
rat chow. Seven experimental protocols were carried
out. For Groups I—VI we had eight normotensive rats
in each group and for Group VII had eight SHR. All
animals, 18 hours prior to study, underwent bilateral
nephrectomy under Na pentobarbital anesthesia, 30
mg/kg. Following nephrectomy, the animals were allowed either no access or free access to food and water
as described below. On the day of the experiment, with
the rat under ether anesthesia, the femoral artery and
vein were cannulated with PE50 tubing. The rats were
restrained and allowed to recover from the anesthetic
for at least 90 minutes, before we recorded control
values and began a standard 2-hour period of experimentation. Mean arterial blood pressure (MAP) and
heart rate (HR) were obtained directly from the arterial
catheter by means of a Statham Pressure Transducer,
Model 23Db, and recorded on a Gould brush recorder
(Gould Inc., Saddle Brook, New Jersey). Prior to infu-
Results
Groups I-IV
Mean arterial pressure (MAP) for rats in control
Group I and in experimental infusion Groups II—IV,
are shown in figure 1. These groups were not allowed
access to food or water after nephrectomy. There was a
significant elevation in MAP over 2 hours in all of the
groups, including Group I, which received no infusion. The average increase in MAP at 2 hours was 7,
13, 13 and 11 mm Hg in Groups I-IV respectively.
There were no differences in the magnitude of the
increase in MAP among the groups. Thus, although
I
I Control
^
1 hour
FZ\ 2 hours
FIGURE 1. Effect of isotonic infusion on
mean arterial pressure (MAP) of normotensive
anephric rats, at time zero, I hour, and 2
hours. Group I served as a time control group;
Group II received an infusion of 0.9% NaCl;
Group III received an infusion of 5% mannitol;
and Group IV received 5% dextrose. Results
are expressed as means ± SEM. *Significance
at p < 0.05.
140
„
120
J-J
I
X
E 100
£
Q.
80
60
No Infusion
NaCl
Mannitol
Dextrose
Group II
Group III
Group 12
(Time control)
Group I
EFFECT OF ISOTONIC INFUSIONS IN THE ANEPHRIC RAT/Kleinert et al.
423
I I Control
^
Ihour
Fa] 2 hours
FIGURE 2. Effect of isotonic infusion on
heart rate of normotensive anephric rats at
time zero, I hour, and 2 hours. Group I served
as a time control group; Croup II received an
infusion of 0.9% NaCl; Croup III received an
infusion of 5% mannitol; and Group IV received a 5% dextrose infusion. Results expressed as means ± SUM. *Significance at p <
0.05.
500
c
E 400
I
300
B 20°
o
I
100
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each group exhibited a significant rise in MAP
throughout the experimental period, the magnitude of
the rise was similar, indicating that no particular treatment exerted a distinguishable effect on MAP.
The effect on HR is shown in figure 2. There was a
small yet statistically significant rise in HR in Group I
receiving no infusion. No significant changes were
seen in the HR of Groups II-IV receiving infusion of
the different solutions.
Effects of Accessibility of Food and Water
To explore the effects of dehydration and starvation,
we conducted similar experiments in Groups V-VII in
which rats were given free access to food and water
following nephrectomy. A comparison was made between control rats in Group I, which were not allowed
access to food and water after nephrectomy and control
Group V, in which rats were given free access to food
and water following nephrectomy. We found a significant rise in MAP over 2 hours and the magnitude of the
increase was similar (fig. 3). Therefore, food and water accessibility did not alter the blood pressure results.
Heart rate did not rise in Group V (table 1).
Group V served as a control for Groups VI and VII.
Group VI received an infusion of isotonic NaCl at a
rate twice that of Group II for 2 hours, totalling 4.4 ml.
The effects on MAP and HR are numerically described
in table 1. The MAP was significantly elevated at 1 and
2 hours, but did not increase more than that of control
Group V. Heart rate was reduced (p < 0.05) at 1 and 2
hours. Following the standard 2-hour period of experimentation, the rate of infusion in Group VI was increased to 1 ml/min, until a total of 100 ml had been
infused. The results are shown in figure 4. As described, MAP was significantly above baseline, but
not higher than in control Group V following 4.4 ml of
saline, and this same increment in blood pressure was
sustained until 20 ml of saline was infused. Following
this, MAP began to decline steadily, as did HR.
Group VII was the only group of SHR used in this
study; the effects of infusing isotonic NaCl solution 4.4
ml at 0.037 ml/min for 2 hours are shown in table 1.
No Infusion
(Time control)
NaCl
Mannitol
Dextrose
Group I
Group II
Group HT
Group W.
Like the normotensive animals, in SHR the MAP was
elevated significantly by 1 hour and the magnitude of
the increase was similar. Heart rate was significantly
reduced as in control animals (Group VI). The magnitude of bradycardia in Groups VI and VII was similar
(p > 0.05). The tendency of HR to fall was also seen in
control Group V, but it did not achieve statistical significance.
Discussion
In this study, there were no differences in the blood
pressure response of normotensive anephric rats to isotonic infusions of saline, mannitol, and dextrose or to
no infusion. Surprisingly, blood pressure increased
gradually and significantly over 2 hours in all animals
I
I Control
[••yy.-j 1 h o u r
im 2 hours
140
T
120
-X.
V
X
_L
*
CP
E 100 E
S:
Q. 80 60 -
No Infusion
No access to food
and H 2 0
Group I
A
No Infusion
Free access to food
and H2O
Group3£
FIGURE 3. Comparison between control groups given free access or no access to food and H2O. Results expressed as means
± SEM. *Significance at p < 0.05.
424
HYPERTENSION
TABLE 1. Effect
VOL 5,
No
4, JULY-AUGUST
1983
1
of Food and Water Accessibilityon
Blood Pressure and Heart Rate after Isotonic NaCI Infusion in
Anephric Rats
MAP (mm Hg)
Control
125±6.0
116±1.9
137±7.1
1 hour
2 hours
135±4.7*
125 ±2.4*
147±5.5*
132±5.5*
Group V
124 it 1.7*
Group VI
145±6.5*
Group VII
Results are expressed as means ± SEM.
•Significant at p < 0.05.
Heart rate (bpm)
1 hour
2 hours
377 ±26.0
418±8.8*
330±19.3*
365±31.0
410±14.6*
315 + 25.0*
gators found no immediate rise in pressure; rather, they
observed an increase of blood pressure after 1 week but
not earlier.
However, the pressor action of chronic sodium administration is not always observed. Wistar rats
weaned and raised on high salt diets failed to develop
hypertension.18 In another study, subtotal nephrectomy resulted in hypertension,19 the incidence of which
was increased in rats given saline, but the level of
hypertension was similar to those not given saline.19
The studies of Lucas and Floyer15 and Pelling and
Ledingham20 have shown that nephrectomized rats
chronically receiving either 0.5% or 1% saline as
drinking water become hypertensive over a period of
several days. However, in the Pelling and Ledingham
study,20 allowing the rats to drink a large supplement of
water rather than saline also increased blood pressure
significantly to the same extent. Thus, it appears that
saline administration was not the common denomina-
o Control
• Infusion
— Mean
en 140I
E
.E 120100-
1
Y
80
FIGURE 4. Group VI. Relationship between
volume of 0.9% NaCI solution infused and
hemodynamic parameters in the normotensive
anephric rat.
1(/>
A
A
500-
XI
A
•
\A
"o
t rate
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including those not receiving any infusion. This rise in
blood pressure following nephrectomy has been reported previously for rats and dogs;" l2 although this
finding has not been observed consistently.l3 i4 Several
explanations for increases in blood pressure following
nephrectomy have been suggested, including reductions in tissue compliance15 and lack of inactivation of
an extrarenal pressor mechanism in the rat.16 It is also
possible that an increase in serum osmolarity accompanied by a concomitant elevation in the circulating ADH
titer may contribute to postnephrectomy blood pressure elevation; however, these measurements have not
been made.
Although studies examining chronic high sodium
intake are fairly numerous,1 5 the literature has few
reports on the acute effects of sodium on blood pressure. The chronic sodium pressor effect has been better
expressed in models that restrict or eliminate kidney
function.3' '7 However, as in the present study, investi-
Control
394 + 21.3
428 ±10.0
355 + 18.0
400-
A
AA
^ nsvx-
A
A
A
A
A
AA
4
•
A
A
A
*
o
t
A
\A
300?nn-
Contro
Infusion
Mean
i
1
1
1
1
-
^
A A
k
•
i
i
^ A
A
2
4
20
40
60
80
Volume of isotonic saline infused (ml)
AA
AA
1
100
EFFECT OF ISOTONIC INFUSIONS IN THE ANEPHR1C RAJ/Kleinert et al.
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tor, since sodium-free fluid increased blood pressure.
In these chronic studies, saline administration itself did
not cause hypertension.
In our acute study, infusion of 0.9% sodium chloride did not induce a pressor response compared to
fluid-infused or noninfused controls. Our animals
were not allowed to drink during the period of experimentation. Thus, isotonic sodium chloride itself, administered acutely, did not act as a pressor agent in our
preparation. We also studied the effect of allowing free
access or no access to food and water during the time
period between nephrectomy and experimentation,
only to find no difference with respect to blood pressure between the groups. Some studies on the effects of
hydration and dehydration on blood pressure corroborate our findings,12-2I but others disagree. n - l4 - 22
Chronic salt-loading hypertension has been suggested to be a precursor to a resultant volume overload
hypertension.2 In our study, however, the results of
Group VI rats that received a saline infusion of 100 ml
indicate that acute hypervolemia induced by saline infusion is not in itself a means of eliciting an acute
pressor response. MAP continued to decline steeply
and steadily as the infusion volume was increased
above 40 ml of isotonic saline. It is possible that the
cardiovascular system was failing to adequately handle
a volume overload of that magnitude, resulting in cardiac failure. It may well be that in our study saline
infusion was not carried out long enough to exhaust the
venous capacity or, more likely, to eliminate the baroreflex buffer system. Cowley and Guyton23 demonstrated that the baroreceptor reflex slows the development of salt-loading hypertension by altering total
peripheral resistance until a level of steady-state hypertension is developed. It is possible that our experiments were not carried out long enough to see a response.
The Hatzinikolaou et al. study7 employing acute
infusion of hypertonic saline raised the possibility of
an independent sodium pressor effect. It is possible
that only a partial blockade of vasopressin was
achieved in their study. We also considered that they
acutely raised the sodium chloride concentration far
above the physiological level and that their administering sodium chloride solution to achieve a serum concentration 10% above the normal range may have been
vasoconstrictive. A concentration-mediated vasoconstrictive effect of sodium would be unlikely in an acute
study such as ours in which isotonic saline was employed. Their study and ours are in agreement concerning the absence of an acute volume effect. On the other
hand, it might be postulated that elevations in blood
pressure were due to the effect of hypertonic saline
drawing intracellular fluid into the circulation. In our
experiment (Group VI), we gave a greater total volume
of saline and ions but in a lower concentration. Our
results show that acute elevations in the number of
sodium ions and also volume do not induce hypertension. Thus, we cannot further clarify their results.
Comparison of the isotonic solutions was made in an
effort to detect a possible specific acute pressor effect
425
of sodium. The hemodynamic effects of isotonic mannitol and dextrose were indistinguishable from saline.
If isotonic sodium chloride exerted a direct independent pressor action in an acute preparation, we would
not expect the effects of mannitol and dextrose on
blood pressure and HR to be comparable.
Several investigations in humans10 and rat24-25 have
presented evidence that predisposition to hypertension
prior to sodium chloride loading sensitizes the subject
to the pressor effect of sodium. In the present study, a
pressor effect could not be demonstrated in the SHR,
which were all established to be hypertensive before
initiating infusion. Thus, in an acute experiment lasting 2 hours, a pressor effect was not exerted by infusion of sodium chloride, regardless of the baseline
level of blood pressure.
Heart rate did not rise in the control group allowed
free access to food and water (Group V), suggesting
that dehydration may indeed have contributed to the
slight increase in HR seen in control Group I, denied
access to food and water. Bradycardia occurred in
Group VI (normotensive anephric rats) and Group VII
(anephric SHR), both of which shared in common free
access to food and water following nephrectomy and
experimental infusion of 4.4 ml of isotonic saline over
a period of 2 hours. It is possible that the larger volume
of saline induced a reflex reduction in HR, not observed in Group II, which received only 2.2 ml of
isotonic sodium chloride over 2 hours. Reflex bradycardia may be manifested independently of reflex
changes in total peripheral resistance.26 The magnitude
of bradycardia experienced by the normotensive rats
(Group VI) and the SHR (Group VII) was similar.
Our findings indicate that a sodium chloride or volume overload pressor effect sometimes seen in particular chronic preparations was not demonstrable acutely
in the anephric rat in spite of the initial level of blood
pressure. From the results of our study, we conclude
that: 1) sodium chloride administered in large excess as
an isotonic solution does not act directly as an acute
pressor agent in normotensive or SHR anephric rats,
and thus, does not have an intrinsic pressor property;
and 2) isovolemic infusions of isotonic sodium chloride, mannitol, and dextrose do not effect blood pressure and HR in the normotensive conscious anephric
rat.
Acknowledgment
The technical assistance of Geoffrey C. Odell was very much
appreciated.
References
1. Murray RH, Luft FC, Bloch R, Weyman AE: Blood pressure
response to extremes of salt intake in normal man. Proc Soc
Exp Biol Med 159: 432, 1978
2. Norman RA, Coleman TG, Wiley TL Jr, Manning RD, Guyton AC: Separate roles of sodium ion concentration and fluid
volumes in salt-loading hypertension in sheep. Am J Physiol
229: 1968. 1975
3. Coleman TG, Guyton AC: Hypertension caused by salt loading in the dog. Circ Res 25: 153, 1969
426
HYPERTENSION
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
4. Laragh JH: Vasoconstriction-volume analysis for understanding and treating hypertension: the use of renin and aldosterone
profiles. Am J Med 35: 261, 1973
5. Haddy FJ: Mechanism, prevention and therapy of sodiumdependent hypertension. Am J Med 69: 746, 1980
6. Haddy FJ, Overbeck HW: The role of humoral agents in volume expanded hypertension. Life Sci 19: 935, 1976
7. Hatzinikolaou P, Gavras H, Brunner HR, Gavras I: Sodiuminduced elevation of blood pressure in the anephric state. Science 209: 935, 1980
8. Ladd M, Raisz LG: Response of the normal dog to dietary
sodium chloride. Am J Physiol 159: 149, 1949
9. Davis JO: The control of renin release. Am J Med 55: 333,
1973
10. Onesti EG, Kwan EK, Greco JA, del Guercio ET, Fernandes
M, Swartz C: Blood pressure regulation in end-stage renal
disease and anephric man. Circ Res (suppl I) 36 and 37:1-145,
1975
11. Braun-Menendez E, Von Euler US: Hypertension after bilateral nephrectomy in the rat. Nature 160: 905, 1947
12. Muirhead EE, Vanatta J, Grollman A: Hypertensive cardiovascular disease: Experimental study of tissue changes in bilaterally nephrectomized dogs. Arch Pathol Lab Med 48: 234, 1949
13. Leonards JR, Heisler CR: Maintenance of life in bilaterally
nephrectomized dogs and its relation to malignant hypertension. Artificial Kidney 167: 553, 1951
14. Orbison JL, Christian CL, Peters E: Studies on experimental
hypertension and cardiovascular disease. Arch Pathol 54: 185,
1952
15. Lucas J, Floyer MA: Renal control of changes in the compli-
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
VOL 5, No 4, JULY-AUGUST
1983
ance of the interstitial space: a factor in the aetiology of renoprival hypertension. Clin Sci 44: 397, 1973
Floyer MA: Further studies on the mechanism of experimental
hypertension in the rat. Clin Sci 14: 163, 1955
ColemanTG, Bower JD, Langford HG. Guyton AC: Regulation of arterial pressure in the anephric state. Circulation 42:
509, 1970
Torii K: Hypertension in Wistar rats is not induced by high
sodium diets. Fed Proc 40: 411, 1981
Seebar AM, Arranz CT: Body fluid changes in hypertensive
rats. Nephron 24: 241, 1979
Pelling D, Ledingham JM: Hemodynamics in the renoprival
hypertensive rat. Clin Sci 38: 4P, 1970
Muirhead EE, Jones F, Graham P: Hypertension in bilaterally
nephrectomized dogs in absence of exogenous sodium excess.
Arch Pathol Lab Med 56: 286, 1953
Houck CR: Effect of hydration and dehydration on hypertension in the chronic bilaterally nephrectomized dog. Am J Physiol 176: 183, 1954
Cowley AW, Guyton AC: Baroreflex reflex effects on transient
and steady-state hemodynamics of salt-loading hypertension in
dogs. Circ Res 36: 536, 1975
Dietz R, Schomig A, Rascher W, Strasser R, Kubler W: Enhanced sympathetic activity caused by salt loading in spontaneously hypertensive rats. Clin Sci 59: 171s, 1980
Chrysant SG, Walsh GM, Kern DC, Frohlich ED: Hemodynamic and metabolic evidence of salt sensitivity in spontaneously hypertensive rats. Kidney Int 15: 33, 1979
Gebber GL, Snyder DW: Hypothalamic control of baroreceptor reflexes. Am J Physiol 218: 124, 1970
Comparable effect of isotonic infusions on blood pressure in the anephric rat.
H D Kleinert, B R Leslie, J H Laragh, E D Vaughan, Jr and J E Sealey
Hypertension. 1983;5:421-426
doi: 10.1161/01.HYP.5.4.421
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