Veterinary Quarterly

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Studies on the mechanism of polyuria induced by

cortisol excess in the dog

J. A. Joles , A. Rijnberk , W. E. van den Brom & J. Dogterom

To cite this article: J. A. Joles , A. Rijnberk , W. E. van den Brom & J. Dogterom (1980) Studies
on the mechanism of polyuria induced by cortisol excess in the dog, Veterinary Quarterly, 2:4,
199-205, DOI: 10.1080/01652176.1980.9693781

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 Studies on the mechanism of polyuria induced
by cortisol excess in the dog

J. A. Jo lest, A. Rijnberkl, W. E. van den Brom', and J. Dogte-

rom2

SUMMARY
Water balance studies were performed in 7 experimental dogs before and during a
period of cortisol-induced polyuria and in one dog with spontaneous hyperadreno-
corticism before and after removal of an adrenocortical carcinoma. Measurements
of urine and plasma osmolality and plasma arginine vasopressin concentrat ion were
made at regular intervals during the water deprivation studies. The results indicate
that cortisol does not block the release of vasopressin but interferes with its action
in the kidney.

INTRODUCTION
Polyuria is one of the foremost symp-
toms of spontaneous hyperadrenocorti-
cism in the dog (17, 20, 12). The polyuria
is presumed to be due to an excess of
corticosteroids, since it can also be in-
duced by administration of excess cor-
tisone to normal dogs (22). Two mecha-
nisms have been postulated; either
hydrocortisone (cortisol) in excess blocks
the release of arginine vasopressin (AVP)
(1), or it interferes with the action of AVP
in the kidney (22).
In an attempt to differentiate between
these two possibilities, AV P levels were
studied in seven experimental dogs
before and during cortisol administra-
tion. In addition, a dog with spontaneous
hyperadrenocorticism due to an adreno-
cortical carcinoma was studied before
and after removal of the tumor.
METHODS
Dogs - These studies were performed with 7 healthy
adult dogs (5 males and 2 females) and one severely
polyuric and polydipsic 8-year-old male Boxer with
confirmed hyperadrenocorticism caused by unila-
teral adrenocortical carcinoma (Dog no. 17 in refe-
rence 4).
Experiments
Twenty-four-hour urine specimens were collected
in a metabolism cage for measurements of volume
and osmolality.
Water deprivation (WD) was used to investigate
urine concentrating ability and plasma AV P release
in response to dehydration. The dogs were deprived
of food for 12 h prior to the dehydration period.
Urine was collected by spontaneous micturition at
0, 3, 6, 9, 12, 15 and 24 hours, after which food and
water were again provided. Immediately after each
micturition the dog was weighed and blood samples
were collected from the cephalic vein incooled hepa-
rinized tubes. After separation by centrifugation at
3° C, plasma samples were stored at 80° C until
assayed for AVP by radioimmunoassay (R1A) (5).

.1 Small Animal Clinic, State University Utrecht, Yalclaan 8, 3508 TD Utrecht, the Netherlands.
2 Central Institute for Brain Research, Amsterdam, the Netherlands.

THE VEIERINARY QUARTERLY, VOL, 2, No. 4, OCTOBER 1980

199
 The minimum detection limit in plasma varied from
0.8 to 2.0 pg/ml.
Osmolality of urine (Uosm) and plasma (Posm) was
determined by a freezing point depression osmome-
ter'.
Cortisol administration
Each of the seven experimental dogs then received
16 mg of hydrocortisone/ kg/24 h orally until po-
lyuria (urine volume exceeding 100 ml/ kg/24 h)
developed (13-27 days).
Subsequently WD was repeated while the polyuria
was maintained by cortisol administration. Dehy-
dration during WD was more rapid during cortisol
treatment than in the control study and therefore
determinations were performed at intervals of 11/2 h.
When Uosm reached a plateau (6-12 h), 5 1.U.
synthetic lysine vasopressin (LVP)2 was injected s.c.
and urine was collected 45 minutes later, after
which food and water were provided.
In the Boxer dog with hyperadrenocorticism due to
an adrenocortical tumor, the WD procedure was
performed before and after surgery. Both tests in-
cluded LVP stimulation.
Statistical analyses
In view of the small number of dogs used, the
median, range, and number of observations are
presented. Linear correlation analysis was applied.
RESULTS
In all but one of the 7 experimental dogs
the administration of cortisol resulted in
loss of weight (median decrease 6.1 per
cent, range 0.0-10.9 per cent).
The median urine osmolality and the
Uosm/ Posm ratio decreased by a factor
of 6.3 (Table I ) and the median urine
volume increased from 26 to 300 ml/ kg
of body weight.
Table I. Water balance data in 7 experimental dogs with and without polyuria (volume > 100 ml/
kg/24 h) due to cortisol administration (16 mg of corlisol/ kg/ 24 h). For each variable the median and
range of values are presented.
control
Urine 1600
Osmolality (500-2270)
(msom/ kg)
Uosm/ Posm 5.35
(1.70-7.40)
Urine volume 26
ml/kg/ 24 h (4-93)
I Knauer Osmometer, Herbert Knauer Co., Berlin, West Germany.
2 Vasopressin Synthetic. Sandoz Pharmaceuticals, Switzerland.
200
In the control study, 24 h of WD caused a
weight loss of 4.4 per cent (range 3.9-5.8
per cent, n= 7). The values of the Uosm/
Posm ratio and plasma AVP are plotted
in Figure 1 and listed in Table 2. Two
dogs (nos. 3 and 6) appear to be incompar-
able to the other 5 dogs because during
WD under normal conditions their AVP
levels were much higher. Therefore we
applied linear correlation analysis to the
results of WD in the group of 5 dogs.
The analysis revealed that during cortisol
excess the plasma AVP concentration
and the ratio Uosm/ Posm were linearly
correlated (r=0.71; p<0.01).
However, no linear correlation was
found under normal conditions at the
significance level p=0.05. The line de-
scribing the regression of plasma AVP
concentration (pg/ ml) on the ratio
Uosm/ Posm during WD under cortisol
excess (expressed by y= -0.30 + I .14x
Uosm/posm) has been drawn in Figure
I. The mean plasma APV concentration
during WD under normal circumstances
was 1.60 pg/ ml.
Under normal conditions WD stimulated
the production of strongly hypertonic
urine without measurable changes of
plasma AVP levels, whereas, in the pe-
riod of cortisol administration, less hy-
pertonic urine was produced with higher
AVP levels during W D. (Fig. I and Table
2). The administration of LVP at the end
of the WD period during cortisol admi-
nistration had no consistent effect on
Uosm (median increase 0.5 per cent,
range 13 per cent to +30.2 per cent,
n=6).
cortisol administration
225
(70-730)
0.85
(0.23-2.40
300
(100-750)
THE VETERINARY QUARTERLY, VOL. 2, No. 4, OCTOBER 1980
 Fig. I. Relation between plasma AVP and the Uosm/ Posm ratio during
water deprivation studies in seven
experimental dogs. The values represent measurements made at regular intervals during water deprivation
tests carried out in the control period (D) and during the period of cortisol administration (+). The values
which were not statistically analized are indicated (Dog no. 3 A; Dog no. 6 0).
The mean plasma A VP level during WD in the control period is indicated bya horizontal line. The regression
line of plasma AVP on Uosm/ Posm for the period of cortisol administration is also shown.
20
A
18

16

lii
14114
1:1
As

12

10
IJ

'E 8
a ES a + +
+

4 + EG I33+

+ ++ +
9+ +
.
lif _
+ .
+ 9.. ++. ++ .
1 2 3 5 4
6 7 8 9 10
Urine osmolality/ Plasma osmolality ratio

The results of the WD studies before and insufficiency, where it was reported that
after surgery in the Boxer with a functio- cortisol affected the action of AV P in the
nal adrenocortical carcinoma were sim- kidneys (10, 14) rather than causing a
ilar to those in the experimental dogs central blockade of AVP release (1, 2). In
during cortisol administration and in the contrast to previous reports (18), plasma
control period, i.e. in reverse order (FiL AVP levels under normal conditions did
2 and 3). not rise in response to dehydration. This
can be explained by the fact that many of
DISCUSSION the observations in the control studies
The administration of excess cortisol to were within the minimal detection limits
normal dogs caused a marked decline in (21). In addition, the administration of
body weight and a marked increase in AVP, after maximum urinary concentra-
urine production without glucosuria. tion had been achieved by WD, should
The finding of increases in circulating have caused a further increase in Uosm if
AVP levels during WD in the period of a central disturbance of AVP release
cortisol administration concurred with were the limiting factor, as in partial
the results of studies on adrenocortical AVP deficiency (13).

THE VETERINARY QUARTERLY, VOL. 2, No. 4, OCTOBER 1980

201
Table 2. Results of water deprivation studies in 7 experimental dogs with and without polyuria due to cortisol administration.

Control Cortisol Administration

Dog
Hours 0 3 6 I 9 12 15 24 0 1.5 3 5 6.5 8 9 10
.
Cosa,-
5.7 5.7 5.2 6.2 6.9 6.8 6.5 1.7 1.9
-----Posm 3.8 4.0 4.6 4.7 -
, Plasma AVP
cp?; 11.6 kg (pg/m1) 3.2 0.8 1.5 2.7 2.5 1.9 2.2 2.9 2.3 2.7 4.4 -
6.1 6.9
Uosm,-
. 3.9 4.3 4.6 4.8 5.0 5.3 5.8 2.1 1.1 1.9 2.8 3.5 3.9
/Tosm 4.1 4.1

Plasma AVP
Cr; 14.2 kg (pg/ml) < 2 < 2 < 2 < 2 < 2 < 2 < 2 < 1 1.1 3.1 3.1 4.8 4.8 6.9 1.1

3.
Uosm,-
1.7 1.6 2.8 3.7 4.3 4.9 5.5 0.5 0.4
----Posm 1.8 2.6 1.9 2.2 -
Plasma AVP
q ; 13.7 kg (pg/ml) 6.6 3.5 4.5 6.1 6.2 6.3 3.1 9.6 13.4 8.8 19.2 14.0 -

4.
Uosm--
5.5 6.2 7.2 7.3 7.1 7.3 6.7 0.6 _ 1.8 3.2 4.0 _ -
---Tosm

Plasma AVP
?; 25.9 kg (pg/ml) < 0.8 <-0.8 < 0.8 < 0.8 _ ... - _
0.9 2.0 1.8 < 0.8 2.3 3.8 4.4

Uosm,-
5. 1.5 2.2 3.0 3.3 3.2 4.2 3.9 1.1 - 1.4 2.0 2.7 3.1 2.7 3.1
----Posm
l
Plasma APV
dr; 31 kg (pg/ml) <0.8 < 0.8 < 0.0 < 0.8 < 0.8 <0.8 < 0.8 < 0.8 - < 0.8 < 0.8 < 0.8 < 0.8 3.8 -

Uosm....-
6. - 7.3 7.3 3.7 9.0 7.1 6.2 0.8 1.3 2.8 4.3 3.8 _
--Tosm
Plasma AVP
Cr; 22.8 kg (pg/ml) 6.2 9.5 13.8 7.5 18.1 14.4 1.3 - 6.6 2.9 3.7 4.6 -

Doss...,
7. 4.7 4.6 5.4 4.5
----7osm 4.9 5.5 5.4 0.5 1.0 - 3.2 3.9 4.5 4.4
.cr ; 25.4 kg P(114m)AVP 1.7 < 1 3.7 2.8 3.3 6.7 3.9 < 1 3.2 - 2.3 - 3.7 6.1 -
 Fig. 2. Results of water deprivation studies in a dog with
hyperadrenocorticism due to adrenocortical
tumor, before (*) and after (I) removal of an adrenocortical tumor.
t= 5 units of lysine vasopressin subcutaneously.

1500

7:7)-

E 1000
>.

To"

0
a)
,-= 500

0
100

98

96

94

92

90

4 8 12 16
Time (hours)

Contrary to the present findings, a 20 per
cent increase of Uosm (from 479 tot 574
mosm/kg) had been found in five dogs
with spontaneous hyperadrenocorticism
following LVP administration (15). This
may be explained by the fact that in the
latter study maximum urinary concen-
tration was not achieved, since the weight
loss due to dehydration was relatively
low (1.9-3.9 per cent).
Two dogs (nos. 3 and 6) were excluded
from the statistical analysis because their

THE VETERINARY QUARTERLY. VOL. 2, No. 4, OCTOBER 1980

203
Fig. 3. Relation between plasma arginine vaso- sumption in excess of the volume requir-
pressin ( AV P) concentrations and Uosm/ Posm ed to compensate the increased diuresis
ratios of a dog during water deprivation tests,
performed before () and after (II) removal of an (9).
adrenocortical tumor. Cortisol appears to have a permissive ef-
fect (8), in that it is essential for the excre-
tion of free water. Perhaps the cortisol
12 increases the perfusion of the vasa recta,
1- causing a 'washout' of the renal medul-
lary solute gradient. The factors regulat-
0 ^ ing the perfusion of the vasa recta, which
cn 1
branch from the efferent arterioles of the
c juxtamedullary glomeruli (6), have not
ELI?) 8
been clarified.
0. It has been suggested that the flow rate in
the vasa recta is the difference between
a 6 glomerular capillary flow rate in the
_ inner cortex and peritubular capillary
'En flow rate in the inner cortex and outer
4 medulla (3). One realistic hypothesis is
that vasopressin causes vasoconstriction
of the efferent arterioles of the glomeruli
2 in the inner cortex (7) and antagonism of
this by cortisol would increase perfusion
of vasa recta and hence decrease of maxi-
0 i i I 1
mum Uosm.
0 1 2 3 4 The maximum transfer of water molecu-
Urine osmolality/plasma osmolality ratio les through the renal tubular cells is de-
pendent upon a sufficient local concen-
tration of AVP (1 I ). A noncompetitive
plasma AVP levels under normal condi- antagonism by cortisol of the action of
tions more than doubled the levels in the AVP on the collection duct is therefore
other dogs; nevertheless also dog no. 3 also a possible explanation for the polyu-
responded with very high plasma AVP ria (16). A competitive antagonism seems
levels (3.1-19.2 pg/ ml) in conjunction unlikely, since administration of exoge-
with a low Uosm/ Posm ratio (0.5-2.6) nous AVP, at the moment that maximal
during cortisol administration. Uosm had been achieved by dehydration,
While our findings are compatible with caused no further increase in Uosm.
the hypothesis that cortisol interferes
with the action of AVP, we cannot ex- ACKNOWLEDGMENTS
clude the possibility that the polydipsia The authors wish to thank Miss Y. W. E. A. Pollak,
was augmented by a direct effect of cor- Mr. J. Fama, and Mr. H. Goedemans for their
tisol on the thirst centre or by water con- skilled assistance.

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