Veterinary Quarterly
Taylor & Francis Taylor & Francis Group
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
To link to this article: http://dx.doi.org/10.1080/01652176.1980.9693781
Published online: 01 Nov 2011.
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Studies on the mechanism of polyuria induced by cortisol excess in the dog
J. A. Joles1, A. Rijnberk!, W. E. van den Brom1, 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 concentration 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, AVP 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 AVP 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 in cooled hepa- rinized tubes. After separation by centrifugation at 3º C, plasma samples were stored at -80° C until assayed for AVP by radioimmunoassay (RIA) (5).
1 Small Animal Clinic, State University Utrecht, Yalelaan 8, 3508 TD Utrecht, the Netherlands.
2 Central Institute for Brain Research, Amsterdam, the Netherlands.
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- ter1.
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 I.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 1) and the median urine volume increased from 26 to 300 ml/kg of body weight.
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 + 1.14x Uosm/posm) has been drawn in Figure 1. 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 WD. (Fig. 1 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).
| control | cortisol administration | |
|---|---|---|
| Urine | 1600 | 225 |
| Osmolality | (500-2270) | (70-730) |
| (msom/kg) | ||
| Uosm/ Posm | 5.35 | 0.85 |
| (1.70-7.40) | (0.23-2.40] | |
| Urine volume | 26 | 300 |
| ml/kg/24 h | (4-93) | (100-750) |
1 Knauer Osmometer, Herbert Knauer Co., Berlin, West Germany.
2 Vasopressin Synthetic. Sandoz Pharmaceuticals, Switzerland.
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The results of the WD studies before and after surgery in the Boxer with a functio- nal adrenocortical carcinoma were sim- ilar to those in the experimental dogs during cortisol administration and in the control period, i.e. in reverse order (Fig 2 and 3).
DISCUSSION
The administration of excess cortisol to normal dogs caused a marked decline in body weight and a marked increase in urine production without glucosuria. The finding of increases in circulating AVP levels during WD in the period of cortisol administration concurred with the results of studies on adrenocortical
insufficiency, where it was reported that cortisol affected the action of AVP in the kidneys (10, 14) rather than causing a central blockade of AVP release (1,2). In contrast to previous reports (18), plasma AVP levels under normal conditions did not rise in response to dehydration. This can be explained by the fact that many of the observations in the control studies were within the minimal detection limits (21). In addition, the administration of AVP, after maximum urinary concentra- tion had been achieved by WD, should have caused a further increase in Uosm if a central disturbance of AVP release were the limiting factor, as in partial AVP deficiency (13).
| Dog | Control | Cortisol Administration | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Hours | 0 | 3 | 6 | 9 | 12 | 15 | 24 | 0 | 1.5 | 3 | 5 | 6.5 | 8 | 9 | 10 | |
| 1. | Uosm ☒ ☒ Posm | 5.7 | 5.7 | 5.2 | 6.2 | 6.9 | 6.8 | 6.5 | 1.7 | 1.9 | 3.8 | 4.0 | 4.6 | 4.7 | - | - |
| ~; 11.6 kg | Plasma AVP (pg/ml) | 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 | - | - |
| 2. | Uosm ☒ Posm ☒ | 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 | 4.1 | 4.1 |
| 8 ; 14.2 kg | Plasma AVP (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 ☒ ☒ Posm | 1.7 | 1.6 | 2.8 | 3.7 | 4.3 | 4.9 | 5.5 | 0.5 | 0.4 | 1.8 | 2.6 | 1.9 | 2.2 | - | - |
| ៛ + ; 13.7 kg | Plasma AVP (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 ☒ ☒ Posm | 5.5 | 6.2 | 7.2 | 7.3 | 7.1 | 7.3 | 6.7 | 0.6 | - | 1.8 | 3.2 | 4.0 | - | - | - |
| ₮; 25.9 kg | Plasma AVP (pg/ml) | < 0.8 | <0.8 | < 0.8 | < 0.8 | 0.9 | 2.0 | 1.8 | < 0.8 | - | 2.3 | 3.8 | 4.4 | - | -- | M - |
| 5. | Uosm ☒ Posm ☒ | 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 |
| 5; 31 kg | Plasma APV (pg/ml) | <0.8 | < 0.8 | < 0.3 | < 0.8 | < 0.8 | <0.8 | < 0.8 | < 0.8 | - | < 0.8 | < 0.8 | < 0.8 | < 0.8 | 3.8 | - |
| 6. | Uosm ☒ Posm ☒ | - | 7.3 | 7.3 | 8.7 | 9.0 | 7.1 | 6.2 | 0.8 | - | 1.3 | 2.8 | 4.3 | 3.8 | - | - |
| ₫; 22.8 kg | Plasma AVP (pg/ml) | 6.2 | 9.5 | - | 13.8 | 7.5 | 18.1 | 14.4 | 1.3 | - | 6.6 | 2.9 | 3.7 | 4.6 | - | - |
| 7. | Uosm ☒ ☒ Posm | 4.7 | 4.6 | 5.4 | 4.5 | 4.9 | 5.5 | 5.4 | 0.5 | 1.0 | - | 3.2 | 3.9 | 4.5 | 4.4 | - |
| 6 ; 25.4 kg | Plasma AVP (pg/ml) | 1.7 | < 1 | 3.7 | 2.8 | 3.3 | 6.7 | 3.9 | < 1 | 3.2 | - | 2.3 | - | 3.7 | 6.1 | - 1 |
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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
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plasma AVP levels under normal condi- tions more than doubled the levels in the other dogs; nevertheless also dog no. 3 responded with very high plasma AVP levels (3.1-19.2 pg/ml) in conjunction with a low Uosm/ Posm ratio (0.5-2.6) during cortisol administration.
While our findings are compatible with the hypothesis that cortisol interferes with the action of AVP, we cannot ex- clude the possibility that the polydipsia was augmented by a direct effect of cor- tisol on the thirst centre or by water con-
sumption in excess of the volume requir- ed to compensate the increased diuresis (9).
Cortisol appears to have a permissive ef- fect (8), in that it is essential for the excre- tion of free water. Perhaps the cortisol increases the perfusion of the vasa recta, causing a ‘washout’ of the renal medul- lary solute gradient. The factors regulat- ing the perfusion of the vasa recta, which branch from the efferent arterioles of the juxtamedullary glomeruli (6), have not been clarified.
It has been suggested that the flow rate in the vasa recta is the difference between glomerular capillary flow rate in the inner cortex and peritubular capillary flow rate in the inner cortex and outer medulla (3). One realistic hypothesis is that vasopressin causes vasoconstriction of the efferent arterioles of the glomeruli in the inner cortex (7) and antagonism of this by cortisol would increase perfusion of vasa recta and hence decrease of maxi- mum Uosm.
The maximum transfer of water molecu- les through the renal tubular cells is de- pendent upon a sufficient local concen- tration of AVP (11). A noncompetitive antagonism by cortisol of the action of AVP on the collection duct is therefore also a possible explanation for the polyu- ria (16). A competitive antagonism seems unlikely, since administration of exoge- nous AVP, at the moment that maximal Uosm had been achieved by dehydration, caused no further increase in Uosm.
ACKNOWLEDGMENTS
The authors wish to thank Miss Y. W. E. A. Pollak. Mr. J. Fama, and Mr. H. Goedemans for their skilled assistance.
REFERENCES
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