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Clinical Science (1980) 58,493-500 Role of antidiuretic hormone in impaired urinary dilution associated with chronic bile-duct ligation 0. S. B E T T E R , G . A. A I S E N B R E Y , T. BERL, R. J. A N D E R S O N , W.A. H A N D E L M A N , S. L. L I N A S , S. J. G U G G E N H E I M A N D R. W.S C H R I E R Department of Medicine, Universiry of Colorado Medical Center, and Department of Pathology, Veterans Administratton Hospital. Denver, Colorado, U S A . (Received 31 July 1979; accepted 2 February 1980) Summary 1. The effect of chronic bileduct ligation on systemic and renal haemodynamics and on the capacity to dilute the urine was studied in conscious rats. Sham-operated rats served as controls. 2. In the rats with bile-duct ligation, the maximal urinary diluting czpacity was impaired, despite an expanded plasma volume, a normal mean arterial pressure and cardiac output, and normal intrarenal determinants of water excretion including distal delivery of fluid and function of the diluting segment. 3. In contrast, maximal urinary dilution capacity was intact in rats with congenital central diabetes insipidus and chronic bile-duct ligation. 4. It is concluded that the defect in urinary dilution in rats with chronic bile-duct ligation is dependent on antidiuretic hormone. Key words: bile duct, haemodynamics, jaundice, liver, water. Introduction Hyponatraemia secondary to an impaired ability of the kidneys to excrete water may be seen in patients with hepatic cirrhosis (Papper, 1958). This abnormality has been attributed, at least in part, to diminished distal delivery of fluid to the diluting site as a result of excessive proximal tubular reabsorption of sodium chloride (Schedl & Bartter, Correspondence: Dr 0.s. Better, Department of Nephrology, Rambam Medical Center, Haifa, Israel. 1961). This conclusion was based on the observation that in patients with cirrhosis manoeuvres employed to augment distal delivery, such as the infusion of iso-osmotic mannitol solution, could correct the defect in renal water excretion (Schedl & Bartter, 1961). In that study, however, suppression of endogenous antidiuretic hormone during the volume expansion produced by mannitol could have contributed to the improved ability to excrete water. Studies of the concentrations of antidiuretic hormone in the blood and urine of patients with cirrhosis of the liver have given conflicting results (Chaudhury, Chuttani & Ramalingswami, 1961; Lee & Kerr, 1963). The purpose of the present study was to examine the role of antidiuretic hormone in the impaired urinary diluting capacity of rats with chronic bileduct ligation. Methods Studies were performed on male SpragueDawley rats of 150-350 g body weight. They were allowed free access to Purina Rat Chow and distilled water until the day of study. Ligation of the common bile duct was performed under pentobarbital anaesthesia. The abdominal cavity was opened and the common bile duct was mobilized. Two tight silk ligatures were placed on the common bile duct at distances of 6 and 8 mm from the duodenum. The laparotomy wound was then sutured in layers. The mortality rate was 15-20% in the 8-10 days after Operation. Of the rats that SUrviVed the Operation 90% developed biochemical changes in the urine 493 0143-5221/80/060493-08S1.50/I 494 0.S . Better et al. and blood characteristic of obstructive jaundice. Post-mortem studies 8-10 days after chronic bile-duct ligation showed gross dilatation of the portion of the bile duct proximal to the ligatures. Rats that failed to show biochemical evidence of obstructive jaundice were excluded from this study. In sham-operated rats the bile duct was exposed and manipulated but not ligated. Sham-operated and chronically bile-duct-ligated rats were studied under similar conditions. The Brattleboro rats we studied came from a breeding colony in this laboratory and had a daily water intake of at least 80% of body weight, and a morning urinary osmolality of 200 mosmol/kg or less. The studies in conscious animals, which required intravenous administration of fluid, were performed in a restraining cage after the introduction of venous and arterial lines under ether anaesthesia. Analytical methods Sodium was determined by flame photometry and inulin by standard methods (Schrier & Earley, 1970). Osmolality was determined by cryoscopy with an Advanced Instruments 3L osmometer. The following measurements were made on plasma: bilirubin (Malloy & Evelyn, 1937); glutamate-xaloacetate transaminase (Amador & Wacker, 1962); alkaline phosphatase (McComb & Bower, 1972); total protein (Kingsley, 1942); albumin (Kaplan & Savory, 1965); cholesterol (AUain, Poon, Chan, Richmond & Fu, 1974); blood urea nitrogen (Beckman Instruments, 197 1); creatinine (Watkins, Feldkamp, Thibert & Zak, 1975). Blood volume was determined by the method described by Thiel, Wilson, Arce & Oken (1967) and by Flamenbaum, Kotchen, Nagle & McNeil (1973). Microsphere techniques were used for haemodynamic studies in chronically bileduct-ligated and control rats (Hsu, Kurtz & Waldinger, 1977) with modifications described by Linas, Berl, Aisenbrey, Better & Anderson ( 1980). Glomerular jiltration rate (GFR) and free water formation in chronically bile-duct-ligated and control rats The right jugular vein and right carotid artery were cannulated with polyethylene 50 tubing and polyethylene 200 tubing was passed into the urinary bladder. During surgery, 0.5% of the body weight of iso-osmotic sodium chloride solution (150 mmol/l) was infused to replace estimated fluid loss. During a 60 min equilibration period a 4% solution of inulin in hypo-osmotic sodium chloride solution (75 mmol/l) was infused at 25 pl/min and an intravenous water load equivalent to 5% body weight was given as 2.5% glucose in water. Three timed urine samples and a midpoint blood sample (0.6 ml) were obtained. The blood was replaced with an equal volume of iso-osmotic saline. The resulting diuresis was then augmented by the infusion of hypo-osmotic saline at rates of 0.2,0.4 and 0.8 ml/min. At each flow rate, the rat was allowed to equilibrate for 30-45 min, after which three timed urine collections and a midpoint blood sample were obtained. All animals on this intravenous loading maintained urine osmolalities below 160 mosmol/kg during the study. G F R was estimated from the clearance of inulin. Absolute and fractional osmolar clearance, free water clearance and sodium clearance were calculated from standard formulae. Distal delivery of sodium was approximated by the term C,, + C,,,,,and sodium chloride reabsorption at the diluting site by C,,,,,. The measurements were made in three groups of rats: six anaesthetized chronically bile-duct-ligated rats. five conscious chronically bileduct-ligated rats, and eleven anaesthetized controls. Oral water load in conscious rats An oral water load of 30 ml/kg body weight was given at 09.00 hours via a gastric tube. This was done under very light ether anaesthesia. The rats were placed in metabolic cages in an unrestrained manner. They usually recovered from the effects of ether within seconds of their placement in the cages. Every specimen of voided urine during a period of 3 h was collected for determination of urinary osmolality and urine volume voided during the 3 h of the experiment. The lowest osmolality was used in the comparison of the groups. Statistical analysis Statistical analyses were performed with the unpaired Student’s t-test. A P value of (0.05 was taken as statistically significant. Mean results k SEM are shown. Results Effect of chronic bile-duct ligation and shamoperation on body weight, liver function, plasma sodium and blood urea nitrogen (Table 1 ) The rats lost weight after the bileduct ligation but 8-10 days after chronic bile-duct ligation their weight was about equal to the operative weight. 495 Urinary dilution in obstructive jaundice TABLE1. Liver-function tests in sham-operated rats, chronically bile-duct-ligated Sprague-Dawley rats and chronically bile-duct-ligatedBrattlehro rats Mean results f SEM are shown with the ranges in parentheses. N.S., Not significant. Bilirubin (mg/l@Qml) ~~~ Plasma glutamatt oxaloacetate transaminasc (i.U.) Cholesterol (mgh00 ml) Total protein WI00 ml) Albumin W100 ml) 68.6 2.1 437 f 48 48.2 f 2.8 (65-77) (236-526) (42-58) 3738 f I749 1058 f 383 93.2 f 11.2 (250-11.260) (300-2320) (60-125) 2854 f 915 586 f 182 138.4 f 50 (1095-5472) (198-1242) (53-319) P < 0.005. N.S. P < 0405 6.0 f 0.05 (5.8-6.1) N.S 3.9 f 0.5 (3.743) 2.6 f 0.2 ( 1 * 7-3.3) 2.4 0.3 (1.4-3.1) P < 0.001 ~ Shamoperated Spraguc-Dawley rats 0.14 f 0.02 (0.1-0.2) (n = 5) Chronically bile-duct-ligated 6.1 f 1.6 Spraguc-Dawley rats (n = 6) (1.0-10.7) 12.3 f 1.5 Chronically bileduct-ligated diabetes insipidus rats (n = 5) (7.7-16.7) Shamoperated Sprague-Dawley P < 0.01 rats vs bileduct-ligated Spraguc-Dawley rats Chronicallybile-duct-ligated P < 0.02 diabetes insipidus rats vs chronically bileduct-ligated diabda insipidus rats Chronically bileduct-ligated P < 0.001 diabetes insipidus rats vs sham-operated Spraguc-Dawley rats Alkaline phosphatase (i.u.) ~ ~~ 6.2 0.4 (4.4-6.5) 5.5 f 0.6 (3.6-6.5) N.S. N.S. N.S. N.S N.S. P < 0.005* NS. P < 0*005* NS. P < 0.05 The Wilcoxon Rank sum test was used to determine this P value, because of the variation in experimental values. Sham operation, on the other hand, did not interfere with normal weight-gain pattern at 8-10 days after operation. Ascites formation after chronic bileduct ligation was seen only very rarely in the present study. Histological examinations of the liver were performed on 16 chronically bile-duct-ligated Sprague-Dawley rats and on all five chronically bile-duct-ligated diabetes insipidus rats reported in the oral water load study. The specimens showed characteristic changes of obstructive jaundice: proliferation of bile canaliculi, acute and chronic inflammatory changes and early fibrosis. The histopathology of the chronically bileduct-ligated Sprague-Dawley rat was indistinguishable from that of the chronically bileduct-ligated diabetes insipidus rat. Liver from sham-operated rats appeared normal on histological examination. Table 1 shows the results of some liver-function tests in three groups of rats. It can be seen that the chronically bileduct-ligated (Sprague-Dawley and diabetes insipidus) rats had statistically significant increases in plasma bilirubin, cholesterol and glutamate-oxaloacetate transaminase, and a decreased plasma albumin. The increase in plasma alkaline phosphatase was not statistically significant. These histopathological and biochemical changes have been reported previously by others (Trams & Symeonidis, 1957; Ryan, Than & Blumgart, 1977). Mean plasma sodium was 137 SEM 0-6 mmolfi in chronically bile-duct-ligated rats (n = 6) and 141 f 1.8 mmol/l in sham-operated rats (n = 6), values not significantly different. Plasma blood urea nitrogen and creatinine were 19-4 f 2.2 and 0.4 f 0.1 mg/dl respectively in chronically bileduct-ligated rats (n = 8), results not statistically different from those for sham-operated rats, 14.7 4 0.8 and 0.6 0.01 mg/dl (n = 13) for plasma blood urea nitrogen and creatinine respectively. -+ Total plasma and blood volumes Plasma and blood volumes were measured in five chronically bile-duct-ligated and four control rats of comparable weight (195 and 210 g respectively). The plasma volume of chronically bile-duct-ligated rats was greater either when expressed in absolute volumes (10.4 f 0.43 vs 6-93 f 0.31 ml, P < 0.001) or when corrected for body weight (5.47 f 0.43 vs 3-56 f 0.25 m1/100 g, P < 0.01). This increase in plasma volume was associated with a decrease in packed cell volume in these rats (38.3 k 1.0 vs 44.4 i- 1.4, P < 0.02), and neither the absolute nor corrected blood volume was different in the two groups. 0.S. Better et al. 496 TABLE 2. Haemodynamic study in conscious chronically bile-duct-ligatedand sham-operafed rats Mean results f SEM arc shown. N.S.,Not significant. Mean arterial pressure (mmHg) Conscious chronically bdeduct-ligated rats (n = 10) Conscious sham-operated rats (n = 9) P Cardiac index (mlmin-' kg-I body wt.) Systemic vax u I ar resistance (mmHg ml min-' kg-l body wt.) Renal blood (mlmin-I 8-l kidney wt.) Total renal vascular resistance (mmHg ml min-l g-I kidney wt.) flow 99 f 5 289 f 31 0.31 f 0.04 3.1 f 0.5 3.4 f 0.4 41.1 f 10.4 104f3 214 f 19 0.39 f 0.03 5.8 f 0.4 5.9 f 0.2 17.7 f 0.9 N.S. N.S. N.S. Studies on systemic and renal haemodynamics (Table 2) Since recent studies in our laboratory have shown that anaesthesia can profoundly affect systemic and renal haemodynamics (Linas et al., 1980), and our preliminary studies revealed that this effect was particularly marked in chronically bile-duct-ligated rats, the present studies were performed in nine conscious sham-operated rats and in ten conscious chronically bile-duct-ligated rats. As shown in Table 2, mean arterial pressure, cardiac index and systemic vascular resistance were not different in these two groups of animals. In contrast, the renal blood flow was lower (P < 0.005) and total renal vascular resistance higher (P < 0.05) in the chronically bile-duct-ligated rats. Thus, in spite of normal systemic haemodynamics, the conscious chronically bileduct-ligated rat had a more than twofold increase in total renal vascular resistance and a decrease of more than 40% in total renal blood flow. GFR in chronical[y bile-duct-ligated and control animals (Table 3) Inulin clearance (GFR) under basal conditions in anaesthetized chronically bileduct-ligated rats (n = 6) was comparable with that seen in anaesthetized controls (n = 11) (1 1.O f 0.8 vs 9.0 f 1.1 ml min-' kg-I body weight). These values were also similar to the basal G F R of conscious chronically bile-duct-ligated rats (n = 5) (8.7 f 0.8 ml min-' kg-' body weight). The increase in G F R after hypotonic volume expansion was similar in anaesthetized control rats, and in conscious chronically bile-duct-ligated rats (1 1.7 f 1.0, 11.O f 1.3 and 11.0 f 1.0 ml min-I kg-' body weight respectively). <0.001 <0.001 <0.05 Studies assessing distal delivery of sodium chloride and the function of the diluting segment limb (Table 3; Fig. 1 ) Hypo-osmotic saline infusions were performed in three groups of animals: (1) control anaesthetized rats (n = l l ) , (2) chronically bile-duct-ligated anaesthetized rats (n = 6) and (3) conscious chronically bile-duct-ligated rats ( n = 5). As can be seen in Table 3, values obtained at peak hypoosmotic volume expansion such as rate of urine flow, absolute and fractional C,,,,, and distal deliveries were comparable in all three groups. In Fig. 1 the relation between calculated fractional distal delivery on the abscissa (CNl + C,,,,,)/GFR is plotted against calculated sodium chloride reabsorption in the diluting segment limb on the ordinate (C,,,,,/GRF). It shows that calculated sodium chloride reabsorption for given rates of calculated distal deliveries are comparable in all three groups studied. It can be concluded from these experimeiits that distal delivery of fluid and sodium chloride and diluting segment function are unchanged in chronically bile-duct-ligated rats despite the increased total renal vascular resistance and diminished total renal blood flow of these animals. Minimal urinary osmolality aJer an oral water load in conscious unrestrained rats (Table 4 ) Included in this study are observations in 17 chronically bileduct-ligated Sprague-Dawley rats, 25 sham-operated Sprague-Dawley rats each studied 'once, and five Brattleboro diabetes insipidus rats each studied twice (once before chronic bile-duct ligation and then again after chronic bile-duct ligation). Results of liver-function tests of six of these 17 chronically bile-duct-ligated P Control anaesthetized vs chronically bile-ductligated anaesthetired rats P Chronically bilcductligated anaesthctizcd rats (n = 6) Control anaesthetizcd rats ( n = 11) Chronically bdcductligated conscious rats (n = 5) Chronically bileductligated conscious vs control anaesthctizcd rats NS. N.S. N.S. NS. 535 f 54 l l . 0 f 1.0 8.7 f 0.8 N.S. N.S. 583 f 43 11.0 f: 1.3 9-0 f 1.1 583 f 63 11.7 f 1.0 Maximum urine flow @/min) 11 *O ? 0.8 Basal lnulin clearance (ml min-' kg-' body wt.) + CN, N.S. N.S. N.S. NS. 538 f 34 244f I8 247 f 26 566 f 58 Od/min) C,,, 262 f 13 CWI, @/min) N.S. N.S. 11.0 f 2.1 14.6 f 2.5 (%I 100 C,,,AGFR + C,J/GFR (%I N.S. N.S. 23.4 f 3.1 32.4 f 8.0 100 (C,,,, TABLE 3. Free waterformation at thepeak of hypo-osmotic volume expansion in anaesthetized chronically bile-duct-ligatedrats and in control rats Mean results 2 SEM are shown. NS. 46.8 f: 3.1 41.6f: 3.0 4' )aN' (%I 100 C,,A (cwalct 0' 3 a. 3 C 0.S. Better et al. 498 TABLE4. Minimal urinary osmolality and percentage of water excreted afler oral water load in conscious sham-operated and bile-duct-ligated rats Mean results f SEM are shown. Sham-operated rats ( n = 25) Spraguc-Dawley bile-duct-ligated rats (n = 17) Diabetes insipidus chronically bikduct-ligated rats ( n = 5) Diabetes insipidus rats before chronic bileduct ligation (n = 5) P < 0.001 Minimal urinary osmolality (mosmol/kd % o f water load excreted 127 i: 7 247 f 25. 115 f 14 94 f 3 83 i: 6 171 f 3 6. 127 f 12 126 i: 21 vs sham-operated rats and vs diabetes insipidus chronically bile-duct-ligated rats. ** P < 0.05 vs sham-operated rats and vs Sprague-Dawley 25J 20 - :: c! 1 5 - -2 -" U L. g 10- e LI. 5- 0 5 10 15 20 25 Distal sodium delivery FIO. 1. Relation between calculated distal delivery (CN, + Cw,tr!ml min-l 100 ml-' GFR) of sodium chloride (horizontal axis) and calculated sodium reabsorption (C,,,,, ml min-' 100 ml-' GFR) in the thick ascending limb (vertical axis) obtained during intravenous infusion of hypo-osmotic sodium chloride solution (75 mmolh). 0,Results obtained from six anaesthetized chronically bile-duct-ligated rats; 0 , results from 11 anaesthetized control rats. The two broken curves delineate the range obtained in normal conscious rats studied in this laboratory by Liaas et al. (1978). It can be seen that sodium reabsorption at the thick ascending limb for given rates of distal delivery is similar in all three groups studied. This suggests normal distal delivery and ascending limb function in the chronically bileduct-ligated rats. Sprague-Dawley rats, five of 25 sham-operated Sprague-Dawley rats and all five chronically bile-duct-ligated Brattleboro diabetes insipidus rats are given in Table 1. Minimal urinary osmolality in the chronically bile-duct-ligated Sprague-Dawley bileduct-ligated rats. rats was higher than in sham-operated SpragueDawley rats (247 f 25 vs 127 f 7 mosmol/kg, P < 0401). Minimal urinary osmolality of chronically bile-duct-ligated Brattleboro diabetes insipidus rats was lower than in chronically bile-duct-ligated Sprague-Dawley rats (115 f 14 vs 247 f 25 mosmol/kg, P < 0.001). Minimal urinary osmolality of the chronically bile-duct-ligated Brattleboro diabetes insipidus rats was comparable before and after chronic bile-duct ligation. The percentage of ingested water excreted was lower in the chronically bile-duct-ligated SpragueDawley rats than in sham-operated SpragueDawley rats. This diminution in urinary volume after a water load in the chronically bile-ductligated Sprague-Dawley rats approached but did not quite reach statistical significance (83 f 6 vs 94 f 3%). Interestingly, the percentage water load excreted in the Brattleboro diabetes insipidus rats was greater after chronic bileduct ligation than before chronic bile-duct ligation. This increase, which suggests augmented distal delivery after chronic bile-duct ligation, was not, however, statistically significant. Discussion Studies of sodium chloride reabsorption along the nephron in rats with bile-duct ligation by micropuncture techniques have yielded conflicting results (Bank & Aynedjian, 1975; Yarger, Schrader & Boyd, 1976; Allison, Moss, Fraser, Dobbie, Ryan, Kennedy & Blumgart, 1978). Our results in conscious rats suggest that proximal tubular reabsorption of sodium chloride is normal after bile-duct ligation. In the present study, renal blood perfusion was Urinary dilution in obstructive jaundice decreased in rats with chronic bile-duct ligation despite normal systemic haemodynamics. Impaired renal blood flow has been associated with liver damage in man (Wilkinson, Smith, Clarke, Arroyo, Richardson, Moodie & Williams, 1977) and several animal models (Dawson, 1964; Bloom, Bomzon, RosendorfF& Kew, 1976; Yarger et al., 1976). The present study shows that liver damage due to chronic bileduct ligation in the rat is associated with an impaired capacity to lower urinary osmolality maximally. The defect in urinary dilution occurred despite adequate systemic circulation and in the face of normal intrarenal determinants of water excretion such as distal delivery of fluid and intact function of the diluting segment. On this background, the observation that the defect in urinary dilution occurred only in animals with an endogenous source of antidiuretic hormone strongly suggests that this defect is antidiuretic hormone-dependent. Our conclusion that the intrarenal dilution mechanism was intact after chronic bile-duct ligation is based mainly on the crucial finding of normal ability to lower urinary osmolality maximally in conscious, unrestrained, non-volumeexpanded rats, with congenital diabetes insipidus and chronic bileduct ligation. The validity of the assumption that C,,,,, reflects sodium chloride transport at the diluting sites assumes that free water is generated at the thick ascending limb by sodium chloride reabsorption and this site is always water impermeable. During water diuresis the distal tubule and collecting duct are relatively impermeable to water and the urine approaches the composition of the tubular fluid leaving from the thick ascending limb. The usefulness and the limitations of using this methodology for assessing diluting segment function have been discussed in detail (Seldin & Rector, 1973; Ish-Shalom, Rapoport, Chaimovitz & Better, 1978). Hyponatraemia is common in patients with cirrhosis, but was not seen in our rats. The reason for this is probably the more severe defect in urinary dilution in advanced cirrhosis, which may be due to a conservation of a diminished distal delivery of fluid and an increased secretion of antidiuretic hormone. On this background, excessive thirst stimulated by inadequate effective blood volume would lead to positive water balance and hyponatraemia. In contrast, our rats with bile-duct ligation could excrete some hypo-osmotic urine despite the defect in maximal lowering of urinary osmolality. This apparently was sufficient 499 to compensate for water ingestion without causing hyponatraemia. In summary; our finding suggests that impaired urinary dilution in conscious rats with chronic bile-duct ligation is due to a sustained secretion of antidiuretic hormone. This is compatible with the finding of lowered osmotic threshold for release of antidiuretic hormone in patients with cirrhosis (Earley & Sanders, 1959) and in dogs with chronic bile-duct ligation (Melman & Robertson, 1977). Acknowledgments This work was published in abstract form (Clinical Research, 1978, 26, 457A) and presented at the meetings of the American Federation for Clinical Research, National Meeting, San Francisco, California, May, 1978. This work was supported by a grant from the National Institutes of Health. AM 19928. 0. S. B. is an Established Investigator, Office of the Chief Scientist, Ministry of Health of Israel, and was a visiting Professor of Medicine on sabbatical leave from Rambam Medical Center and Technion School of Medicine, Haifa, Israel. R. J. A. is a recipient of a NIH Research Career Development Award. We are grateful to Abby Erickson, Marilyn Bard, Patricia Arnold and David Hyde for technical assistance and to Linda Benson for secretarial assistance. 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