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Effect of protein intake and urea on sodium excretion during inappropriate antidiuresis in rats

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Effect of protein intake and urea on sodium excretion during inappropriate antidiuresis in rats
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  Effect of Protein Intake and Urea on Sodium Excretion During Inappropriate ntidiuresis in Rats zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPON Joseph G. Verbalis, Ernest F. Baldwin, Pamela N. Neish, and Alan G. Robinson Administration of urea to patients with the syndrome of inappropriate antidiuresis WAD) is thought to ameliorate hyponatremia by both producing an osmotic diuresis and diminishing ongoing natriuresis. The present study evaluated these effects in a rat model of SIAD utilizing dilutional hyponatremia induced by continuous infusion of l-deamino- [8-o-arginine] vasopressin. Following 48 hours of sustained hyponatremia, separate groups of rats were then refed with either: (1) 5% dextrose alone, (2) a 20% protein chow, (3) an isocaloric protein deficient (0%) chow, or (4) the isocaloric protein-deficient chow supplemented with oral urea. Our results demonstrate that rats refed a 20% protein diet significantly improved their plasma [Na+] as compared to rats refed protein deficient diets, and this improvement was accompanied by decreases in natriuresis despite an increased glomerular filtration rate and an unchanged negative free water clearance. Identical effects were observed in rats refed a protein deficient diet but supplemented with oral urea, suggesting that urea generation from catabolism of dietary protein is responsible for the effect of protein refeeding to decrease urinary sodium excretion. Both the protein and urea refed rats had significantly higher inner medullary urea contents and concentrations compared to rats refed protein-deficient diets and also to rats studied immediately before protein refeeding, supporting the hypothesis that urea and dietary protein decrease natriuresis in patients with SIAD in association with increased inner medullary urea concentrations. o 1888 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA y Grune Stratton, Inc. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCB U REA has recently been utilized therapeutically in patients with the syndrome of inappropriate antidiure- sis (SIAD). Administration of oral urea to such patients was found to ameliorate hyponatremia not only by inducing an osmotic diuresis, but also by diminishing natriuresis.‘** One hypothesized mechanism for decreased urinary sodium excretion following administration of urea to patients with SIAD is that an increased inner medullary urea concentra- tion allows greater sodium chloride reabsorption, possibly from the ascending limb of the loop of Henle, suggested by previous studies utilizing urea infusions in rats.3-5 In the present report we used an animal model of SIAD that allowed maintenance of sustained dilutional hypona- tremia without significant escape from antidiuresi.@ to study the effects of urea on sodium excretion in SIAD. Urea metabolism was varied by alterations of dietary protein and by administration of urea. In addition to evaluating sodium metabolism, the content and concentration of urea nitrogen in the inner medulla of the kidneys was directly measured to allow a comparison between renal inner medullary urea and sodium excretion. This enabled us to evaluate the hypothesis that increases in inner medullary urea accompany the changes in sodium clearance that occur as a result of high protein diets or urea administration during periods of inap- propriate antidiuresis. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA From the Department of Medicine, University of Pittsburgh and the Pittsburgh VA Medical Center. Supported by research grants AM-31302 and AM-16166 from the National Institutes of Health and by the Veterans Administra- tion. Presented in part at the American Federation for Clinical Research. National Meetings, Washington, DC, 1984 and at the Seventh International Congress of Endocrinology, Quebec. Canada, 1984. Address reprint requests to Joseph G. Verbalis, MD, 930 Scaife Hall, University of Pittsburgh, Pittsburgh, PA 15261. o 1988 by Grune & Stratton, Inc. 0026-0495/88/3701-0009 03.00/O zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 46 MATERIALS AND METHODS Animals Adult male Sprague-Dawley rats (Zivic-Miller, Allison Park, PA) weighing 250 to 325 g were maintained on pelleted rat chow (Wayne Lab-Blox, Chicago) and ad libitum tap water prior to study. Animals were housed in a temperature controlled room (22T) with lights on from 8 AM to 8 PM. All animals had indwelling jugular venous catheters implanted at least 48 hours prior to beginning any study. These consisted of silastic tubing (1.19 mm OD, Dow- Corning, Midland, MI) inserted to the level of the right atrium and connected to a length of polyethylene tubing (PE-60, Clay-Adams, Parsippany, NJ) that exited from the skin between the scapulae. Catheters were filled with a solution of polyvinyl pyrrolidone (0.5 g/dL, Eastman Kodak, Rochester, NY) in heparin (1,000 U,/mL) between blood sampling. A total of 57 rats were used for the combined studies reported here. Establishment of Hyponatremia Hyponatremia was induced using techniques recently described.6 At the start of each study rats with chronic indwelling jugular venous catheters were placed in plastic metabolic cages (Nalgene Model 650-0100, Rochester, NY) and maintained for four to five days on a low sodium (0.01% by weight), 20% protein diet (Teklad 170840, Madison, WI) with ad libitum drinking water. Following this equilibration period, all rats received continuous infusions (10 rig/h)) of I-deamino-[8-o-arginine] vasopressin, dDAVP, (USV Pharmaceuticals, NY) for four days via osmotic minipumps (Alzet Model 2001, Palo Alto, CA) implanted subcutaneously under light ether anesthesia. Food was withheld and 5% dextrose in water (DSW) was substituted for drinking water beginning 24 hours before pump insertion and continuing in all cases for 48 hours after pump insertion. As demonstrated previously, using this model rats develop severe dilutional hyponatremia (plasma [Na+] ~120 mEq/L) within 24 hours secondary to water retention, and relatively stable hyponatremia is then maintained for the duration of the dDAVP infusions.6 Refeeding Studies Following the development of stable dilutional hyponatremia via ingestion of excess DSW in the absence of food, some animals were then refed while the dDAVP infusions continued in order to study Metabolism, Vol 37, No 1 (January), 1988: pp 46-54  EFFECT OF DIETARY PROTEIN AND UREA IN SIADH 47 the effects of dietary protein intake in animals with established hyponatremia secondary to inappropriate antidiuresis. Three sepa- rate studies were performed. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Study I (n = 22). For the initial studies, on day 3 of the dDAVP infusion these rats were divided into a group of 11 rats that were refed a normal protein diet (Teklad 6170840, 0.01% sodium, 20% protein) and a group of 11 rats that continued on DSW as their only caloric intake. Study II (n = 25). In order to achieve a greater degree of hyponatremia in the second study, the oral D,W intake was supple- mented with 25 mL of D,W administered intraperitoneally at the time of osmotic minipump insertion. On days 3 and 4 of dDAVP infusion a group of five rats were refed the same diet (0.01% sodium, 20 protein) as in study I, and a group of I 1 rats received a matched diet except that all casein was replaced by an isocaloric amount of corn starch rendering this diet protein deficient (Teklad TD 83342). In order to standardize both the sodium and water intake of these two groups, all rats received I5 mL/d of 2.5% dextrose plus 0.5 mEq of sodium (28.95 mg NaCl) via three divided intraperitoneal injections (q 8 h) while all oral fluids were withheld (this volume of fluid was chosen to approximate the measured daily insensible water loss of rats maintained in our animal roomr?). A third group of nine rats were also refed with the isocaloric protein deficient diet on days 3 and 4, but were additionally given 1 g of urea by gavage on each day in three divided doses (q 8 h). The urea was administered in 3.0 mL of the same solution used for the infraperitoneal injections and the volume of the injections adjusted so that the rats receiving urea had the same total NaCl and water intake as the animals receiving the isocaloric low protein diet only. Study III (n = IO). A final study was done to ascertain the effects of protein refeeding on glomerular filtration as estimated by creatinine clearance. Rats in this study were made hyponatremic as in study 11. On days 3 and 4 of dDAVP infusion a group of five rats were refed the 20% protein diet and the remaining five rats were refed the isocaloric protein deficient diet. Throughout the refeeding period rats had ad lib access to D,W as in study I. Balance Studies Throughout each of the four days of dDAVP infusion daily blood and urine samples were collected. Blood samples (0.5 mL) were obtained immediately before dDAVP pump insertion and every 24 hours thereafter until completion of the study. The samples were placed into heparinized borosilicate tubes and centrifuged (3,000 x g for 15 minutes) at 4°C within 20 minutes. Plasma [Na’] and [K+] were measured by sodium and potassium specific electrodes (Beck- man Electrolyte Analyzer II) and BUN via urea conductivity (Beckman BUN Analyzer 2). Daily 24-hour urines were collected during each of the four days of dDAVP infusion, and analyzed for [Na+], [K+] and urea nitrogen as above, as well as osmolality by freezing point depression (Advanced Instruments Osmometer, Model 3D). Plasma and urine creatinine (Beckman Creatinine Analyzer) were measured only in study III. Drinking and urine volumes, food intake, and weights were measured daily throughout the studies. Sodium balance was calculated as the sum of all sodium intake (intraperitoneal injections plus ingested food) minus the urinary sodium loss. Feces production following 48 hours of only D,W without solid food was minimal (< 1 g/24 hours on days 3 and 4) and was not analyzed for the balance calculations. In order to verify the sodium contents of the test diets, food samples were dried to constant weight, homogenized in known volumes of distilled water, and eluted for 72 hours.’ Following centrifugation, [Na+] in the supernatants was measured in quadruplicate by flame photometry (Beckman KlinaFlame). There was no significant difference between sodium content of the 0.01% sodium, 20% protein diet (3.91 + 0.19 mmol/kg) and the 0.01% sodium protein-deficient diet (4.33 it 0.12 mmol/kg), but both were far less than the sodium content of regular Wayne Lab-Blox rat chow (170.0 + 3.4 mmol/kg). Standard calculations were used for deriving the sodium (Cu.,), creatinine (Cc,), and negative free water (Tc,,*o) clearances from the plasma and urine results. In addition, sodium-free water clearance (C,,+rw) was calculated as: C,,,, = U, - CNa+. All clearances are expressed in nL/min. Kidney Inner Medullary Analysis Some rats from studies 1 and II were decapitated at the end of day 4 after completion of the 48-hour refeeding period. Kidneys were rapidly removed and the inner medullas (IM) immediately dis- sected. Each IM consisted of zones 1 through 3 (papilla and white inner medulla) as per Atherton.’ After weighing each IM (Roller- Smith Precision Balance, Biolar Corp, North Grafton, MA). the right IMs were placed in 1 O mL of water in covered ground glass homogenizers, and were incubated in a boiling water bath for 20 minutes. They were then homogenized and stored at 22°C. The next day an aliquot of the supernatant (0.4 mL) was enriched with sodium chloride to render the concentration of the final solution I50 mmol/L in Na+. Urea nitrogen was measured in this aliquot using the Beckman BUN Analyzer 2.9 The remaining nonsalinized super- natant was utilized for measurement of IM sodium concentration (animals in study II only). The left IMs were placed in foil, oven dried overnight at lOO”C, then reweighed the next day for determi- nation of IM dry solid weight. Inner medullary urea nitrogen content was calculated in mmol/lOO g urea nitrogen-free dry solid (UNFDS). Inner medullary urea concentration was calculated in umol/g H,O. Inner medullary sodium content was calculated in mEq/lOO g UNFDS and concentration in umol/g H20. Statistical Analysis All results are expressed as mean + SE. Statistical significance was determined by Student’s two-tailed t-test where indicated for comparison of paired groups, or by ANOVA with a posteriori analysis by the method of Newman-Keuls for comparison of three or more groups. RESULTS Plasma Sodium Concentration All animals developed marked hyponatremia by 48 hours with the dDAVP infusions (Fig l), and as planned the animals in study II reached a significantly lower plasma [Na+] as a result of the additional intraperitoneal D,W load (103 + 1 v 116 ? 2 mEq/L, P < ,001). The animals in study I that remained on D,W as their only caloric intake had a slowly progressive further decrease in plasma [Na+] on days 3 and 4, while those refed the 20% protein diet showed a significant improvement in plasma [Na’], resulting in a + 15 + 2 mEq/L increase over 48 hours. Based on the quan- tity of food ingested during this time (36 + 2 g) exogenous Na+ intake amounted to only 0.14 + 0.01 mEq, which by itself would be sufficient to increase plasma [Na+] by only 3.2 mEq/L, assuming total equilibration throughout the extracellular fluid space (estimated to be 33% of total body water, or 22% of body weight). To further control for variations in exogenous sodium intake, animals in study II were refed identical diets except for the protein content and were all given 1.0 mEq of Na’ intraperitoneally. Animals  48 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 140 130 100 90 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA G - + + PROTEIN o---o + PROTEIN OR UREA M - PROTEIN 90 ’ J 1 I 1 I 0 1 2 3 4 DAY Fig 1. Plasma sodium concentrations on successive days of dDAVP infusion to rats in study (A) and study II (Bl. After day 2. rats ware refed with either (1) 20% protein chow or protein deficient chow with supplemental urea (0). or (21 5% dextrose or protein deficient chow alone (0). Each point represents the mean k SEM for 22 rats in study I (11 +protein, 11 D,W only) and 26 rats in study II (14 +protein or urea, 11 -protein). Significance levels are shown between the protein or urea refed and the protein deprived rats on days 3 and 4 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA +P < .05. P -c .Ol). refed the low protein diet remained severely hyponatremic, while those given either the 20% protein diet or supplemental urea again showed a significant improvement in the plasma [Na+]. Although the absolute level of plasma [Na+] reached after day 4 was lower than was observed in the rats in study I, the relative increments over basal sodium concentrations were similar for both groups (+ 15 + 2 mEq/L study I, + 12 + 2 mEq/L study II). Thus, protein or urea refed hypona- tremic rats had significant improvements in plasma [Na+] both in comparison to rats given DSW only or fed an isocaloric protein deficient diet. The rats in study III had results virtually identical to studies I and II; rats refed the 20% protein diet improved their plasma [Na+] from 103 + 1 to 118 f 4 mEq/L after two days of refeeding, while those refed the isocaloric low protein diet had no significant VERBALIS ET AL increase in plasma [Na+] (102 + 1 mEq/L before refeeding and 100 f 1 mEq/L after two days of refeeding, P < .Ol difference between the final [Na+] for the two groups). zyxwvutsrqpon Metabolic Measurements Tables 1 and 2 summarize the metabolic data and results of the daily plasma and urine analyses for studies I and II. For each day of the dDAVP infusions separate means are shown for the different refeeding subgroups (Study I: DSW only [D=,W, n = 1 l] and 20% protein diet [ +P, n = 111; study II: isocaloric protein deficient diet [-P, n = 11],20% protein diet [ +P, n = 51, and isocaloric protein deficient diet with supplemental oral urea [-P + U, n = 91). Each column shows the metabolic data for successive days of dDAVP infusion, and the weights and plasma concentrations at the end of each 24-hour period. The last column shows cumula- tive results for the entire two day refeeding period, or the net changes between the start (day 2) and the end (day 4) of the refeeding period for body weights, plasma concentrations and urine osmolalities. Differences between the two studies are apparent as a result of modifications to the protocols used for both estab- lishment of hyponatremia and refeeding; however, within each study the relative differences between the protein or urea refed rats and the rats that remained protein deficient (DSW alone in study I and isocaloric low protein diet in study II) were consistent. In each study all animals were treated identically during days 1 and 2 of dDAVP infusion, and no significant differences were found among any of the refeed- ing subgroups for these two days in either study I or study II except for a slightly higher starting weight in the urea refed group of study II. All rats had a significantly positive measured water balance (drinking volume minus urine out- put) on the first day of dDAVP infusion, thus establishing the dilutional hyponatremia, but thereafter came into rela- tive balance, as has been noted previously using this model.6 There was a greater spontaneous fluid intake in the protein refed rats in study I during refeeding, along with a similar trend toward a more positive water balance in the study II protein refed rats. The protein refed rats also ate more than rats refed isocaloric low protein chow, an effect which was most marked on day 4, the second day of refeeding. The net result of greater food and fluid intake by the protein refed rats is reflected in the relative weight changes; in both studies protein refed rats lost less weight than the rats that remained protein deficient. However, this effect did not become pro- nounced until the second day of the refeeding period, and no significant changes in weights were observed on the first refeeding day when most of the improvement in plasma [Na+] occurred (Fig 1). Furthermore, no significant differ- ences in weight, food intake, or fluid balance were noted between the protein deficient rats and those refed urea. No significant changes in plasma BUN were seen throughout the period of study in either group, including the rats receiving supplemental urea. Urine concentration was significantly increased following protein or urea refeeding in the rats in study II. While this effect was not observed in the protein refed rats during study I, the starting urine osmolality was higher in this group  EFFECT OF DIETARY PROTEIN AND UREA IN SIADH zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Table 1. Experimental Results: Study I 49 dDAVP Infusion Baseline 0 1 2 Refeeding 3 4 - Metabolic data Weight (g) Intake/output (mL/24 h) Food intake (g/24 h) Plasma measurements pINa+] (mEq/L) BUN (mg/dLI Urine measurements U_ ImOsm/kg H,O) U,,+ I@Eq/24 h) U,, (mg/24 h) DEW +P D,W P D,W +P D,W fP D&W +P D,W +P DsW +P D,W fP ‘P -c zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA O 1, relative to D,W group. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA tP < .05, relative to D,W group. 216 * 5 216 t 4 137 + 1 137 + 1 10 _t 1 g-t1 - - - - 224 t 12 201 * 5 221 * 10 202 r? 5 24 ? 313 +- 1 13+2/5+ 1 29 + 214 z+ 1 7 2 217 t 1 0 0 0 0 1,941 + 216 1,710 + 118 278 f 118 356 t 115 95 + 9 146 + 11 118 * 3 113 * 2 St1 lo* 1 2.082 f 165 1,845 ? 146 358 + 80 599 + 91 158 & 15 184 + 14 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJI 190 ? 5 199 * 4 10 + l/6 ? 1 8 & 2/8 + 1 0 18* 1 110*2 126 + 2’ 921 lo* 1 1,841 * 175 1,785 t 173 581 * 156 189 + 41’ 188 f 34 293 ? 22t 17724 207 f 5’ 7+ l/6*2 15&2t/6+ 1 0 182 1 107 + 1 128?3* 102 1 13* 1 1,924 t 283 2,100 + 208 521 + 141 93 + 12’ 176 + 32 229 + 33 - Cumulative Day 3 f 4 --23 + 2 +4 * 5. 17 f 2112 f 2 23 t 2t/14 ? 2 0 36 + 2 --11 * 2 i- 15 * 2’ +1_+ 1 t3 * 2 -191 ? 360 f255 t 188 1,028 t 274 282 + 43* 345 _t 43 523 + 61t Table 2. Experimental Results: Study II dDAVP Infusion Baseline 0 1 2 Refeeding Cumulative 3 4 Oav3+4 Metabolic data Weight (g) Intake/output (mL/24 h) Food intake (g/24 h) Plasma measurements p[Na+] (mEq/L) BUN (mg/dL) Urine measurements U,, (mDsm/kg H,O) U,,+ (LcEq/24 h) U,, (mg/24 h) -P fP --P+u -P +P -p+u -P +P -p+u -P +P --P+u -P +P -p+u -P fP -P+U -P fP -p+u -P fP -p+u 278 * 5 279 + 4 311 t 131 - - 137 & 2 143 + 2 136 * 2 9&l 13 & 3 8+2 - - - - - 304 * 6 298 + 4 330 r 13’ 48~ l/6+ 1 46 i l/6 ? 1 43 ? 217 + 1 0 0 0 - 1.377 f 93 1,302 + 155 1,134 * 137 178 f 52 70+ 15 223 & 94 110 * 20 92 -c 14 93 + 20 286 + 6 284 + 6 321 t 15’ 14 + 2114 t 2 18 -+ 3/12 + 2 14+2/7_t 1 0 0 0 101 * 2 102 r 3 107 + 2 10 * 2 se1 10 f 2 1,071 * 133 1,018 + 52 1,345 + 120 1,127 * 171 926 + 369 617 + 160 149 + 18 144 f 19 127 + 33 275 * 6 277 & 5 312 & 16* 15112 + 2 15111 2 3 15110 + 1 8+1 15 + 1t IO* 1 104 + 2 112 + 1’ 114 + 2t 7+1 8-+1 Sk2 910 + 78 1,499 i 263 1,903 + 187t 665 ? 146 180 + 65t 182 + 37t 95+- 15 232+31 358 + 36t 263 + 6 272 + 5 302 ” 16” 15113 * 2 1518 -+ 2 15/10 * 1 4? 1 15 r 1t 8-rl 104 + 2 115 * 2t 118 + 3t 9+2 8?1 sr2 639 t 46 1.396 r 147’ 1,734 * 144t 929 * 232 388 & 175 306 f 92 102 * 31 143 + 21 316 + 27t --23 _t 3 -12*4t -19%2 30125 + 3 30119 + 3 30120 t 3 12 + 2 29+ It 18 ? 3 f3 t 2 f13 + 2** +1ti2* -1+3 -1 I 1 -1 f 1 -431 + 151 +38O t 141t +389 % 172t 1,596 c 290 568 ? 182t 487 + 114* 190 + 33 377 + 52 674 + 56t < .05, relaive to -P group. tP < .O 1, relative to -P group  50 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA VERBALIS ET AL potentially obscuring any significant urea-mediated increase in urinary concentrating ability. In both studies the subse- quent decreases in urinary Na+ following protein or urea refeeding on day 3 are significant and large. This antina- triuretic effect persisted throughout both refeeding days in the rats in study I, but in the animals in study II urine Na+ again increased on day 4, although not to the levels of the protein deficient rats. As expected, urinary urea nitrogen excretion was significantly greater in the protein refed rats. However, except for the rats given supplemental urea, this effect also was statistically significant only on day 3, the first day of refeeding. Figure 2 summarizes the daily urinary excretion of sodium and urea nitrogen for both studies throughout the four days of dDAVP infusion. Supplemental urea feeding caused virtually identical effects on urinary Na+ excretion as did protein refeeding, although despite significantly higher urinary urea nitrogen excretion in the urea fed rats on both days of refeeding, no further inhibition of natriuresis was seen for these rats than for the protein refed animals. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA s +l.O g 8 z +0.5 4 a:p *, +v) 0 2% WO -“.5 z -1.0 P -P+U D5W +P -? v’ -1 As expected from the urinary excretion results, total sodium balance was significantly less negative in protein or urea refed rats for both studies (Fig 3). However, the overall sodium balances were very different between the two studies. The only source of exogenous sodium in the protein refed rats in study I was the small amount present in the low sodium (0.01%) chow. Consequently, despite significantly decreased natriuresis, these animals remained in a slightly negative overall sodium balance, although not nearly as negative as for the rats on D,W alone. In contrast, in study II all rats received 0.5 mEq/d of Na’ via intraperitoneal injections. As a result, the protein or urea fed rats in this study were able to maintain a positive sodium balance, but despite administra- tion of exogenous sodium the protein-deficient rats in this study remained in a net negative sodium balance. Therefore, achievement of a positive sodium balance was not a prerequi- site for improvement in plasma [Na+] following protein or urea refeeding. Fig 3. Cumulative sodium balance over the 4B-hour refeeding period for rats in study I (left) end study II (right). Significance levels are shown between the protein or urea refed rats and the protein deprived rats (*P < .05, f < .Ol). zyxwvutsrqponmlkjihgfedcbaZ Clearance Calculations Creatinine clearances (Cc,) were calculated for all four days of dDAVP infusion in study III, to ascertain whether a decrease in GFR in protein-refed animals could account for the observed decreases in sodium excretion observed in studies I and II. As shown in Table 3, Cc, decreased substantially in the dDAVP-infused hyponatremic rats, pre- sumably secondary to the protein deprivation during this period.‘“” However, animals fed the isocaloric low protein chow (-P, n = 5) then continued to have an unchanged Ccc for the next two days of refeeding, whereas those fed the 20% protein diet (+P, n = 5) corrected their Ccr back to levels not significantly different from the basal pre-dDAVP levels. Following refeeding with the 20% protein diet or supple- mental urea, CNa+ decreased significantly as compared both to the rats in study I maintained on D,W and the rats in study II on the isocaloric protein deficient diet, as predicted from the balance data. This occurred despite the signifi- cantly higher creatinine clearances in the protein refed rats found in study III. In contrast to the changes in sodium clearance, no significant differences were found in the nega- tive free water clearances of the protein refed rats as compared to the rats in study I maintained on D,W and the rats in study II on the isocaloric protein deficient diet. Figure 4 shows the calculated sodium-free water clear- ances for both studies I and II, which reflects the combined effect of dietary protein or urea on both sodium and water P 3 Fig 2. Daily Z&hour urinary sodium and urea nitrogen excre- tion during dDAVP infusions to rats in study I (Al and study II (B). Following refeeding results are expressed separately for the protein refed (n = 5) end urea supplemented (n - 91 rats in group II. Significance levels are shown relative to the protein deficient rats (above bars) es well as between the protein and uree refed subgroups (brackets) (‘P -c .05. P < .Ol). Table 3. Creatinine Clearances: Study Ill zyxwvutsrqponml Baseline Hyponatremic zyxwvutsrqponmlkjihg efed (Day ) lDay 21 (Day 1 C (pL/min) -P 2,216 + 74 1,322 + 161 879 * 40 +P 2,399 + 412 1,228 & 37 2,129 + 312. < .Ol, relative o -P group.
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