Evidence in Hyponatremia Related to Inappropriate Secretion of ADH That V1 Receptor Stimulation Contributes to the Increase in Renal Uric Acid Clearance1’2

Home , Hypoproteinemia

Evidence in Hyponatremia Related to Inappropriate Secretion of ADH that V1 Receptor Stimulation Contributes to the Increase in Renal Uric Acid Clearance1’2

G. Decaux,3 B. Namias, B. Gulbis, and A. Soupart

atremia (6.4 ± 1.5 mL/min and 5.4 ± 0.9%). On the

G. Decaux, B. Namias, A. Soupart. Unite de Recherche other hand, in Group II, both parameters were In- du M#{233}tabolisme Hydromin#{233}ral, Service de M#{233}decine creased (17.8 ± 2.9 mL/mln and 19.6 ± 5.3%; P < Interne, HOpital Universitaire Erasme, Universit#{233} Libre 0.001) and both values were higher than In the de Bruxelles, Brussels, Belgium dDAVP-induced hyponatremia (P < 0.01). AdditIon- B. Gulbis, Laboratoire de Chimie, HOpital Universitaire ally, the administration of a potent V1-receptor ago- Erasme. Universit#{233} Libre de Bruxelles, Brussels, Belgium nist (triglycyl-lysine-vasopressin) in a patient with central diabetes insipidus with preexisting dDAVP- (J. Am. Soc. Nephrol. 1996; 7:805-810) induced hyponafremia produced a rapid increase of urate clearance. Because dDAVP acts only on the V2 ABSTRACT receptors, these data suggest that the higher urate In hyponatremla related to syndrome of Inappropri- clearance observed during hyponatremla related to ate antidiuretic hormone (SIADH), hypouricemia Is SIADH is not only the consequence of an increased explained primarily by the high uric acid clearance “effective vascular volume,” but that V1-receptor stim- rate that results from the decrease in tubular uric acid ulation also contributes to It, by a mechanism that reabsorption. This modification of tubular handling of remains to be determined. uric acid is considered to be Induced by the Increase Key Words: Hyponatremla, urcte clearance, V7 receptor, V2 in the “effective vascular volume.” This study was receptor, “effective vascular volume” designed to determine if V1-receptor stimulation par- ticipates in the development of a high uric acid H yponatremia is typically associated with hy- clearance rate as in SIADH, in which the antidiuretic pouricemla ( 1 ,2) in the syndrome of inappropri- hormone acts on V and V2 receptors. Therefore, the ate secretion of antidiuretic hormone (SIADH), urate clearance rate was measured in seven volun- whereas in hypovolemic hyponatremia, the uric acid teers with 1-desamino-8-o-arglnlne vasopressin concentration is generally normal or increased (2). Hypouricemla is primarily the consequence of an high (dDAVP)-lnduced hyponatremia, with dDVAP stimu- uric acid clearance related to a decrease in tubular lating exclusively the V2 receptors (Group I), and In six uric acid reabsorption ( 1 ,2). Correction of the hypona- patients with SIADH (Group II) during both normo- and tremia by water restriction normalizes the uric acid hyponatremia. As expected, In both groups, the Se- clearance despite the persistent inappropriate secre- rum uric acid concentration decreased during hypo- tion of ADH ( 1 ,2). It is generally believed that the natremia, but did so to a larger extent in the patients changes in tubular handling of uric acid observed in with SIADH (-53% versus -29%, P < 0.02). Despite the SIADH is secondary to the increase in the “effective similar levels of hyponatremia (126 ± 5 mmol/L and vascular volume” associated with this syndrome (2),

125 ± 5.5 mmol/L), of hypoproteinemia (64 ± 5 g/L although the mechanisms of this regulation remain unknown. We had the opportunity to study the uric and 63 ± 5 g/L) and of salt excretion (FENO, 0.66 ± acid clearance rate in a patient with postoperative 0.28% and 0.73 ± 0.25%), the urafe clearance (8.3 ± central diabetes insipidus who developed hyponatre- 3.3 mL/min) and the fractional excretion of filtered mia after 1 -desamino-8-D-arginine vasopressin uric acid (5.7 ± 2%) in Group I were not significantly (dDAVP) administration. In this patient, the uric acid different during hyponatremia than during normon- clearance rate was not increased, despite the hyponatremia. This situation differed from the classical SI- 1 Received July 27. 1995. Accepted February 6, 1996. ADH in that water retention was induced by dDAVP. 2 PortIons otthis work were presented at the 27th Annual Meeting ofthe American This hormone acts only on V2 receptors, and has no Society of Nephrology and published in abstract form (J Am Soc Nephroi 1994;5:366). significant effect on V1 receptors (3), contrary to the

3 correspondence to Dr. G. Decaux, Service de M#{233}decine Inteme, H#{244}pltal arginine vasopressin (AVP) secreted in the SIADH. Universitaire Erosme, Route de Lennik, 808, 1070 Brussels, Belgium. This prompted us to investigate the uric acid clear- 1046-6673/0705.0805$03.OO/O ance rate in hyponatremia induced by dDAVP in Journal of the American Society of Nephrology Copyright C 1996 by the American Society of Nephrology volunteers. We confirm that, in this model of hypona-

Journal of the American Sociely of Nephrology 805 Hyponatremia Related to SIADH

tremia, the increase in the uric acid clearance rate is The fractional excretion of ifitered sodium and uric acid less important than that of classic SIADH, despite a were also determined in the morning during several days of similar increase in the “effective vascular volume”. mild hyponatremia. All serum and urinary chemical measurements were per- PATIENTS AND METHOD formed by the hospital clinical laboratory. Uric acid was measured by the uricase method. Hyponatremia Induced by dDAVP in Volunteers Effect of Triglycyl-Lysine Vasopressin (TGLV) on In seven physicians (aged 25 to 40 yr), dDAVP (Minirin, Urate Clearance in a Patient with Central Ferring. Belgium) was administered by nasal route for 4 days. dDAVP was given at the dose of 20 g every 8 h. The Diabetes Insipidus (CDI) and Hyponatremia first day, the subjects were submitted to mild water restric- Induced by dDAVP tion (10 mL/kg) followed during the subsequent days by a free water intake. The subjects were on a stable food and salt We evaluated the effects of acute V1 -receptor stimulation on urate clearance by triglycyl-lysine vasopressin (TGLV) intake diet during all of the procedures (70 to 150 mmol/ administration (Glypressin; Ferring, Malm#{246},Sweden). TGLV day). Body weight was determined each morning. Alcohol was prohibited for 5 days before and during the study. Serum acts as a chemical depot or “hormonogen” according to its ability to release slowly the parent hormone lysine vasopres- electrolytes, protein, creatinine, and uric acid concentrations sin and thus to exert protracted biological effects (at least 4 h) were measured on the mornings of each day (until Day 5) (4,5). after an overnight fast. Twenty-four h urine samples were In the subject studied, a 35-year-old man with CDI, serum collected during Day 1 and Day 4. None presented neurolog- ADH was not measurable despite mild hypernatremia (148 ical symptoms. The fractional excretions of ifitered uric acid mEq/L). After providing informed consent, he was submitted (FEuric acid) and sodium (FENa) (h1 %) were calculated as the to the same protocol as the normal volunteers. Sufficient (urine/serum) concentration of uric acid and sodium multi- water intake amounts (> 1 .5 L/day) were required over 5 plied by the (serum/urine) concentration of creatinine multiplied by 1 00 and were measured each morning between 8 days to obtain mild hyponatremia. On Day 4 (Table 2) urine and 10 am. samples were collected between 8 and 10 a.m. and then ever 2 h over four consecutive periods after lv administration over Hyponatremia Related to SIADH 30 mm of7.5 pg/kg ofTGLV, dissolved in 100 mL 5% glucose (4). Blood pressure and pulse rate were monitored every 10 In six asymptomatic patients with SIADH (three related to min during the test for the first h and then every 30 mm. The oat cell carcinoma, one idiopathic, and two related to brain patient stood up only to void, and drank a volume of water disease) and mild hyponatremia, the same measurements every 2 h that was equivalent to the urine volume voided were made as with the volunteers. Uric acid clearance rate during the preceding 2 h, to ensure a relatively stable “water” was determined during the hyponatremic state and after expanded state. Blood was collected in the middle of each normalization of the serum sodium by severe water restric- collection period for determinations of the same parameters tion (In 3 to 4 days) (Table 1). These patients were also on as with the volunteers. The patient fasted after a moderate stable food and salt intakes (70 to 150 mmol/day) during the breakfast eaten at 8 am. normo- or hyponatremic periods. Alcohol was prohibited as Because the patient developed mild hypertension during with the volunteers. the first hour after TGLV administration, which could have

TABLE 1 . Evolution of body weight and of some biochemical data during normonatremia and hyponatremia in our volunteers with dDAVP-induced water retention or in patients with SIADH#{176}

Hyponatremia In duced by dDAVP Hyponafremla Related to SIADH = 7) (N 6) Parameter (N Water Restriction Free Water Intake Water Restriction Free Water Intake

Body Weight (kg) 77 ± 8 80.3 ± 9 70 ± 9 72.5 ± 8 Serum (mmol/L) 138 ± 1 126 ± 5b 139 ± 1 125 ± 55b Serum Protein (gil) 69 ± 4 64 ± 5b 68 ± 5 63 ± Serum Uric Acid (mg/dL)e 5.5 ± 0.6 3.9 ± 0.4c 4.5 ± 1.3 2.1 ± 03c.d Creatinine Clearance (mi/mm) 1 19 ± 20 147 ± 28 91 ± 30 100 ± 34

Uric Acid Clearance (mi/mm) 6.4 ± 1 .5 8.3 ± 3.3 7.8 ± 3.4 17.8 ± 29b.d 24-hr urate excretion (mg) 505 ± 79 475 ± 133 461 ± 154 525 ± 150C FEUdC acid (%) 5.4 ± 0.9 5.7 ± 2 8.4 ± 2.6 19.6 ± 5,3cd FENa (“#{176}) 0.61 ± 0.15 0.66 ± 0.28 0.55 ± 0.20 0.73 ± 0.25 Urine Flow (mL/min) 0.84 ± 0.4 1.4 ± 0.4 0.60 ± 0.22 0.86 ± 0.6

a SIADH. syndrome of inappropriate antidiuretic hormone. bp< OO01 cp< d p < 0.01 compared with values observed during hyponatremia induced by dDAVP. e Conversion factor in mmol/L = mg/dL x 0.059. f P < 0.05 compared with values observed during normonatremia in the same group.

806 Volume 7 - Number 5 ‘ 1996 Decaux et al

TABLE 2. Evolution of biochemical parameters after lv administration of triglycyl-lysine-vasopressin (TGLVP) in a patient with central diabetes Insipidus and preexisting mild hyponatremia under dDAVP substitution0

During dDAV P-Related Hyponatremia

After TGLVP After TGLVP Parameter dDAVP (7.5 ,g/kg/per 30 mm) (2.5 g/kg/per 30 mm)

8to lOh lOtol2h l2to Mh l4to 16h l#{243}to18h 8to lOh lOto 12h l2to 14h l4to 16h

Na(mmol/L) 138 131 130 131 130 129 127 127 126 126 Uric Acid 6.8 5.8 5.7 5.5 5.1 5 5 4.8 4.6 4.6 (mg/dL) CrClearance 111 134 113 146 125 122 120 123 147 120 (mL/min) Uric Clearance 7.2 1 0.8 1 1 .5 19.8 13 10 9.9 1 3.3 16.5 10 (mL/mln) FEuric acid (%) 6.5 8 10.2 13.6 10.4 8.2 8.4 10.9 1 1.2 8.3 FENa (#{176}“#{176}) 0.8 1.35 2.8 2.2 1.4 0.63 0.7 1.3 1.7 1.2 Urine Flow 1 2 2.33 4.5 2.1 1.2 1.25 1.3 2 1.4 (mi/mm) Urine 642 510 505 490 530 550 480 650 550 560 Osmolality (mosmol/kg H20)

a dDAVP. 1-desamino-8-D-arglnine vasopressin; Cr. creatinine.

induced some “pressure diuresis” (Table 2), a second test was only in the volunteers (1 19 ± 20 mL/min to 147 ± 28 performed the next morning with a lower dose of TGLV (2.5 mL/min; P < 0.05). pg/kg) injected in the same way. This dose produces an In the six patients with hyponatremia related to increase in plasmatic antidiuretic activity close to that of SIADH, the hypouricemia observed during the hy- endogenous arginine-vasopressin concentrations (4). ponatremic state ( 125 ± 5.5 mmol/L) was more im- The results are presented as mean ± SD, and conventional portant (2. 1 ± 0.3 mg/dL; a decrease of 53%) than or paired t tests were used as appropriate. We also used linear regression. that ofthe dDAVP-induced hyponatremia (-29%; P < 0.02). There was no significant difference in uric acid levels in both groups during normonatremia (4.5 ± RESULTS 1.3 mg/dL and 5.5 ± 0.6 mg/dL; not significant INS]). Figure 1 shows the individual data of the volunteers Uric acid clearance (17.8 ± 2.9 mL/min) and frac- and of the patients with SJADH. The patient with tional uric acid excretion (19.6 ± 5.3%) increased central diabetes insipidus (0) is presented also in the largely during the hyponatremic state in the patients Figure. A few weeks after hypophysectomy for tumor- with SIADH (for both parameters P < 0.00 1). Both related Cushing’s disease, this patient developed cen- were also significantly higher than the value observed tral diabetes insipidus. He presented mild hyponatre- during dDAVP-induced hyponatremia (P < 0.01). mia (124 mmol/L) during dDAVP administration, There was also a mild increase in absolute 24-h uric which was associated with a slight decrease in serum acid excretion in the hyponatremic patients with SI- uric acid level from an initial level of 3.6 mg/dL to 3 ADH(from46l ± 154mg/24hto525 ± l5Omg/24h; mg/dL, but the fractional uric acid excretion was not P < 0.01). The mean body weight increase, protein modified (uric acid’ during normonatremia concentrations, fractional excretion ofifitered sodium, and hyponatremia). Similarly, in the volunteers with and the urine flow rate were similar in both hy- dDAVP-induced hyponatremla, we observed a de- ponatremic groups (Table 1). crease in serum uric acid concentrations from mean Our patient with CDI had no measurable endoge- value of 5.5 mg/dL to 3.9 mg/dL (-29%) whereas nous ADH secretion. When hyponatremia was in- serum sodium concentration decreased to a mean duced by water retention secondary to dDAVP admin- value of 126 mmol/L (-9%). Mean uric acid clearance istration, we observed a mild increase in uric acid tended to increase by 30% but this was not significant clearance (from 7.2 mL/min to 10.8 mL/min) and (6.4 ± 1.5 to 8.3± 3.3 mL/mln; P < 0.10) (Table 1), fractional excretion (from 6.5% to 8%) (Table 2). After and the fractional excretion of ifitered uric acid was TGLV administration, the urate clearance and frac- not modified (5.4 ± 0.9% before and 5.7 ± 2% during tional excretion of uric acid rates acutely increased hyponatremia). The creatinine clearance rate in- over at least 4 h (from 10.8 mL/min to 19.8 mL/min creased significantly during the hyponatremic state and from 8% to 13.6%, respectively) (Table 2). During

Journal of the American Society of Nephrology 807 Hyponatremia Related to SIADH

HYPONATREMIA INDUCED HYPONATREMIA RELATED with DDAVP to SIADH 30 0 P< 0.001 L.P< 0.001 0 25

0 0

0 20 0 0 0 #{149}0 00 I 115 =‘ p<0.01 p< o.ooi U 15 0 . 0 w 00 Li. 00 0

10 dDAVP r= 0.78 P99J P< 0.01

: 25 5. a 2O Q 15

10 #{176} #{176} i... I 0o::1:5 FE . Na ( %) Water Free water Water Free water Restriction intake Restriction intake Figure 2. Positive correlation between FE.Na and FE.uric acid in dDAVP-lnduced hyponatremia (#{149})(y = 2.75 + 5.2x; r = Figure 1 . Evolution of serum sodium, uric acid concentra- 0.78; P < 0.01) and lack of significant correlation between tions, and fractional excretion of uric acid (FE.uric acid) both parameters in the SIADH (0) (r = 0.33; NS). during water restriction and free water Intake in volunteers taking dDVAP (N = 7) or patients with SIADH (N = 6). The

patient with central diabetes insipidus who developed hy- DISCUSSION ponatremia after dDAVP Intake Is presented by an open circle (0). In SIADH patients, the values obtained after the Hyponatremia related to SIADH is typically associ- correction of hyponatremia are presented first. The doffed ated with hypouricemia, a high uric acid clearance line represents the 95% normal limits. To convert uric acid rate, and high fractional excretion of ifitered uric acid from mmol/Lto mg/di. we multiplied the number of mmol/L ( 1 ,2). It is generally accepted that these changes are by 0.059. the consequence of increased “effective vascular vol-

ume. “ In hyponatremia associated with a decreased “effective vascular volume,” serum uric acid concen- the 7.5 pg/kg TGLV test, the patient presented skin tration is normal or increased (2,6). In our study, pallor of the face and hands for about 90 min, with a volunteers with dDAVP-induced hyponatremia pre- concomitant significant increase in blood pressure sented similar levels of hypoproteinemia and salt ex- (120/80 mm Hg to a maximum of 160/ 100 mm Hg at cretion than did patients with SIADH, suggesting the end of the TGLV perfusion). No significant modifi- similar degrees of plasma volume expansion (7). Nev- cation of pulse rate was observed. With the lower dose ertheless, reduction in serum uric acid levels was of TGLV (2.5 pg/kg), no skin pallor or blood pressure clearly less important in the group with dDAVP-in- and pulse rate changes could be observed. With the duced hyponatremia than in patients with SIADH. The

lower dose ofTGLV, the urate clearance rate increased greater decrease in uric acid concentration ( - 29%) from 9.9 mL/min to 16.5 mL/min, and the fractional than was expected for the dilution (serum sodium, excretion rate from 8.4% to 1 1.2%. -9%) observed with dDAVP is probably the result of In our volunteers, we observed a positive correlation the mild (although not significant) increase in the uric between FENa and FEuric acid (r = 0.78, N = 14; P < acid clearance rate (6.4 ± 1 .5 mL/min to 8.3 ± 3.3 0.0 1 ) (Figure 2). These data were collected when our mL/min; P < 0. 10) recorded in this group with stable volunteers were hyponatremic (Na < 132 mEq/L) and urinary flow rate (8) and salt excretion (9). presented a body weight at least 2% higher than that Patients with SIADH served as control subjects seen during the normonatremic state. In our patients because long-acting AVP (Pitressin) is no longer avail- with SIADH, no significant correlations were observed able. However, our data can be compared with those between these two parameters (r = 0.33; N = 18; NS) published regarding five volunteers with Pitressin- when measured during conditions similar to those of induced hyponatremia of a similar level (Na, 128 ± 2 the volunteers. mEq/L) than that found in our study (Na, 126 ± 5

808 Volume 7 . Number 5 ‘ 1996 Decaux et al

mEq/L) ( 1 ). In that study, uric acid clearance was models are the results of discrepancies between AVP determined after 2 or 3 days of hyponatremia, and and dDAVP stimulation of V1 and V2 receptors. increased from 8.7 ± 2.4 mL/min to 19 ± 5.9 mL/min We know that dDAVP acts only on the V2-receptor (P < 0.0 1 ), a value similar to that observed in our sites (3), whereas AVP is effective on both V1 and V2 patients with SIADH (17.8 ± 2.9 mL/min). In the receptors. Although it was not measured in this study, patient with CDI and no residual AVP secretion, the endogenous AVP was likely suppressed by the hy- development of hyponatremia during dDAVP substi- ponatremic state induced by dDAVP, as observed in tution was associated with a mild increase in uric acid animals (7). clearance from 7.2 to 10.8 mL/min. TGLV infusion, The mechanisms underlying our observation re- which slowly releases lysine-vasopressin during at main to be determined. Some possibilities could be least 4 h (4,5), and thus also newly stimulates the V1 suggested. Uric acid reabsorption is situated primarily receptors, was followed by a striking additional in- in the proximal tubule and is indirectly coupled to crease in uric acid clearance ( 10.8 to 19.6 mL/min). sodium reabsorption ( 1 7, 1 8). In SIADH, hyponatre- This enhanced uric acid excretion rate is independant mia is associated with a decrease in proximal sodium of the blood pressure changes observed with higher reabsorption. It is possible that V1-receptor stimula- doses (7.5 pg/kg) ofTGLV because at a lower dose (2.5 tion affects systemic and/or intrarenal hemodynam- j.g/kg) and unchanged blood pressure, uric acid ics and thus indirectly influences proximal sodium clearance remained largely increased (9.9 to 16.5 and urate reabsorption. Another possibility is that mL/min). AVP induces natriuresis ( 19,20) by acting on a V1 A transient increase in salt excretion and urinary subtype or perhaps a novel V3 receptor (20,2 1 ). Some flow rates, presumably because of “pressure diuresis,” authors have suggested that this receptor could be usually follows vasopressin escape ( 10). Nevertheless, located in the S nephron segment (22), where uric with a low dose of TGLV, the uric acid clearance rate acid reabsorption is most important ( 1 1). It is possible increased despite normal blood pressure, although that the decrease in salt reabsorption is more specif- mild increases in GFR, urine flow rate, and fractional ically localized in the nephron segment in the AVP excretion of sodium was noticed. It is known that model, whereas in dDAVP-related hyponatremla, salt urate clearance in man results from ifitration, reab- reabsorption is decreased more distally, which ex- sorption, secretion, and postsecretory reabsorption plains why uric acid reabsorption is influenced less in ( 1 1 ). Glomerular filtration does not affect final urico- the second situation. However, it must be noted that suria, which is in fact primarily dependent on tubular the normal fractional uric acid excretion rate ob- urate secretion and pre- and postsecretory reabsorp- served, despite mild hypouricemia during dDAVP- tion ( 1 1 ). Urate clearance normally does not increase induced hyponatremia, is an unexpected observation. significantly during rapid isotonic saline infusion un- Indeed, induction of a low uric acid concentration is til very high excretion rates for sodium are reached normally associated with a decrease in the uric acid (9, 1 2, 1 3). For example, in one study performed in clearance rate and fractional excretion secondary to a man, FEuric acid’ after a stable degree of isotonic vol- fall in tubular uric acid secretion ( 1 1). This means that ume expansion, increased from a mean value of 8% to there was probably also some decrease in tubular uric 9.8% whereas FENa increased frankly from a mean of acid reabsorption in this model (23). 1% to 4.4% ( 12). It is known that the relationship between the fractional excretion of urate and frac- ACKNOWLEDGMENTS tional excretion of sodium is entirely attributed to This work was supported by a grant from the Fonds National de la their mutual correlation with volume expansion (13). Recherche Scientifique (FNRS) (1-5.175.94 F; 1.5.193.96 F). We noted a positive correlation between FENa and FEuric acid only in the dDAVP group. Most patients with REFERENCES SIADH have a FEuric acid higher than 12% (2) (14,15), 1 . Dorhout Mees EJ, Blom van AssendelfTP, Nieuwenhuis and their uric acid clearance is not correlated with salt MG: Elevation of uric acid clearance caused by Inappro- excretion (Figure 2) ( 15). The mechanisms for explain- priate antidiuretic hormone secretion. Acta Med Scand ing this difference remain to be determined. The van- 1971; 189:69-72. 2. Beck LH: Hypouricemia in the syndrome of inappropri- ation in urine flow rates in our study are also too small ate secretion of antidiuretic hormone. N Engl J Med to affect urate clearance ( 1 1). 1979;30l:528-530. Our observation suggests that, in SIADH, in addi- 3. Vavra J, Machova A: Effect of a synthetic analogue of vasopressin In animals and in patients with diabetes tion to the increase in “effective vascular volume,” insipidus. Lancet 1968; 1:948-952. stimulation of V1 receptors contributes to the devel- 4. Forsling ML, Aziz LA, Miller M, Davies R, Dovovan B: opment of high uric acid clearance. Conversion of trlglycyclvasopressin to lysine-vasopressin in man. J Endocrinol 1980;85:237-244. In rats, there is no difference in water retention 5. Nilsson 0, Lindblom P, Ohlin M, Berling R, Vernersson induced by either dDAVP or AVP (7), although some E: Pharmacokinetics of terlipressin after single IV. doses investigators have reported a more negative sodium to healthy volunteers. Drugs Exp Clin Res 1 990;XVI: balance with AVP when fluid intake is forced ( 16). One 307-314. 6. Decaux G, Schiesser M, Coffernils M, et at.: Uric acid, could hypothesize that the difference in uric acid anion gap and urea concentration In the diagnostic clearance rates observed between both hyponatremic approach to hyponatremla. Chin Nephrol 1994;42: 102-

Journal of the American Society of Nephrology 809 Hyponatremia Related to SIADH

108. drome of inappropriate secretion of antidiuretic hor- 7. Verbalis JG, Drutarosky MD, Ertel RJ, Voilmer RR: mone related to salt excretion. Clin Sci (Lond) 1990;78: Adaptative responses to sustained volume expansion in 451-455. hyponatremic rats. J Endocrinol 1989; 122:421-431. 16. Gross PA, Anderson RJ: Effects of DDAVP and AVP on 8. Diamond HS, Lazarus R, Kaplan D, Halberstra D: Effect sodium and water balance in conscious rat. Am J Physiol of urine flow rate on uric acid excretion in man. Arthritis 1982;243:R512-R519. Rheum l972;l5:338-342. 17. Pritchard JB, Miller DS: Mechanisms mediating renal 9. Cannon PJ, Svahn DS, Demartini FE: The influence of secretion of organic anions and cations. Physiol Rev hypertonic saline infusions upon the fractional reab- 1993;4:765-796. sorption of urate and other Ions in normal and hyperten- 18. Kahn AM: Indirect coupling between sodium and urate sive man. Circulation 1970;XLI:97-108. transport in the proximal tubule. Kidney mt 1989;36: 10. Hall JE, Montani JP, Woods LL, Mizelle HL: Renal 378-384. escape from vasopressin: Role of pressure diuresis. Am J 19. Dixey JJ, Williams TDM, Lightman SL, Lant AF, Brew- Physiol l986;250:F907-F9 16. elton DA: The effect of indomethacin on the renal re- 1 1 . Grantham JJ, Chonko AM. Renal handling of organic sponse to arginine vasopressin in man. Clin Sci (Lond) anions and cations: excretion of uric acid. In Brenner 1986;64:407-423. BM, Rector FC. Eds. The Kidney. 4th ed. Philadelphia: 20. Chan WY, Hruby VJ: Natriuretic action of neurohypoph- W.B. Saunders; 1991:483-509. ysial peptides: Effects of agonists and antagonists and 12. Steele TH: Evidence for altered renal urate reabsorption implication of natriuretic receptor. J Pharmacol Exp during changes in volume ofthe extracellular fluid. J Lab Ther 1988;246:597-602. Clin Med 199;74:288-299. 2 1 . Smith CP, Balment RJ: Arginine vasopressin-induced 13. Diamond H, Melsel A Influence of volume expansion, natriuresis in the anaesthetized rat: Involvement of V1 serum sodium and fractional excretion of sodium on and V2 receptors. J Endocrinol 1993; 136:283-288. urate excretion. Pfluegers Arch Eur J Physiol 1975;356: 22. Jung KY, Endou H: A novel vasopressin receptor in rat 47-57. early proximal tubule. Biochem Biophys Res Commun 1 4. Decaux 0, Dumont I, Waterlot Y, Hanson B: Mecha- 1991; 180: 13 1-137. nisms of hypouricemia In the syndrome of inappropriate 23. Prospert F, Soupart A, Brimiouffle S, Decaux G: Evi- secretion of antidiuretic hormone. Nephron 1985;39: dence of defective tubular reabsorption and normal se- 164-168. cretion of uric acid in the syndrome of inappropriate 15. Decaux G, Prospert F, Cauchie P. Soupart A: Dissocia- secretion of antidiuretic hormone. Nephron 1993;64: tion between uric acid and urea clearances in the syn- 189-192.

810 Volume 7 ‘ Number 5 ‘ 1996