Role of vasopressin in regulation of renal kinin excretion in Long-Evans and diabetes insipidus rats.

To study the relationship between vasopressin and the renal kallikrein-kinin system we measured the rate of excretion of kinins into the urine of anesthetized rats during conditions of increased and decreased vasopressin level. The excretion of immunoreactive kinins in Brattleboro rats with hereditary diabetes insipidus (DI) (24 +/- 3 pg min-1 kg-1) was lower than in the control Long Evans (LE) rats (182 +/- 22 pg min-1 kg-1; P less than 0.05). The DI rats also exhibited negligible urinary excretion of immunoreactive vasopressin, reduced urine osmolality, and increased urine flow and kininogenase excretion. In LE rats, volume expansion by infusion of 0.45% NaCl-2.5% dextrose to lower vasopressin secretion reduced (P less than 0.05) kinin excretion, vasopressin excretion, and urine osmolality to 41, 26, and 15% of their respective control values, while increasing (P less than 0.05) urine flow and kininogenase excretion. On the other hand, the infusion of 5% NaCl, which promotes vasopressin secretion, increased (P less than 0.05) the urinary excretion of kinins and vasopressin to 165 and 396% of control, while increasing (P less than 0.05) urine flow and kininogenase excretion. Infusion of vasopressin (1.2 mU/h, intravenous) enhanced (P less than 0.05) kinin excretion by two to threefold in DI rats and in LE rats during volume expansion with 0.45% NaCl-2.5% dextrose, while decreasing urine flow and increasing urine osmolality. This study demonstrates that the urinary excretion of immunoreactive kinins varies in relation to the urinary level of vasopressin, irrespective of urine volume and osmolality and of the urinary excretions of sodium and kininogenase. The study suggests a role for vasopressin in promoting the activity of the renal kallikrein-kinin system in the rat.

The handling of immunoreactive vasopressin by the isolated perfused rat kidney.

Using the isolated rat kidney perfused with an artificial medium containing glucose as the sole fuel, we studied the renal handling of immunoreactive arginine vasopressin (AVP) and determined the effect of various factors on the ability of the kidney to remove AVP. In control kidneys perfused with AVP at concentrations below 116 muU/ml, the organ clearance of AVP (OC(AVP)) was 1,145+/-47 (SE) mul/min, whereas glomerular filtration rate (GFR) averaged 515+/-37 mul/min. Filtration could thus account for up to 45% of the OC(AVP), the balance presumably being cleared from the peritubular circulation. Of the AVP filtered, only 38% could be recovered in the urine (urinary clearance AVP averaged 205+/-12 mul/min) suggesting that the balance was taken up by the tubular epithelium and degraded. Fractional excretion of filtered AVP rose significantly in the presence of anoxia and cold (10 degrees C) to 49 and 59%, respectively, but was not affected by ouabain or high levels of AVP (458+/-58 muU/ml). The OC(AVP) was not significantly altered by the absence of glucose in the perfusate, anoxia, or ureteral ligation, maneuvers that were associated with significant reductions in GFR. In these and the control experiments, there was a significant inverse correlation between GFR and peritubular clearance emphasizing the importance of the latter (r = -0.749; P < 0.001). Cold, ouabain, and high concentrations of AVP reduced the clearance of AVP by the kidneys. On the basis of these studies we conclude that the kidney clears AVP from the circulation via two pathways, glomerular clearance and peritubular clearance. This exposes both the luminal and contraluminal surfaces of the tubular cells to the hormone, allowing these cells to remove AVP from the filtrate and the peritubular compartment. Noteworthy is the observation that under several conditions when GFR falls reducing the glomerular clearance of AVP, peritubular clearance increases and the total clearance of AVP by the kidney remains constant.

Vasopressin in rats with genetic and streptozocin-induced diabetes.

Rats were administered streptozocin (STZ; 50 or 75 mg/kg i.v., tail vein) or vehicle. Approximately 2 wk later, venous and arterial catheters was implanted for subsequent (24 h later) vasopressin, electrolyte, and hemodynamic measurements. STZ-induced diabetic (STZ-D) rats demonstrated a dose-dependent increase in the plasma glucose concentration, plasma osmolality, and plasma vasopressin concentration. Mean arterial blood pressure (MABP) was unchanged, but heart rate was reduced. Diabetes-prone BB rats, maintained on or withdrawn from insulin treatment for 24-48 h, and diabetes-resistant rats were instrumented and studied as above. Spontaneous-diabetes-prone rats demonstrated increase in plasma glucose concentration and plasma osmolality similar to STZ-D rats but had significantly greater plasma vasopressin concentrations. The significant decrease in MABP observed in these animals probably contributed to the enhanced vasopressin response. We conclude that both osmotic and cardiovascular parameters play important roles in vasopressin secretion in diabetic rats.

Role of brain prostaglandins in the control of vasopressin secretion in the conscious rat.

Administration of 10 micrograms prostaglandin D2 (PGD2), the primary PG identified in the rat brain, into the lateral cerebral ventricle of conscious rats resulted in a significant elevation in the plasma vasopressin (AVP) concentration, without a change in mean arterial blood pressure or heart rate. The central administration of indomethacin (100 micrograms) resulted in a significant attenuation of the AVP response to a peripheral osmotic stimulus (iv 2.5 M NaCl; 100 microliters/kg X min for 30 min), but had little effect on the AVP response to hemorrhage (two successive 10% reductions in the estimated blood volume). Administration of another PG synthetase inhibitor, meclofenamate (100 micrograms, into the lateral cerebral ventricle), resulted in a significant attenuation of the AVP response to both the osmotic stimulus and hemorrhage. It is concluded that brain PGs play a central role in the control of AVP secretion.

Effects of nonhypotensive hemorrhage on renal organ and urinary clearances of vasopressin in the dog.

A study was undertaken to investigate the effects of moderate nonhypotensive hemorrhage on the renal organ and urinary clearances of vasopressin in anesthetized dogs. A nonhypotensive hemorrhage was conducted in nine dogs by withdrawal of 12 ml/kg arterial blood over 10 min. This reduction in blood volume increased the plasma vasopressin concentration from a prehemorrhage value of 4.3 +/- 0.5 to 12.5 +/- 3.4 microU/ml (P less than 0.01) in the 15-min period immediately after hemorrhage and to 8.1 +/- 1.4 microU/ml (P less than 0.01) in the 45- to 60-min period after hemorrhage. The increased plasma vasopressin concentration was not associated with changes in either plasma osmolality or mean arterial blood pressure. The urinary excretion of vasopressin increased significantly after hemorrhage (P less than 0.01, 0-15 min after hemorrhage; P less than 0.05, 45-60 min after hemorrhage) and correlated significantly with the plasma vasopressin concentration (r = 0.92; P less than 0.001). However, this moderate nonhypotensive hemorrhage did not change the renal vasopressin extraction ratio or the renal organ and urinary clearances of vasopressin from their prehemorrhage values of 0.27 +/- 0.02, 2.00 +/- 0.20 ml/min X kg, and 1.43 +/- 0.13 ml/min X kg, respectively. At no time were these values different from those in nine time control dogs. Thus, changes in the renal handling of vasopressin do not contribute to the increase in the plasma vasopressin concentration after moderate nonhypotensive hemorrhage.

Vasopressin release in male and female rats: effects of gonadectomy and treatment with gonadal steroid hormones.

We have found, in normal Wistar rats 10-11 weeks old, that the plasma vasopressin concentration (PADH) and the 24-h urinary excretion of vasopressin (UADHV) were higher in males than in females (P less than 0.01). In rats that were gonadectomized when they were 3 weeks old and studied when they were 10-11 weeks old, PADH and UADHV were reduced in males (P less than 0.01) and increased in females (P less than 0.01 for UADHV; PADH not significant) compared to those in intact males and females, respectively. Treatment of castrated male rats with testosterone tended to increase PADH, but estradiol, progesterone, or a combination of estradiol and progesterone were without effect; UADHV was increased by testosterone (P less than 0.01) and lowered by estradiol plus progesterone (P less than 0.01). In ovariectomized rats, PADH was unaffected by either testosterone or estradiol, but was decreased by progesterone alone (P less than 0.05) or in combination with estradiol (P less than 0.05). In these ovariectomized rats, UADHV was unaffected by testosterone and was decreased by estradiol and progesterone individually or in combination (P less than 0.01). These findings suggest that the gonadal steroid hormones can act either centrally to affect ADH release or peripherally to affect ADH metabolism. Compared to intact male rats, the lower PADH in intact female rats was accompanied by lower urine osmolality and greater urine volume, but further study will be required to appreciate fully the physiological significance of the differing PADH in males and females.

The metabolic clearance rate of and pressor responses to vasopressin in male and female rats.

Recent evidence indicates that the plasma vasopressin concentration is higher in males than in females and that this may be due to sexually dimorphic effects of the gonadal steroids. However, whether this difference in plasma vasopressin levels reflects differences in secretion or metabolism of the hormone could not be determined from the available data. Therefore, we measured the MCR of vasopressin in conscious male and female rats over a broad range of plasma concentrations of the hormone. No differences were observed in MCR either within a sex or between the sexes over the ranges of plasma concentrations of vasopressin tested. This indicates that the differences in basal plasma vasopressin concentration that were previously reported between male and female rats reflect differences in secretion. In addition, the pressor responses to infused vasopressin were 2 to 3 times greater (P less than 0.01) in male than in female rats, even though the plasma vasopressin concentrations achieved in the two groups were identical. Although the basal heart rate was higher (P less than 0.01) in female than in male rats, the decreases in heart rate observed in response to the vasopressin infusions were similar between the sexes. The mechanisms responsible for the differences in basal vasopressin secretion and pressor responsiveness between males and females are uncertain, but could involve actions of the gonadal steroids on the central nervous system and the peripheral vasculature.

The role of central adrenoreceptors in the control of vasopressin release and blood pressure.

In order to investigate the role of central noradrenergic neurons in the control of vasopressin (ADH) release and cardiovascular regulation, norepinephrine (1.4 microgram/kg), clonidine (0.1 microgram/kg), and isoproterenol (1.4 microgram/kg were infused into the lateral cerebral ventricle of the anesthetized dog. The drugs were given over a 20-min period, dissolved in 0.9% saline at a volume rate of 10 microliter/min. Both norepinephrine and clonidine markedly reduced ADH release and lowered arterial blood pressure and heart rate. Isoproterenol had no effect on ADH release and produced a slight reduction in arterial pressure and a large increase in heart rate. Pretreatment with phenoxybenzamine (100 microgram/kg, iv) completely blocked the effects of norepinephrine on blood pressure and heart rate but only partially (about 50%) inhibited the norepinephrine effect on ADH release. Intravenous isoproterenol lowered blood pressure and increased ADH release and heart rate. In none of the experiments could changes in ADH release be attributed to changes in plasma osmolality or plasma sodium and potassium concentrations. It is concluded that, in the anesthetized dog, intraventricular norepinephrine and clonidine decreased ADH release, blood pressure, and heart rate by stimulating alpha-adrenoreceptors. The increased release of ADH after peripheral administration of isoproterenol was presumably due to the reduction in blood pressure and decreased baroreceptor inhibition of ADH release.

Removal of immunoreactive arginine vasopressin by the perfused rat liver.

To assess the ability of the liver to remove immunoreactive arginine vasopressin (AVP) from the circulation and to determine the effect of certain metabolic factors on the process, a study was carried out with rat livers perfused at 37 C with an oxygenated albumin--electrolyte solution containing AVP (117 +/- 4.5 muU/ml). In controls, the hepatic clearance of AVP was 795 +/- 120 microliter/min (SEM). The addition of AVP in concentrations up to 9029 microU/ml, perfusion with a glucose-free medium, or perfusion without oxygen did not significantly alter the hepatic clearance of AVP. However, perfusion with cold medium (11 C) significantly altered AVP removal in that initially AVP removal increased, while later on AVP removal became completely inhibited. This phenomenon may possibly be a consequence of a cold-induced increase in hepatic AVP trapping which is rapidly saturated due to a cold-induced depression of AVP transport and degradation. Support for this thesis was provided by finding that high AVP concentrations depressed the cold-endhancing removal phase.

Central atrial natriuretic factor reduces vasopressin secretion in the rat.

Atrial natriuretic factor (ANF, Arg 101-Tyr 126; 0.5 and 2.5 micrograms) administered into the lateral cerebral ventricle of conscious euhydrated and dehydrated rats resulted in a significant reduction in the plasma vasopressin concentration. The effect of ANF on vasopressin secretion was greater in the water-deprived animal. Central ANF was without effect on mean arterial blood pressure in both euhydrated and dehydrated rats. The data suggest that ANF occurring in the central nervous system may be important in the control of vasopressin secretion.

Effects of changes in steady state plasma vasopressin levels on renal and urinary vasopressin clearances in the dog.

A study was made of the effects of changes in the plasma vasopressin concentration on the extraction ratio and the renal organ and urinary clearances of vasopressin. Plasma vasopressin levels were increased in a stepwise fashion in anesthetized dogs by the iv infusion of vasopressin at rates of 100, 400, and 800 microU/min . kg. A steady state was achieved by infusing vasopressin for 60 min at each dose. Before the infusion of vasopressin, the extraction ratio and the renal and urinary clearances of vasopressin (one kidney) were 0.30 +/- 0.04, 1.8 +/- 0.2, and 1.4 +/- 0.1 ml/min . kg, respectively. The urinary clearance of vasopressin did not differ significantly from the inulin clearance (1.5 +/- 0.1 ml/min . kg). The infusion of vasopressin, which increased the plasma vasopressin concentration from an initial value of 4.3 +/- 1.3 to 54.6 +/- 2.4 microU/ml at the highest rate of infusion, was without effect on the vasopressin extraction ratio and the renal and urinary clearances of vasopressin. The MCR of vasopressin was estimated to be approximately 16 ml/min . kg. The renal clearance of vasopressin, calculated for both kidneys in all periods of all experiments, accounted for approximately 27% of the total clearance of vasopressin from the plasma. Thus, over a broad range of plasma vasopressin concentrations, a constant fraction of the vasopressin delivered to the kidney was removed from the blood perfusing the kidney, and the mechanisms for the renal extraction of vasopressin were not saturated.

Gonadal hormones modulate deoxycorticosterone-salt hypertension in male and female rats.

We have shown previously that, in rats with deoxycorticosterone (DOC)-salt hypertension, arterial blood pressure rises more rapidly and reaches a higher level in male than in female rats and that the course of the hypertension was ameliorated by gonadectomy in male rats and exacerbated by gonadectomy in female rats. The present investigation was undertaken to examine the role of the gonadal steroid hormones in modulating the course of DOC-salt hypertension in the rat. Our previous findings with respect to the effects of gender and gonadectomy on DOC-salt hypertension were confirmed in this study. Chronic treatment with gonadal steroids was begun 1 week before the start of the DOC-salt protocol. 17 beta-Estradiol attenuated the course of the hypertension in intact male rats and in gonadectomized females. Testosterone exacerbated the development of the hypertension in gonadectomized male rats but was without effect in intact females. Progesterone alone had no effect on the hypertension in ovariectomized rats but when given to ovariectomized rats in combination with estradiol transiently prevented the ameliorating effect of the estradiol. These effects of the gonadal steroid hormones could not be attributed to effects of saline intake. Thus, these findings demonstrate that the gonadal steroid hormones play an important role in modulating the pathogenesis of DOC-salt hypertension in the rat. It is suggested that the effects of the gonadal hormones on the course of the hypertension may be due to modulation of the cardiovascular and renal actions of vasopressin, since vasopressin is required for this model of hypertension.

Contribution of vasopressin to hypertension.

The contribution of vasopressin to the hypertensive process has been examined in a number of models of hypertension. Vasopressin is essential for the production of DOC-salt hypertension in the rat, It is likely that vasopressin is required in the early stages of this model of hypertension for its antidiuretic activity and contributes to the later stages of the hypertension as a pressor agent. Vasopressin secretion is increased in SHR, but there may be some differences between the SHR and stroke-prone SHR strains. The pressor action of vasopressin appears to be important in the stroke-prone SHR with well-established hypertension, but not in the young SHR. Vasopressin secretion is greater in Dahl S rats on a high salt diet than in similarly treated R rats. Blockade of vasopressin's pressor activity failed to lower blood pressure in these S rats, unless they were pretreated with captopril. There is insufficient information to determine whether vasopressin has a role in the hypertension in NZGH rats. Vasopressin appears to function as a pressor agent in some, but not all, rats with two-kidney, one clip hypertension. Although vasopressin is not essential for the production of one-kidney, one clip hypertension, it apparently contributes to the hypertension by virtue of its antidiuretic activity. Vasopressin secretion is elevated in partial nephrectomy-salt hypertension, and here, too, it is needed for its antidiuretic action. The question of whether vasopressin secretion is elevated in human essential hypertension is controversial, and its role remains to be determined.

Vasopressin release does not contribute to pressor action of enkephalin in SHR.

The effects of injection of a peptidase-resistant analog of methionine-enkephalin, [D-ala2]-methionine-enkephalin, on blood pressure (BP), heart rate, and vasopressin release were studied in spontaneously hypertensive rats (SHR). Intravenous injection of [D-Ala2]-methionine-enkephalin (DAME) increased BP in both SHR and normotensive Wistar-Kyoto (WKY) controls, with a significantly greater increase in hypertensive rats. Intracerebroventricular injection of DAME produced a biphasic increase in BP and an increase in heart rate in both groups. The initial pressor effect was significantly greater in the SHR, Plasma vasopressin levels in SHR were depressed relative to both untreated hypertensive rats and animals given vehicle control injections. Intravenous pretreatment with a vasopressin vasopressor antagonist, [l-(beta-mercapto-beta-beta-cyclopentamethylenepropionic acid),2-(O-methyl)tyrosine] arginine-vasopressin, did not block either component of the central enkephalin response in hypertensive rats. These date indicate that central enkephalin injection does not release vasopressin and that SHR are hyperresponsive to enkephalin. It is concluded that pressor systems other than that of vasopressin mediate the enkephalin-induced cardiovascular effects.

Pressor responsiveness to vasopressin in the rat with DOC-salt hypertension.

To further characterize the role of vasopressin in DOC-salt hypertension, four groups of unilaterally nephrectomized rats were studied: control rats given no further treatment, rats treated with DOC and given 1% saline to drink, or rats treated with only DIC or 1% saline had similar pressor responses to exogenous vasopressin and angiotensin II. Within the DOC-salt group, two populations of rats were identified: one with normal pressor responsiveness to vasopressin, and one with markedly enhanced pressor responsiveness to vasopressin. Incidence of enhanced responsiveness increased with duration of treatment. Urinary excretion of vasopressin was elevated in the 1% saline and DOC-salt groups after 1 week of treatment, and in the DOC group after 4 weeks. However, the plasma vasopressin concentration was elevated only in the rats treated with both DOC and saline. It is suggested that vasopressin is essential for the expansion of blood volume in the early stages of DOC-salt hypertension, and functions as a direct pressor agent only in the later stages.

Sex difference in the development of deoxycorticosterone-salt hypertension in the rat.

To investigate a possible sex difference in the development of deoxycorticosterone (DOC)-salt hypertension in rats, systolic blood pressure was measured over 6 weeks in unilaterally nephrectomized male and female rats with or without DOC-salt treatment. Throughout the treatment, systolic blood pressure was significantly lower in female than in male DOC-salt rats (at the end of the sixth week: 190 +/- 8 vs 163 +/- 7 mm Hg, p less than 0.05). The difference in blood pressure was also confirmed by the direct measurement of mean arterial pressure at the end of the experiment. The 24-hour urinary excretion of vasopressin was significantly higher in male control rats than in female control rats; however, no difference was observed between male and female DOC-salt rats, in which the urinary excretion of vasopressin was four to five times higher than in control rats. The plasma vasopressin concentration was higher in DOC-salt rats, but there were no differences between sexes. There were no differences in the metabolic clearance rate of vasopressin among the four groups of rats. This indicates that the elevated plasma vasopressin concentration in DOC-salt hypertensive rats is due to increased release of the hormone, rather than to impaired metabolism. Thus, although vasopressin plays a pivotal role in the pathogenesis of DOC-salt hypertension, the sexual dimorphism in this form of hypertension cannot be attributed to differences in the secretion, metabolism, or plasma concentration of vasopressin.

Nonosmotic stimuli alter osmoregulation in patients with spinal cord injury.

Studies on two quadriplegic patients who developed severe hyponatremia during episodes of acute respiratory distress were performed to determine whether differences in osmoregulation of vasopressin release could be identified in these patients compared to other quadriplegic subjects previously studied in a similar manner. Both patients were clinically stable and normonatremic, with no signs or symptoms of respiratory distress, when the studies were performed. However, both exhibited evidence of hemodynamic instability in the sitting posture. Linear regression analysis of the plasma vasopressin/plasma osmolality (Pavp:Posm) relationship during infusions of 0.85 M sodium chloride showed no significant differences in either the slope (sensitivity) or abscissal intercept (osmotic threshold) of this relationship compared to that of other quadriplegic subjects when the patients were supine. In contrast, when the patients were studied in the sitting posture there was a marked shift in the relationship of Pavp:Posm indicative of increased sensitivity and reduced osmotic threshold for vasopressin release. The slopes of the Pavp:Posm relationships were 0.249 and 0.178 for the two patients, respectively, compared to 0.092 +/- 0.03 ( +/- SD) for previously studied quadriplegic subjects. Oral water-loading studies performed on one patient revealed marked impairment of urine-diluting ability and free water clearance in the sitting posture compared with observations in similar studies performed when the patient was supine. Impairment of renal water excretion could not be attributed to an effect of vasopressin, which was reduced to unquantifiable levels by water loading. These studies have shown that hemodynamic stress related to autonomic dysfunction in quadriplegic patients may result in marked alteration of osmoregulation of vasopressin release in more severely affected individuals. Such altered osmoregulation, which may also be associated with vasopressin-independent impairment of renal water excretion in the sitting posture, may be a predisposing factor in the development of hyponatremia, especially in the presence of other potent nonosmotic stimuli.

The importance of vasopressin in the development and maintenance of DOC-salt hypertension in the rat.

Experiments were performed to determine the role of vasopressin in deoxycorticosterone (DOC)-salt hypertension. In order to determine if vasopressin is necessary for the development of DOC-salt hypertension, rats with hereditary diabetes insipidus (DI) and normal Long-Evans rats (LE) were unilaterally nephrectomized, treated with DOC Pivalate (30 mg/kg . week) and given saline to drink for 8 weeks. A second group of DI rats were unilaterally nephrectomized, but received no treatment. Systolic blood pressure (SBP) increased 40 mm Hg in the LE group (p less than 0.01) but failed to increase significantly in either DI group. Urinary excretion of vasopressin (UADHV) and SBP were measured in unilaterally nephrectomized LE rats treated with DOC and salt (DOC-LE), salt alone (NaCl-LE) and untreated rats (H2O-LE). The UADHV was elevated in DOC-LE (p less than 0.01) and NaCl-LE (p less than 0.05), but only the DOC-LE rats became hypertensive. Finally, the I.V. injection of analogs of vasopressin, which block its pressor but not antidiuretic activity, lowered mean arterial blood pressure 27 +/- 5 mm Hg in 11 conscious DOC-salt hypertensive rats. It is concluded that vasopressin plays a major role as a pressor agent in both the onset and maintenance of DOC-salt hypertension.

Effect of intracerebroventricular captopril on vasopressin and blood pressure in spontaneously hypertensive rats.

In conscious, unrestrained spontaneously hypertensive rats (SHR), mean arterial blood pressure (MAP) increased from a pretreatment value of 150 +/- 4 to 179 +/- 7mm Hg within 10 min (p less than 0.01) following an intracerebroventricular (i.c.v.) injection of captopril (2 mg/kg body weight), and the plasma vasopressin concentration was increased eightfold (p less than 0.01). MAP than fell to 131 +/- 5 mm Hg at 120 minutes (p less than 0.01), and plasma vasopressin concentration returned to pretreatment levels. The initial increase in MAP was due in large part to increased plasma vasopressin levels since this increase was reduced 50% by pre-treatment with a specific antagonist of the pressor action of vasopressin. The reduction in MAP at 120 minutes in captopril-treated rats may been nonspecific, since a similar effect was observed in SHR given an i.c.v. injection of a control solution. In (Wistar-Kyoto) WKY rats, i.c.v. captopril was without a statistically significant effect on MAP, but the plasma vasopressin concentration increased three-fold (p less than 0.01). These findings may reflect an increased sensitivity of the control system for vasopressin release in the SHR.

Chronic hyponatremia due to resetting of the osmostat in a patient with gastric carcinoma.

A 54-year-old schizophrenic patient who presented with hyponatremia and nephrotic-range proteinuria was subsequently discovered to have a gastric adenocarcinoma. Psychogenic water drinking, sodium depletion, and cardiac, adrenal, hepatic, and thyroid disease were excluded as causes of hyponatremia. The serum creatinine concentration was normal, and, although renal biopsy showed changes consistent with immune complex glomerulopathy, proteinuria remitted without treatment. Moderately severe hyponatremia persisted, and the diagnosis of gastric adenocarcinoma was made after the onset of early satiety 1 year later. Surgical exploration at the time of partial gastric resection revealed local metastatic lymph node involvement. Following the patient's uneventful recovery from surgery, studies of osmoregulation of vasopressin release and renal water handling were performed to determine the cause of chronic hyponatremia refractory to sodium chloride administration. Oral water loading studies revealed normal urinary diluting ability and appropriate suppression of plasma vasopressin concentrations. However, hypertonic sodium chloride infusion studies revealed a highly significant correlation between plasma osmolality and plasma vasopressin concentration, and a low osmotic threshold for vasopressin release based on linear regression analysis of the plasma vasopressin response to increasing plasma osmolality. Low osmotic threshold for vasopressin release was confirmed by exponential (log linear) and parabolic methods of data analysis. The findings in these studies are consistent with the typical features of the reset osmostat variant of the syndrome of inappropriate antidiuresis. To our knowledge, this is the first report of the occurrence of this syndrome in association with gastric adenocarcinoma.