Phosphorylation profile of human AQP2 in urinary exosomes by LC-MS/MS phosphoproteomic analysis.

BACKGROUND: Aquaporin-2 (AQP2) is a key water channel protein which determines the water permeability of the collecting duct. Multiple phosphorylation sites are present at the C-terminal of AQP2 including S256 (serine at 256 residue), S261, S264 and S/T269, which are regulated by vasopressin (VP) to modulate AQP2 trafficking. As the dynamics of these phosphorylations have been studied mostly in rodents, little is known about the phosphorylation of human AQP2 which has unique T269 in the place of S269 of rodent AQP2. Because AQP2 is excreted in urinary exosomes, the phosphoprotein profile of human AQP2 can be easily examined through urinary exosomes without any intervention. METHODS: Human urinary exosomes digested with trypsin or glutamyl endopeptidase (Glu-C) were examined by the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) phosphoproteomic analysis. RESULTS: The most dominant phosphorylated AQP2 peptide identified was S256 phosphorylated form (pS256), followed by pS261 with less pS264 and far less pT269, which was confirmed by the western blot analyses using phosphorylated AQP2-specific antibodies. In a patient lacking circulating VP, administration of a VP analogue showed a transient increase (peak at 30-60 min) in excretion of exosomes with pS261 AQP2. CONCLUSION: These data suggest that all phosphorylation sites of human AQP2 including T269 are phosphorylated and phosphorylations at S256 and S261 may play a dominant role in the urinary exosomal excretion of AQP2.

Soluble (pro)renin receptor via ß-catenin enhances urine concentration capability as a target of liver X receptor.

The extracellular domain of the (pro)renin receptor (PRR) is cleaved to produce a soluble (pro)renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR-His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent ß-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR-His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism.

Is environmental temperature related to renal symptoms, serum lithium levels, and other laboratory test results in current lithium users?

OBJECTIVE: Lithium continues to be an important mood disorder treatment. Although patients exposed to higher environmental temperatures may have serum lithium level elevations due to dehydration, there is conflicting data in the literature. In addition, no study has assessed the association between temperature and other renal laboratory tests and symptoms in lithium users. METHODS: This is a cross-sectional analysis of 63 current lithium users who participated in the McGill Geriatric Lithium-induced Diabetes Insipidus Clinical Study. The relationship between mean daily temperature with diabetes insipidus symptoms, glomerular filtration rate, urine osmolality, serum sodium, lithium level, and lithium dose-level ratio was assessed. RESULTS: Although a higher temperature on the day of laboratory testing trended toward being independently associated with a lower lithium dose-level ratio (Beta = -0.17, p = 0.08), this was not found when using a dichotomous measure of temperature (T > 20°C). No association was observed between temperature and other renal parameters. CONCLUSIONS: The association of temperature with lithium levels, renal symptoms, and laboratory tests appears to be of relatively little clinical importance in lithium users in temperate climates. However, future research should re-examine patients living in climates with extreme temperatures (e.g., >40°C), who may theoretically be at higher risk.

Cerebral salt wasting in a postoperative period.

Cerebral salt wasting syndrome (CSW-cerebral salt wasting) was first described in 1950 by Peters. This syndrome can occur in patients who have sustained damage to the central nervous system (e.g. patients with subarachnoid bleeding, bacterial meningitis or after neurosurgery). Patients present with excessive natriuresis and hyponatremic dehydration. Differentiating this syndrome with the syndrome of inappropriate antidiuretic hormone secretion (SIADH-syndrome of inappropriate antidiuretic hormone secretion), which may occur in the same group of patients, is necessary in order to administer the correct treatment which consists of fluid restriction and sodium replacement in SIADH and fluid and sodium replacement as well as occasional mineralocorticoid therapy in CSW.

Quantification of human urinary exosomes by nanoparticle tracking analysis.

Exosomes are vesicles that are released from the kidney into urine. They contain protein and RNA from the glomerulus and all sections of the nephron and represent a reservoir for biomarker discovery. Current methods for the identification and quantification of urinary exosomes are time consuming and only semi-quantitative. Nanoparticle tracking analysis (NTA) counts and sizes particles by measuring their Brownian motion in solution. In this study, we applied NTA to human urine and identified particles with a range of sizes. Using antibodies against the exosomal proteins CD24 and aquaporin 2 (AQP2), conjugated to a fluorophore, we could identify a subpopulation of CD24- and AQP2-positive particles of characteristic exosomal size. Extensive pre-NTA processing of urine was not necessary. However, the intra-assay variability in the measurement of exosome concentration was significantly reduced when an ultracentrifugation step preceded NTA. Without any sample processing, NTA tracked exosomal AQP2 upregulation induced by desmopressin stimulation of kidney collecting duct cells. Nanoparticle tracking analysis was also able to track changes in exosomal AQP2 concentration that followed desmopressin treatment of mice and a patient with central diabetes insipidus. When urine was stored at room temperature, 4°C or frozen, nanoparticle concentration was reduced; freezing at -80°C with the addition of protease inhibitors produced the least reduction. In conclusion, with appropriate sample storage, NTA has potential as a tool for the characterization and quantification of extracellular vesicles in human urine.

Diabetes insipidus associated with propofol anesthesia.

Diabetes insipidus is a clinical entity that is often seen in neurosurgical patients either during or immediately after transsphenoidal hypophysectomy. Rarely, diabetes insipidus can manifest as a new entity months later in patients who have previously had an intracranial injury or operation.

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.

Clofibrate-induced antidiuresis.

Normal subjects and patients with antidiuretic hormone (ADH) deficiency were studied to determine the mechanism of the antidiuretic action of clofibrate. Before clofibrate treatment, the patients' ability to concentrate urine with a standardized dehydration procedure correlated with the amount of ADH which was excreted. During clofibrate administration all six patients with ADH deficiency developed an antidiuresis which was like that of ADH, since there was no change in sodium, potassium, total solute, or creatinine excretion. There was a correlation between the patients' ability to concentrate urine during dehydration and the subsequent response to clofibrate, and the excretion of ADH during dehydration correlated with the excretion of ADH on clofibrate therapy. Clofibrate-induced antidiuresis in these patients was partially overcome by ethanol and by water loading. Clofibrate interfered with the ability of patients and subjects to excrete a water load and prevented the water load from inhibiting ADH excretion in the normal subjects. These studies suggested that clofibrate was acting through endogenous ADH and this thesis was supported by the failure of clofibrate to produce an antidiuresis when injected into rats with total ADH deficiency (Brattleboro strain) although an antidiuresis was produced in water-loaded normal rats. When the drug was injected into Brattleboro rats with exogenous ADH, clofibrate either did not alter or it inhibited the action of the ADH. The data demonstrate that clofibrate has a significant ADH-like action. This action appears to be mediated through the release of endogenous ADH.

On the role of antidiuretic hormone in the inhibition of acute water diuresis in adrenal insufficiency and the effects of gluco- and mineralocorticoids in reversing the inhibition.

In order to determine whether or not antidiuretic hormone (ADH) is essential to the inhibition of an acute water diuresis in adrenal insufficiency, the response to oral water loads was tested in rats with hereditary hypothalamic diabetes insipidus (DI) which lack ADH. It was found that 60 min after water loads of 3 or 5% of body weight urine flow was significantly lower and urine osmolality significantly higher in adrenalectomized DI rats than in the same DI rats before removal of their adrenal glands. The efficacy of gluco- and mineralocorticoids in reversing the inhibition was then determined in the same adrenalectomized DI rats. Prednisolone alone, administered either acutely or chronically, restored the response in urine flow to that seen in the same rats before adrenalectomy, but failed to correct the defect in urinary dilution. Aldosterone when given alone tended to correct the diluting ability but not the response in urine flow. When these two adrenal cortical hormones were given simultaneously, both the urine flow and urine osmolality were nearly identical to what they had been in the same DI rats before adrenalectomy. These studies strongly suggest (a) that ADH is not essential to the inhibition of an acute water diuresis in adrenal insufficiency, although it may abet the inhibition in individuals without diabetes insipidus, which can elaborate ADH; and (b) that both gluco- and mineralocorticoids are required in adrenal insufficiency in order to fully restore the water diuresis as judged by the dual criteria of urine flow and urine osmolality.

Chlorpropamide action on renal concentrating mechanism in rats with hypothalamic diabetes insipidus.

To determine vasopressin (VP)-potentiating effect of chlorpropamide (CPMD), we studied the effect of CPMD in vivo and in vitro in kidneys and in specific tubule segments of rats with hypothalamic diabetes insipidus, homozygotes of the Brattleboro strain (DI rats). Rats on ad lib. water intake were treated with CPMD (20 mg/100 g body wt s.c. daily) for 7 d. While on ad lib. water intake, the urine flow, urine osmolality, urinary excretion of Na +, K +, creatinine, or total solute excretion did not change. However, corticopapillary gradient of solutes was significantly increased in CPMD-treated rats. Higher tissue osmolality was due to significantly increased concentration of Na +, and to a lesser degree urea, in the medulla and papilla of CPMD-treated rats. Consequently, the osmotic gradient between urine and papillary tissue of CPMD-treated rats (delta = 385 +/- 47 mosM) was significantly (P less than 0.001) higher compared with controls (delta = 150 +/- 26 mosM). Minimum urine osmolality after water loading was higher in CPMD-treated DI rats than in controls. Oxidation of [14C]lactate to 14CO2 coupled to NaCl cotransport was measured in thick medullary ascending limb of Henle's loop (MAL) microdissected from control and CPMD-treated rats. The rate of 14CO2 production was higher (delta + 113% +/- 20; P less than 0.01) in CPMD-treated MAL compared with controls, but 14CO2 production in the presence of 10(-3) M furosemide did not differ between MAL from control and from CPMD-treated rats. These observations suggest that CPMD treatment enhances NaCl transport in MAL. Cyclic AMP metabolism was analyzed in microdissected MAL and in medullary collecting tubule (MCT). MCT from control and from CPMD-treated rats did not differ in the basal or VP-stimulated accumulated of cAMP. The increase in cAMP content elicited by 10(-6) M VP in MAL from CPMD-treated rats (delta + 12.0 +/- 1.8 fmol cAMP/mm) was significantly (P less than 0.02) higher compared with MAL from control rats (delta + 5.1 +/- 1.0 fmol cAMP/mm). Preincubation of MAL dissected from Sprague-Dawley rats with 10(-4) M CPMD in vitro increased cAMP accumulation in the presence of VP, but no such enhancement was found in preincubated MCT. Adenylate cyclase activity, basal or stimulated by VP, 5'guanylimidodiphosphate, or by NaF, assayed in isotonic medium did not differ between MAL or MCT from control rats and MAL or MCT from CPMD-treated rats. When assayed in hypertonic medium (800 mosM), the adenylate cyclase activity in the presence of 10(-6) M VP was significantly higher in MAL of CPMD-treated rats. MAL and MCT from control and CPMD-treated rats did not differ in the activities of cAMP phosphodiesterase. The rate of [(14)C]prostaglandin E2 by medullary and papillary microsomes was not different between the control and CPMD-treated rats; likewise, there was no difference in accumulation of immunoreactive prostaglandin E2 in the medium of in vitro incubated medullary or papillary slices prepared from control and CPMD-treated rats. Based on the findings recounted above, we propose a hypothesis that CPMD administration enhances the antidiuretic effect of VP, primarily by increasing medullary and papillary tonicity dye to increased NaCl reabsorption in MAL. There is no evidence that CPMD sensitizes collecting tubules to the action of VP, at least at the camp-generation step. Therefore, increased antidiuretic response to VP in the kidneys of CPMD-treated DI rats is due to enhanced osmotic driving force for water reabsorption (lumen-to-interstitium osmotic gradient) in collecting tubules, rather than due to increased VP-dependent water permeability of tubular epithelium.

Diagnostic value of the water deprivation test in the polyuria-polydipsia syndrome.

OBJECTIVE: Diabetes insipidus (DI) and primary polydipsia (PP) are characterised by polyuria and polydipsia. It is crucial to differentiate between these two disorders since the treatment is different. The aim of this study was to evaluate the diagnostic value of the short and an extended variant of the water deprivation test (WDT) and of measuring urinary vasopressin (AVP) in patients with polyuria and polydipsia. DESIGN: A retrospective, single-centre study based on WDTs performed between 2004 and 2014 including 104 consecutive patients with the polyuria-polydipsia syndrome. During a strict water deprivation, weight, urinary osmolality, urinary vasopressin and specific gravity were collected until one of the following was reached: i) >3% weight reduction, ii) Urinary specific gravity >1.020 or, urinary osmolality >800 mOsm/L, iii) Intolerable adverse symptoms such as excessive thirst. RESULTS: Out of 104 patients (67 women, 37 men), 21 (20%) were diagnosed with DI and 83 (80%) with PP. The median (interquartile range; range) test duration was 14 hours (10-16; 3-36) in patients with DI and 18 hours (14-24; 7-48) in patients with PP (P=0.011). Of those diagnosed with PP, 22 (26%) did not reach urinary specific gravity >1.020 nor urine osmolality >800 mOsm/L. Urine AVP did not overlap between patients with PP and patients with central DI. CONCLUSIONS: The short WDT is of limited value in the diagnostic work-up of polydipsia and polyuria and a partial DI may have been missed in every fourth patient diagnosed with PP. Urinary AVP has excellent potential in discriminating PP from central DI.

The value of urine specific gravity in detecting diabetes insipidus in a patient with uncontrolled diabetes mellitus: urine specific gravity in differential diagnosis.

When a patient with diabetes mellitus presents with worsening polyuria and polydipsia, what is a sensible, cost-effective approach? We report the unique coincidence of type 2 diabetes mellitus and diabetes insipidus. A 46-year-old woman with poorly controlled type 2 diabetes complained of polyuria with a daily output of 5 L. Although urinalysis demonstrated significant glucosuria, diabetes insipidus was suspected owing to a low urine specific gravity (1.008). The low specific gravity persisted during a water deprivation test. Ultimately, diabetes insipidus was confirmed when urine specific gravity and urine osmolality normalized following desmopressin administration. This case emphasizes the importance of accurately interpreting the urine specific gravity in patients with polyuria and diabetes mellitus to detect diabetes insipidus.

Diabetes insipidus following neurosurgery at a university hospital in Western Saudi Arabia.

OBJECTIVES: To review the incidence, spectrum of clinical manifestation, course, risk factors, as well as treatment of diabetes insipidus (DI) following neurosurgery of the pituitary gland. METHODS: The files of 24 patients that underwent neurosurgery for sellar lesions, or tumor near the hypothalamus or pituitary gland at the Department of Neurosurgery, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia were retrospectively reviewed between January 2011 to December 2014. A total of 24 patients were studied, and were divided into 2 groups namely; DI and non-DI. Patient characteristics were studied using descriptive statistics. The differences in proportion between the 2 groups were found out using Z-test for proportion in 2 populations. The mean differences in the hormonal abnormalities for the 2 groups were assessed using independent t-test. All statistics are considered statistically significant when p less than 0.05. RESULTS: During hospitalization, 13 (54.2%) out of 24 patient that underwent neurosurgery had manifestations of DI, which was transient in 5 (38.8%) and permanent in 8 (61.2%). The DI subgroup contained higher prevalence of prolactinoma, craniopharyngioma, pre-operative panhypopituitarism, and macroadenoma in MRI imaging and transphenoidal surgery. Furthermore, urine osmolality was significantly lower in the DI group post-operatively with a significant p=0.023. It was recognized that the permanent DI documented more significant numbers than other studies. CONCLUSION: In our study group, it was recognized that permanent DI meant that our patients needed desmopressin for more than 3 months, which documented a more significant number than other studies.

Indomethacin in the treatment of lithium-induced nephrogenic diabetes insipidus.

Nephrogenic diabetes insipidus (NDI) is a frequent complication in patients receiving long-term lithium therapy. Both thiazide diuretics and amiloride may reduce the polyuria, but the use of each is associated with problems. We report the results of a clinical trial using the nonsteroidal anti-inflammatory drug indomethacin to treat a patient with well-documented lithium-induced NDI that persisted following cessation of lithium treatment. The administration of a single dose of indomethacin resulted in a dramatic decrease in urine volume and increase in urine osmolality that persisted for several hours, and was independent of renal hemodynamic changes. Subsequently, the patient experienced a sustained, favorable effect on her polyuria during long-term (3 months) indomethacin therapy without a deleterious effect on her renal function. Indomethacin may be a useful therapeutic tool for the amelioration of lithium-induced NDI.

Familial neurohypophyseal diabetes insipidus associated with a signal peptide mutation.

We studied the pathophysiology, natural history, and genetic basis of familial neurohypophyseal diabetes insipidus (FNDI) in a caucasian kindred. Twelve members had polyuria and a deficiency of plasma vasopressin (AVP), which progressed in severity over time. Another had normal urine volumes and plasma AVP when first tested at age 3 yr, but developed severe FNDI a year later. For unknown reasons, one man had a normal urine volume despite severe AVP deficiency and a history of polyuria in the past. When the AVP-neurophysin-II gene was amplified and sequenced, exon 2/3 was normal, but 7 of 12 clones of exon 1 contained a base substitution (G-->A) predicting a substitution of threonine for alanine at the -1 position of the signal peptide. Restriction analysis found the mutation in all 14 affected members, but in none of the 41 controls or 19 adult members with normal urine volumes and plasma or urinary AVP (lod score = 5.7). The mutation was also found in 2 infants in whom AVP was normal when tested at 6 and 9 months of age. We hypothesize that a mutation in exon 1 of the AVP-neurophysin-II gene causes FNDI in this kindred by making an abnormally processed precursor that gradually destroys vasopressinergic neurons.

Urinary excretion of aquaporin-2 in the diagnosis of central diabetes insipidus.

We determined whether alteration in urinary excretion of aquaporin-2 (UAQP-2) is of value to diagnose central diabetes insipidus (CDI). First, UAQP-2 was determined in 16 normal subjects under ad libitum water drinking (n = 6) and after an overnight dehydration (n = 10). UAQP-2 has a positive correlation with plasma arginine vasopressin (AVP) levels (r = 0.61, P < 0.05) but not with urinary osmolality (Uosm). Second, a hypertonic saline (5% NaCl)-infusion test was studied in 5 normal subjects (21 to 25 yr old) and 10 patients with CDI (22-68 yr). After drinking water ad libitum, they were given 20 mL/kg water orally and then given 5% NaCl (0.05 mL/kg x min) i.v. for 120 min. Finally, 0.1 U of AVP was administered i.v. During the period, 30-min urine collections were made. In the normal subjects, after the infusion of 5% NaCl, plasma AVP levels and Uosm markedly increased in parallel with an increase in plasma osmolality (Posm, 294-320 mOsm/kg H2O; Uosm, 102-737 mOsm/kg H2O; AVP, 0.4-2.6 pg/mL, P < 0.001). In the CDI patients, plasma AVP and Uosm failed to increase, despite an increase in Posm (Posm, 306-332; Uosm, 102-164; AVP, 0.9-1.2). UAQP-2 was markedly greater in the normal subjects than the CDI patients (7.2 vs. 0.9 pmol/L/mg creatinine, P < 0.05) under water intake ad libitum. UAQP-2 was changeable in the wide range in physiological condition. After the 5%-NaCl infusion, UAQP-2 elevated to 12.5 from 0.9 pmol/L x mg creatinine in the normal subjects. In contrast, UAQP-2 remained low during the 5%-NaCl infusion in the CDI patients. Exogenous AVP promptly increased UAQP-2 to a similar extent in two groups of the normal subjects and the CDI patients. These results indicate that measurement of UAQP-2 is of value to diagnose CDI in the 5%-NaCl infusion test.

Urinary excretion of aquaporin-2 water channel differentiates psychogenic polydipsia from central diabetes insipidus.

The present study was undertaken to determine whether urinary excretion of aquaporin-2 (AQP-2) water channel under ad libitum water intake is of value to differentiate polyuria caused by psychogenic polydipsia from central diabetes insipidus. A 30-min urine collection was made at 0900 h in 3 groups of: 11 patients with central diabetes insipidus (22-68 yr old), 10 patients with psychogenic polydipsia (28-60 yr old), and 15 normal subjects (21-38 yr old). In the patients with central diabetes insipidus, the plasma arginine vasopressin level was low despite hyperosmolality, resulting in hypotonic urine. Urinary excretion of AQP-2 was 37 +/- 15 fmol/mg creatinine, a value one-fifth less than that in the normal subjects. In the patients with psychogenic polydipsia, plasma arginine vasopressin and urinary osmolality were as low as those in the patients with central diabetes insipidus. However, urinary excretion of AQP-2 of 187 +/- 45 fmol/mg creatinine was not decreased, and its excretion was equal to that in the normal subjects. These results indicate that urinary excretion of AQP-2, under ad libitum water drinking, participates in the differentiation of psychogenic polydipsia from central diabetes insipidus.

Blunted pressure natriuresis in the Brattleboro diabetes insipidus rat.

Antidiuretic hormone is known to stimulate the renal synthesis of prostaglandins. These autacoids, in turn, modulate the pressure natriuresis phenomenon. Accordingly, the present study was done to test the hypothesis that, in the absence of antidiuretic hormone and antidiuretic hormone-dependent prostaglandin synthesis, the pressure natriuresis response is blunted. Experiments were performed on Brattleboro diabetes insipidus rats (n = 7) and Long Evans control rats (n = 14). A change in perfusion pressure in the Long Evans rats from 89.3 +/- 1.0 to 108.7 +/- 1.1 mm Hg (p less than 0.05) was associated with significant increases in the fractional excretion of sodium (1.1 +/- 0.2 to 2.3 +/- 0.3%) and the urinary prostaglandin excretion (32.6 +/- 6.8 to 56.6 +/- 10.0 pg/min). In contrast, a similar change in perfusion pressure in the diabetes insipidus rat from 88.6 +/- 1.4 to 106.2 +/- 1.5 mm Hg (p less than 0.05) resulted in no significant increases in either sodium or prostaglandin excretions. Treatment of a third group of diabetes insipidus rats (n = 9) with 1-desamino-8-D-arginine vasopressin (1 microgram/day) restored the natriuretic response to increases in renal perfusion pressure. Treated diabetes insipidus and Long Evans control rats had comparable natriuretic responses to increases in renal perfusion pressure. Untreated diabetes insipidus rats, on the other hand, had blunted responses. In summary, the pressure natriuresis response in diabetes insipidus rats is blunted compared with Long Evans control rats. We conclude that antidiuretic hormone is necessary for the complete expression of the pressure natriuresis response.

1-Deamino-8-D-arginine vasopressin and urine cyclic adenosine monophosphate excretion in diabetes insipidus.

The response to 1-deamino-8-D-arginine vasopressin (DDAVP), an intranasally administered analogue of vasopressin, was investigated in children and adults with central diabetes insipidus. To assess the action of DDAVP on the distal nephron, cyclic adenosine monophosphate (cAMP) excretion was assayed in urine collected 4 hr before and during four subsequent 4-hr periods after intranasal administration of 5 micrograms DDAVP. Maximal effects on urine volume and concentration were observed between 4 and 12 hr, coinciding with an elevated cAMP excretion in seven subjects. The pretreatment 4-hr cAMP excretion (micrograms/gm creatinine) correlated inversely with age (p less than 0.02) and surface area (p less than 0.001). Subsequent cAMP excretion after DDAVP increased inconsistently with no relationship to duration of antidiuresis, indicating that urinary cAMP is a poor index of antidiuretic hormone action on the distal nephron. We also confirmed that DDAVP intranasally induces antidiuresis in patients with diabetes insipidus over approximately 12 hr.