Vasopressin V2 Receptor Agonist Research Articles

Biased activation of the vasopressin V2 receptor probed by molecular dynamics simulations, NMR and pharmacological studies

G protein-coupled receptors (GPCRs) control critical cell signaling. Their response to extracellular stimuli involves conformational changes to convey signals to intracellular effectors, among which the most important are G proteins and β-arrestins (βArrs). Biased activation of one pathway is a field of intense research in GPCR pharmacology. Combining NMR, site-directed mutagenesis, molecular pharmacology, and molecular dynamics (MD) simulations, we studied the conformational diversity of the vasopressin V2 receptor (V2R) bound to different types of ligands: the antagonist Tolvaptan, the endogenous unbiased agonist arginine-vasopressin, and MCF14, a partial Gs protein-biased agonist. A double-labeling NMR scheme was developed to study the receptor conformational changes and ligand binding: V2R was subjected to lysine 13CH3 methylation for complementary NMR studies, whereas the agonists were tagged with a paramagnetic probe. Paramagnetic relaxation enhancements and site-directed mutagenesis validated the ligand binding modes in the MD simulations. We found that the bias for the Gs protein over the βArr pathway involves interactions between the conserved NPxxY motif in the transmembrane helix 7 (TM7) and TM3, compacting helix 8 (H8) toward TM1 and likely inhibiting βArr signaling. A similar mechanism was elicited for the pathogenic mutation I130N, which constitutively activates the Gs proteins without concomitant βArr recruitment. The findings suggest common patterns of biased signaling in class A GPCRs, as well as a rationale for the design of G protein-biased V2R agonists.

A cAMP-biosensor-based assay for measuring plasma arginine–vasopressin levels

Arginine–vasopressin (AVP), a cyclic peptide hormone composed of nine amino acids, regulates water reabsorption by increasing intracellular cyclic adenosine monophosphate (cAMP) concentrations via the vasopressin V2 receptor (V2R). Plasma AVP is a valuable biomarker for the diagnosis of central diabetes insipidus (CDI) and is commonly measured using radioimmunoassay (RIA). However, RIA has several drawbacks, including a long hands-on time, complex procedures, and handling of radioisotopes with special equipment and facilities. In this study, we developed a bioassay to measure plasma AVP levels using HEK293 cells expressing an engineered V2R and a cAMP biosensor. To achieve high sensitivity, we screened V2R orthologs from 11 various mammalian species and found that the platypus V2R (pV2R) responded to AVP with approximately six-fold higher sensitivity than that observed by the human V2R. Furthermore, to reduce cross-reactivity with desmopressin (DDAVP), a V2R agonist used for CDI treatment, we introduced a previously described point mutation into pV2R, yielding an approximately 20-fold reduction of responsiveness to DDAVP while maintaining responsiveness to AVP. Finally, a comparison of plasma samples from 12 healthy individuals demonstrated a strong correlation (Pearson's correlation value: 0.90) between our bioassay and RIA. Overall, our assay offers a more rapid and convenient method for quantifying plasma AVP concentrations than existing techniques.

Improvement of gut-vascular barrier by terlipressin reduces bacterial translocation and remote organ injuries in gut-derived sepsis.

Gut-vascular barrier (GVB) serves as the last barrier to limit the migration of intestinal toxins into the blood circulation. The efficacy of terlipressin (a vasopressin V1 receptor agonist) in reducing GVB and multiple organ damage in gut-derived sepsis is unknown. In this study, we hypothesized that, besides other intestinal barriers, GVB play a key role in gut-derived sepsis and terlipressin improve GVB damage and then reduce bacterial translocation and organ injuries. In vivo, a cecal ligation and puncture mouse model was established. The mice were subjected to examine the damage of GVB determined by intestinal plasmalemma vesicle-associated protein-1(PV-1) and vascular endothelial-cadherin. And the intestinal permeability was assessed by translocation of intestinal bacteria and macromolecules. In vitro, transendothelial electrical resistance (TER) during interleukin (IL)-1β stimulation was measured on endothelial cells with or without small interfering RNA targeting β-catenin (si β-catenin). Terlipressin significantly improved GVB damage and reduced translocation of intestinal macromolecules and bacteria by activating PI3K signaling. Of note, intestinal PV-1 expression was significantly correlated with translocation of macromolecules, and dramatic increase of macromolecules was observed in intestinal tissues whereas fewer macromolecules and bacteria were observed in blood, liver and lung following terlipressin treatment. In vitro, terlipressin restored TER during IL-1β stimulation and si β-catenin transfection blocked the changes delivered by terlipressin. Collectively, terlipressin alleviated GVB damage and subsequent bacterial translocation via blood vessels after sepsis challenge, resulting in reduced distant organ injuries and the responsible mechanisms may involve the activation of PI3K/β-catenin pathway.

Pathophysiology of Drug-Induced Hyponatremia

Drug-induced hyponatremia caused by renal water retention is mainly due to syndrome of inappropriate antidiuresis (SIAD). SIAD can be grouped into syndrome of inappropriate antidiuretic hormone secretion (SIADH) and nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The former is characterized by uncontrolled hypersecretion of arginine vasopressin (AVP), and the latter is produced by intrarenal activation for water reabsorption and characterized by suppressed plasma AVP levels. Desmopressin is useful for the treatment of diabetes insipidus because of its selective binding to vasopressin V2 receptor (V2R), but it can induce hyponatremia when prescribed for nocturnal polyuria in older patients. Oxytocin also acts as a V2R agonist and can produce hyponatremia when used to induce labor or abortion. In current clinical practice, psychotropic agents, anticancer chemotherapeutic agents, and thiazide diuretics are the major causes of drug-induced hyponatremia. Among these, vincristine and ifosfamide were associated with sustained plasma AVP levels and are thought to cause SIADH. However, others including antipsychotics, antidepressants, anticonvulsants, cyclophosphamide, and thiazide diuretics may induce hyponatremia by intrarenal mechanisms for aquaporin-2 (AQP2) upregulation, compatible with NSIAD. In these cases, plasma AVP levels are suppressed by negative feedback. In rat inner medullary collecting duct cells, haloperidol, sertraline, carbamazepine, and cyclophosphamide upregulated V2R mRNA and increased cAMP production in the absence of vasopressin. The resultant AQP2 upregulation was blocked by a V2R antagonist tolvaptan or protein kinase A (PKA) inhibitors, suggestive of the activation of V2R-cAMP-PKA signaling. Hydrochlorothiazide can also upregulate AQP2 in the collecting duct without vasopressin, either directly or via the prostaglandin E2 pathway. In brief, nephrogenic antidiuresis, or NSIAD, is the major mechanism for drug-induced hyponatremia. The associations between pharmacogenetic variants and drug-induced hyponatremia is an area of ongoing research.

Genetic Deletion of the Prostaglandin EP4 Receptor in the Kidney Tubule of Adult Male Mice Has Mild Impact on Kidney Water Handling

Prostaglandin E2 (PGE2) is an essential lipid mediator modulating several aspects of renal function. PGE2 acts via four PGE2 receptors, EP1‐EP4. EP4 is abundant in the kidney glomerulus, where it plays a role in renal hemodynamics. EP4 is also expressed in the collecting duct, and constitutive deletion of EP4 from this segment in mice suggests it plays a role in urine concentration. To assess the tubular role of EP4 in adult mice we generated a mouse model with doxycycline‐dependent deletion of EP4 along the renal tubule (Pax8Cre system) and assessed their renal phenotype regarding water handling. Two weeks after treatment with doxycycline, EP4 mRNA expression was reduced by >80% in the renal medulla (RT‐q‐PCR) of knockout mice compared to control mice. Under basal conditions, there were no significant differences between genotypes in food and water intake, bodyweight or plasma biochemistries. EP4 knockout males showed a small increase in basal urinary output and a decreased osmolality, concomitant with lower urinary Na+, K+, Cl‐, urea and creatinine concentrations. There were no differences between genotypes in their renal handling of water during water deprivation for 14 hours, or in their response to the vasopressin V2 receptor agonist dDAVP. In a water overloading test only the EP4 knockout females showed an increased urinary output after 1 hour of the water overload. In conclusion, EP4 in the renal tubule has a mild role in renal water handling. This new model provides a novel tool for assessing the role of EP4 in other aspects of kidney function or disease independently of potential developmental abnormalities or systemic effects.

Genetic Deletion of the Prostaglandin EP3 Receptor in the Kidney Tubule of Adult Mice Has No Impact on Kidney Water Handling

Prostaglandin E2 (PGE2) is an important lipid mediator modulating various aspects of kidney function. PGE2 exerts its effects via four PGE2 receptors, EP1-EP4. The EP3 receptor is expressed in the thick ascending limb (TAL) and the collecting duct, where it is proposed to inhibit cAMP generation and NaCl and water reabsorption. However, EP3 is also expressed in endothelial cells of arteries and arterioles, which also play a role in kidney function. Therefore, to assess the tubular role of EP3 in adult mice we generated a mouse model based on the Pax8Cre system with doxycycline-dependent deletion of EP3 along the renal tubule and assessed their renal phenotype in respect to water handling. RNAscope confirmed that EP3 was highly expressed in cortical and medullary TAL and collecting ducts, but it was non-detected in proximal tubule and thin limbs. Two weeks after treatment with doxycycline, EP3 mRNA expression was reduced by >80% in whole kidney (RT-q-PCR) and non-detectable (RNAscope) in tubules of knockout mice compared to control mice. There were no compensatory changes in other EP receptors. Under basal conditions, there were no significant differences in food and water intake, bodyweight, urinary output or plasma and urine biochemistries in both male or female control and knockout mice. There were no differences between genotypes in their renal handling of water during an acute water load, or in their response to the vasopressin V2 receptor agonist dDAVP. Rats drinking 1% NaCl for several days in combination with an EP3 antagonist have increased urine output (Hao et al., 2016). However, relative to controls, we could not detect significant differences in urine volume or osmolality in tubular EP3 knockout mice during 1% NaCl intake. In conclusion, EP3 in the renal tubule is not important for renal water handling or compensatory mechanisms exist. This new model provides a novel tool for examination of the role of EP3 in other aspects of renal function or kidney disease independently of potential developmental abnormalities or systemic effects.

ВЛИЯНИЕ ВАЗОПРЕССИНА НА КОЛЛАГЕНАЗНУЮ АКТИВНОСТЬ КЛЕТОК ПАПИЛЛЯРНОЙ ЗОНЫ ПОЧЕК КРЫС

To find out whether matrix metalloproteinases can be involved in the implementation of the antidiuretic effect of vasopressin, the effect of this hormone on the gelatinase activity of renal papillary cells in Wistar rats was studied by zymography. It was shown that the addition of the hormone to the suspension of renal papillary cells caused an increase in the gelatinase activity of proteins with a molecular weight of 52, 57 and 89 kDa. This effect was imitated by desmopressin, a vasopressin V2 receptor agonist. Vasopressin, but not desmopressin, caused an increase in the secretion of 57 and 89 kDa proteins by renal papillary cells in the incubation medium. The role of matrix metalloproteinases in vasopressin-induced increasing the water permeability of the intercellular matrix in the rat renal papilla is discussed.

Vasopressin escape and memory impairment in a model of chronic syndrome of inappropriate secretion of antidiuretic hormone in mice.

Recently, chronic hyponatremia, even mild, has shown to be associated with poor quality of life and high mortality. The mechanism by which hyponatremia contributes to those symptoms, however, remains to be elucidated. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a primary cause of hyponatremia. Appropriate animal models are crucial for investigating the pathophysiology of SIADH. A rat model of SIADH has been generally used and mouse models have been rarely used. In this study, we developed a mouse model of chronic SIADH in which stable and sustained hyponatremia occurred after 3-week continuous infusion of the vasopressin V2 receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP) and liquid diet feeding to produce chronic water loading. Weight gain in chronic SIADH mice at week 2 and 3 after starting dDAVP injection was similar to that of control mice, suggesting that the animals adapted to chronic hyponatremia and grew up normally. AQP2 expression in the kidney, which reflects the renal action of vasopressin, was decreased in dDAVP-infused water-loaded mice as compared with control mice that received the same dDAVP infusion but were fed pelleted chow. These results suggest that "vasopressin escape" occurred, which is an important process for limiting potentially fatal severe hyponatremia. Behavioral analyses using the contextual and cued fear conditioning test and T-maze test demonstrated cognitive impairment, especially working memory impairment, in chronic SIADH mice, which was partially restored after correcting hyponatremia. Our results suggest that vasopressin escape occurred in chronic SIADH mice and that chronic hyponatremia contributed to their memory impairment.

Effects of OPC-51803, a Novel, Nonpeptide Vasopressin V2-Receptor Agonist, on Micturition Frequency in Brattleboro and Aged Rats

Effects of OPC-51803, a Novel, Nonpeptide Vasopressin V2-Receptor Agonist, on Micturition Frequency in Brattleboro and Aged Rats

Terlipressin protects intestinal epithelial cells against oxygen-glucose deprivation/re-oxygenation injury via the phosphatidylinositol 3-kinase pathway

Intestinal ischemia/reperfusion (I/R) injury is associated with a high morbidity and mortality. Vasopressin is administered to critically ill patients with potential intestinal I/R. However, the impacts of vasopressin on intestinal epithelia under ischemic/anoxic conditions remain unclear. The aim of the present study was to evaluate the effects of terlipressin, a highly selective vasopressin V1 receptor agonist, on oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced damage in intestinal epithelial cells (IEC-6). IEC-6 cells were subjected to OGD for 4 h, followed by 4 h re-oxygenation. Terlipressin was incubated with cells for 4 h following OGD. Following OGD/R, IEC-6 cell viability, proliferation and apoptosis, as well as cell cycle dynamics, were assessed and the levels of tumor necrosis factor (TNF)-α and 15-F2t-isoprostane in the culture medium were measured. In addition, wortmannin, a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, was administrated to investigate the mechanism of terlipressin action. The results demonstrated that IEC-6 cell viability and proliferation decreased, and cell apoptosis increased, following OGD/R. However, IEC-6 cell cycle dynamics did not significantly change 4 h after OGD. Incubation with 25 nM terlipressin significantly improved cell viability, proliferation and apoptosis. Furthermore, terlipressin inhibited the secretion of TNF-α and 15-F2t-isoprostane from IEC-6 cells following OGD/R. The aforementioned effects of terlipressin were completely abolished following the application of 2 µM wortmannin. Therefore, the current study demonstrated that terlipressin administration following OGD attenuates OGD/R-induced cell damage via the PI3K signaling pathway. These results may help physicians to better understand and more effectively use terlipressin in a clinical setting.

Efficiency of Osmotic Concentration after Combined Treatment with Vasopressin and Blockage of Prostaglandin Synthesis.

We performed a complex functional study of the effects of prostaglandin synthesis blockage with diclofenac on manifestation of the hydroosmotic effect of vasopressin V2-receptor agonist desmopressin in the kidneys of Wistar rats with normal synthesis of endogenous vasopressin and homozygous Brattleboro rats with hereditary impaired synthesis of neurohypophyseal hormone vasopressin. Blockage of prostaglandin synthesis led to more pronounced increase in urine osmolality in Brattleboro rats than in Wistar rats due to elevation of not only urine but also sodium gradient at the expense of elimination of the inhibitory effect of prostaglandins on sodium reabsorption and membrane permeability for urine. During combined treatment, the effects of the hormone predominated: the increase in urine osmolality in Wistar and Brattleboro rats did not differ from that after desmopressin administration.

Imidafenacin exerts the antidiuretic effect by enhancing vasopressin-related responses in orally water-loaded rats

Imidafenacin, an antimuscarinic agent for treating overactive bladder, has an antidiuretic effect, but the detailed mechanisms of action remain unclear. The cholinergic and vasopressin systems are known to interact, for example, in the suppression of vasopressin-induced water reabsorption through muscarinic stimulation in the renal collecting duct. We, therefore, investigated whether vasopressin signaling pathway would participate in the antidiuretic effect of imidafenacin. In female Sprague-Dawley rats, urine production was measured by collecting urine from cystostomy chatheter using a Bollman restraining cage for 2h after drug i.v. injection and water load (25ml/kg p.o.). Both imidafenacin and a vasopressin V2 receptor agonist desmopressin acetate (desmopressin) dose-dependently suppressed urine production. The combination of imidafenacin and desmopressin at the minimum effective doses suppressed the urine production more strongly than each alone. Mozavaptan hydrochloride (mozavaptan, 3mg/kg), a vasopressin V2 receptor antagonist, completely inhibited the antidiuretic effects of imidafenacin and desmopressin at their respective minimum effective doses. The antidiuretic effect of desmopressin emerged at the maximum antidiuretic dose level (0.1µg/kg) even under mozavaptan-treatment, whereas that of imidafenacin (300µg/kg) was still kept suppressed by mozavaptan. When 300µg/kg imidafenacin was added to the combination of mozavaptan 3mg/kg and desmopressin 0.1µg/kg, the antidiuretic effect was further enhanced. The present study suggests that vasopressin signaling pathway participates in the antidiuretic effect of imidafenacin, and that imidafenacin exerts its antidiuretic effects by enhancing some part of the vasopressin signaling pathway in orally water-loaded rats.

Selective V₂-Agonist of Vasopressin Desmopressin Stimulates Activity of Serum Hyaluronidase.

Effects of desmopressin (arginine vasopressin V2 receptor agonist) were studied for elucidation of the possible role of the kidneys in the regulation of blood hyaluronidase activity. Similar to vasopressin, intraperitoneal administration of desmopressin to Wistar rats increased blood hyaluronidase activity by 30%. Against the background of water load, nether desmopressin nor vasopressin increased blood hyaluronidase activity. The possibility of renal secretion of hyaluronidase into the blood as a mechanism of antidiuretic activity of vasopressin and its role in the regulation of water metabolism are discussed.

The Selective Vasopressin Type 1a Receptor Agonist Selepressin (FE 202158) Blocks Vascular Leak in Ovine Severe Sepsis*

To determine if the selective vasopressin type 1a receptor agonist selepressin (FE 202158) is as effective as the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist vasopressor hormone arginine vasopressin when used as a titrated first-line vasopressor therapy in an ovine model of Pseudomonas aeruginosa pneumonia-induced severe sepsis. Prospective, randomized, controlled laboratory experiment. University animal research facility. Forty-five chronically instrumented sheep. Sheep were anesthetized, insufflated with cooled cotton smoke via tracheostomy, and P. aeruginosa were instilled into their airways. They were then placed on assisted ventilation, awakened, and resuscitated with lactated Ringer's solution titrated to maintain hematocrit ± 3% from baseline levels. If, despite fluid management, mean arterial pressure fell by more than 10 mm Hg from baseline level, an additional continuous IV infusion of arginine vasopressin or selepressin was titrated to raise and maintain mean arterial pressure within no less than 10 mm Hg from baseline level. Effects of combination treatment of selepressin with the selective vasopressin V2 receptor agonist desmopressin were similarly investigated. In septic sheep, MAP fell by ~30 mm Hg, systemic vascular resistance index decreased by ~50%, and ~7 L of fluid were retained over 24 hours; this fluid accumulation was partially reduced by arginine vasopressin and almost completely blocked by selepressin; and combined infusion of selepressin and desmopressin increased fluid accumulation to levels similar to arginine vasopressin treatment. Resuscitation with the selective vasopressin type 1a receptor agonist selepressin blocked vascular leak more effectively than the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist arginine vasopressin because of its lack of agonist activity at the vasopressin V2 receptor.

Analysis of the efficiency of osmotic concentration in Wistar and Brattleboro rats under the effect of desmopressin.

We studied the effect of vasopressin V2 receptor agonist (desmopressin, 5 μg/100 g body weight for 2 days) on the efficiency of osmotic concentration in Wistar rats and homozygous Brattleboro rats defective by the synthesis of antidiuretic hormone. Specific differences in the reaction of the osmotic concentration system components (urine osmolality and urea, sodium, and potassium content in the renal tissue) involved in the realization of the hydroosmotic effect of the hormone depend on genetically determined capacity to vasopressin synthesis in these animals.

Reciprocal interactions between tumor and endothelial cells: effects of selective vasopressin V2 receptor peptide agonists

Fil: Garona, Juan. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Oncologia Molecular; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas; Argentina

2270 ADMINISTRATION OF FEDOVAPAGON CAUSES A DOSE-RESPONSIVE REDUCTION IN NOCTURNAL POLYURIA INDEX

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Urodynamics Testing1 Apr 20132270 ADMINISTRATION OF FEDOVAPAGON CAUSES A DOSE-RESPONSIVE REDUCTION IN NOCTURNAL POLYURIA INDEX Georg Golor, Hilary McElwaine-Johnn, Rachel Handy, Christopher Yea, and John Lambert Georg GolorGeorg Golor Berlin, Germany More articles by this author , Hilary McElwaine-JohnnHilary McElwaine-Johnn Southampton, United Kingdom More articles by this author , Rachel HandyRachel Handy Southampton, United Kingdom More articles by this author , Christopher YeaChristopher Yea Southampton, United Kingdom More articles by this author , and John LambertJohn Lambert Harrow, United Kingdom More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2199AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Nocturia, defined as waking to void at least once per night between periods of sleep, is a common complaint and shows an age-dependent increase in both prevalence and severity. It has been linked to age-dependent loss in circadian release of nocturnal vasopressin which leads to over production of urine at night (nocturnal polyuria, NPU). NPU is generally diagnosed in subjects aged >65 years when night time urine production exceeds 33% of the total 24 hour (h) urine production. Fedovapagon (VA106483), a novel non-peptide drug, is a selective vasopressin V2-receptor agonist in development for the treatment of nocturia. METHODS Thirty older male subjects (aged >65 years) with a history of BPH and nocturia (mean age 69.2 years [SD 3.2]) were randomised in this IEC approved double-blind, placebo-controlled, five-way cross-over study. Each subject received five treatment periods, each of 2 nights, comprising 0.5 mg - 1 mg - 2 mg - 4 mg fedovapagon and placebo administered in a double-blind fashion in a randomised treatment sequence, each separated by a 1 night single-blind placebo. Subjects had free access to fluid throughout the study, ensuring thirst was satisfied at all times. Subjects were dosed with Investigational Medicinal Product (IMP) at approximately 9 pm. Subjects were prompted to void 1 h post IMP (bedtime void) and again at 9 h (first morning void). Urine voided after the prompted bedtime void and up to and including the first morning void was included in the NUV. 24 h urine volume was assessed throughout the study period. Nocturnal polyuria index (NPUI) was calculated as NUV / 24 h urine volume × 100%. RESULTS There was no discernible effect of fedovapagon treatment on the overall 24 h urine volume. Fedovapagon reduced NPUI in a dose responsive manner from 37.1% following placebo to 24.6% at the 4 mg dose. Fedovapagon was effective on the first night of dosing. There was no apparent carry-over effect of fedovapagon on nocturnal polyuria indices during the single-blind treatment between randomised treatment periods. CONCLUSIONS Fedovapagon treatment was well tolerated in the study population. The dose-responsive reduction in NPUI on fedovapagon shown in this study indicates a shift of urine production from the night time period to the daytime period in this population of older male subjects with nocturia and BPH. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e930-e931 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Georg Golor Berlin, Germany More articles by this author Hilary McElwaine-Johnn Southampton, United Kingdom More articles by this author Rachel Handy Southampton, United Kingdom More articles by this author Christopher Yea Southampton, United Kingdom More articles by this author John Lambert Harrow, United Kingdom More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Chronic activation of vasopressin V2 receptor signalling lowers renal medullary oxygen levels in rats

In the present study, we aimed to elucidate the effects of chronic vasopressin administration on renal medullary oxygen levels. Adult Sprague Dawley or vasopressin-deficient Brattleboro rats were treated with the vasopressin V2 receptor agonist, desmopressin (5ng/h; 3d), or its vehicle via osmotic minipumps. Immunostaining for pimonidazole and the transcription factor HIF-1α (hypoxia-inducible factor-1α) were used to identify hypoxic areas. Activation of HIF-target gene expression following desmopressin treatment was studied by microarray analysis. Pimonidazole staining was detected in the outer and inner medulla of desmopressin-treated rats, whereas staining in control animals was weak or absent. HIF-1α immunostaining demonstrated nuclear accumulation in the papilla of desmopressin-treated animals, whereas no staining was observed in the controls. Gene expression analysis revealed significant enrichment of HIF-target genes in the group of desmopressin-regulated gene products (P=2.6*10(-21) ). Regulated products included insulin-like growth factor binding proteins 1 and 3, angiopoietin 2, fibronectin, cathepsin D, hexokinase 2 and cyclooxygenase 2. Our results demonstrate that an activation of the renal urine concentrating mechanism by desmopressin causes renal medullary hypoxia and an upregulation of hypoxia-inducible gene expression.

AGONIST OF V2 VASOPRESSIN RECEPTOR REDUCES DEPRESSIVE DISORDERS IN POST-STROKE PATIENTS

Poststroke depression is one of the common psychiatric complications after stroke. Thus, the research of new ways for treatment depressed mood after stroke is actual. The previous researches revealed vasopressin to be effective in patients with memory, speech and motor function disorders after stroke. The purpose of the study was to investigate influence of vasopressin on depression after stroke. Fourteen patients with affective disorders have been treated with subendocrine doses of 1-desamino-8-D-arginin-vasopressin (DDAVP) daily by intranasal application during 1,5-2 months. Vasopressin was effective in correcting both apatoadinamic and anxious depression. Treatment effect was durable, lasts for 0,5-1 year after the first course of therapy. The results of this pilot study demonstrate perspective of using selective agonist of vasopressin V2 receptors, DDAVP, in therapy of post-stroke depression.

Sex differences in vasopressin V2 receptor expression and vasopressin-induced antidiuresis

The renal vasopressin V(2) receptor (V(2)R) plays a critical role in physiological and pathophysiological processes associated with arginine vasopressin (AVP)-induced antidiuresis. Because clinical data suggests that females may be more prone to hyponatremia from AVP-mediated antidiuresis, we investigated whether there are sex differences in the expression and function of the renal V(2)R. In normal Sprague-Dawley rat kidneys, V(2)R mRNA and protein expression was 2.6- and 1.7-fold higher, respectively, in females compared with males. To investigate the potential physiological implications of this sex difference, we studied changes in urine osmolality induced by the AVP V(2)R agonist desmopressin. In response to different doses of desmopressin, there was a graded increase in urine osmolality and decrease in urine volume during a 24-h infusion. Females showed greater mean increases in urine osmolality and greater mean decreases in urine volume at 0.5 and 5.0 ng/h infusion rates. We also studied renal escape from antidiuresis produced by water loading in rats infused with desmopressin (5.0 ng/h). After 5 days of water loading, urine osmolality of both female and male rats escaped to the same degree physiologically, but V(2)R mRNA and protein in female kidneys was reduced to a greater degree (-63% and -73%, respectively) than in males (-32% and -48%, respectively). By the end of the 5-day escape period, renal V(2)R mRNA and protein expression were reduced to the same relative levels in males and females, thereby abolishing the sex differences in V(2)R expression seen in the basal state. Our results demonstrate that female rats express significantly more V(2)R mRNA and protein in kidneys than males, and that this results physiologically in a greater sensitivity to V(2)R agonist administration. The potential pathophysiological implications of these results are that females may be more susceptible to the development of dilutional hyponatremia because of a greater sensitivity to endogenously secreted AVP.