Vasopressin-V2 Receptor Stimulation Reduces Sodium Excretion in Healthy Humans

Bankir, Lise; Fernandes, Sarah; Bardoux, Pascale; Bouby, Nadine; Bichet, Daniel G.

doi:10.1681/asn.2004121079

Cited by 121 publications

(93 citation statements)

References 41 publications

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“…In patients with a mean urinary output of 12 L/d, a theoretical decrease of urine volume to 6 L/d could be obtained provided that a sustained drug effect could be reached through optimization of the drug regimen. A nonsignificant decrease in sodium excretion was observed, possibly indicating that these patients were not strictly in Na ϩ balance and/or pointing to the possible restoration of an AVP antinatriuretic effect (47). The highest increase in urine osmolality and consequent decrease in urine volume was observed with patient 3 with a maximal increase in urine osmolality after dDAVP of 248 mOsm/kg.…”

Section: Discussionmentioning

confidence: 89%

Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus

Bernier¹,

Morello²,

Zarruk³

et al. 2006

Journal of the American Society of Nephrology

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215

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In many mendelian diseases, some mutations result in the synthesis of misfolded proteins that cannot reach a transportcompetent conformation. In X-linked nephrogenic diabetes insipidus, most of the mutant vasopressin 2 (V2) receptors are trapped in the endoplasmic reticulum and degraded. They are unable to reach the plasma membrane and promote water reabsorption through the principal cells of the collecting ducts. Herein is reported two types of experiments: In vivo studies to assess clinically a short-term treatment with a nonpeptide V1a receptor antagonist (SR49059) and in vitro studies in cultured cell systems. In patients, SR49059 decreased 24-h urine volume (11.9 ؎ 2.3 to 8.2 ؎ 2.0 L; P ‫؍‬ 0.005) and water intake (10.7 ؎ 1.9 to 7.2 ؎ 1.6 L; P < 0.05). Maximum increase in urine osmolality was observed on day 3 (98 ؎ 22 to 170 ؎ 52 mOsm/kg; P ‫؍‬ 0.05). Sodium, potassium, and creatinine excretions and plasma sodium were constant throughout the study. A lthough the activities of the protein synthesis quality control systems are generally advantageous to the cell, on occasion this stringent monitoring process can lead to intracellular retention of salvageable proteins. In recent years, its has been observed that a group of diseases stem from mutations that promote such retention and are collectively referred to as conformational or protein-misfolding diseases (1,2). Nephrogenic diabetes insipidus (NDI) (3,4), which is characterized by a loss of arginine vasopressin (AVP)-mediated antidiuresis, is one of these diseases. In congenital NDI that results from mutations in the AVPR2 gene that encodes the V2 receptor, most missense mutations are misfolded, trapped in the endoplasmic reticulum, and unable to reach the basolateral cell surface to engage the circulating antidiuretic hormone, AVP (5-14).The natural history of untreated X-linked NDI includes hypernatremia, hyperthermia, mental retardation, and repeated episodes of dehydration in early infancy (15,16). In five new patients who were younger than 1 year and were from North America and in whom we provided molecular testing over the past 12 mo, plasma sodium was in every case Ͼ155 mEq/L at the time of diagnosis. We and others initially thought that close monitoring of infants whose AVPR2 mutations were diagnosed pre-or perinatally not only would prevent episodes of dehydration but also would permit close to normal growth and development. Although a low-sodium diet and distal tubule diuretics prescribed to these patients may achieve a 20 to 30% decrease in urine output (17), the low-sodium diet is difficult to follow, and affected children continue to drink large amounts of water. As a result of a physiologic gastroesophageal reflux and to the large amount of water in their stomach, these children often vomit, and, as a consequence, their nutritional intake is not optimal. There is a need, therefore, for a safe further reduction in urine output. We recently used pharmacologic compounds to rescue misfolded mutant V2 receptors by demonstrating in cultured cells t...

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Section: Discussionmentioning

confidence: 89%

Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus

Bernier¹,

Morello²,

Zarruk³

et al. 2006

Journal of the American Society of Nephrology

Self Cite

215

183

View full text Add to dashboard Cite

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“…At physiological concentrations of 10 Ϫ11 M, the antidiuretic action of vasopressin is mediated via V2 receptors coupled to adenylate cyclase, inducing PKA-mediated AQP2 phosphorylation and its translocation to the apical membrane of principal collecting duct cells (43). AVP not only induces water reabsorption in collecting ducts, but also modulates Na ϩ reabsorption (10,21,42) and K ϩ secretion (4,40).…”

Section: Discussionmentioning

confidence: 99%

Axial heterogeneity of vasopressin-receptor subtypes along the human and mouse collecting duct

Carmosino¹,

Brooks²,

Cai³

et al. 2007

American Journal of Physiology-Renal Physiology

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Vasopressin and vasopressin antagonists are finding expanded use in mouse models of disease and in clinical medicine. To provide further insight into the physiological role of V1a and V2 vasopressin receptors in the human and mouse kidney, intrarenal localization of the receptors mRNA was determined by in situ hybridization. V2-receptor mRNA was predominantly expressed in the medulla, whereas mRNA for V1a receptors predominated in the cortex. The segmental localization of vasopressinreceptor mRNAs was determined using simultaneous in situ hybridization and immunohistochemistry for segment-specific markers, including aquaporin-2, Dolichos biflorus agglutinin, epithelial Na channels, Tamm Horsfall glycoprotein, and thiazide-sensitive Na ϩ -Cl Ϫ cotransporter. Notably, V1a receptor expression was exclusively expressed in V-ATPase/anion exchanger-1-labeled alpha-intercalated cells of the medullary collecting duct in both mouse and human kidney. In cortical collecting ducts, V1a mRNA was more widespread and detected in both principal and intercalated cells. V2-receptor mRNA is diffusely expressed along the collecting ducts in both mouse and human kidney, with higher expression levels in the medulla. These results demonstrate heterogenous axial expression of both V1a and V2 vasopressin receptors along the human and mouse collecting duct. The restricted expression of V1a-receptor mRNA in intercalated cells suggests a role for this receptor in acid-base balance. These findings further suggest distinct regulation of renal transport function by AVP through V1a and V2 receptors in the cortex vs. the medulla. in situ hybridization; vasopressin receptors; intercalated cell ARGININE VASOPRESSIN (AVP) is the key hormone responsible for producing a concentrated urine and is secreted in high concentrations during antidiuresis. At least two different vasopressin

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“…22 In humans, acute dDAVP administration also induced a two-fold reduction in sodium excretion rate that was observed in healthy individuals and in individuals with nephrogenic diabetes insipidus as a result of mutations of AQP2 but not in those with mutations of the V2R. 23 In the isolated, erythrocyte-perfused kidney (a model in which a good oxygenation allows an efficient urine concentration), dDAVP induced a five-fold decrease in the fractional excretion of sodium. 24 Noteworthy, in the present experiments, the antidiuretic effects of dDAVP reached their maximum for low doses, whereas the effects on solute excretion rate rose progressively with increasing doses (Figure 1).…”

Section: V2r Effectsmentioning

confidence: 97%

Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists

Perucca

Bichet²,

Bardoux

et al. 2008

Journal of the American Society of Nephrology

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The mechanisms by which arginine vasopressin (AVP) exerts its antidiuretic and pressor effects, via activation of V2 and V1a receptors, respectively, are relatively well understood, but the possible associated effects on sodium handling are a matter of controversy. In this study, normal conscious Wistar rats were acutely administered various doses of AVP, dDAVP (V2 agonist), furosemide, or the following selective non-peptide receptor antagonists SR121463A (V2 antagonist) or SR49059 (V1a antagonist). Urine flow and sodium excretion rates in the next 6 h were compared with basal values obtained on the previous day, after vehicle treatment, using each rat as its own control. The rate of sodium excretion decreased with V2 agonism and increased with V2 antagonism in a dose-dependent manner. However, for comparable increases in urine flow rate, the V2 antagonist induced a natriuresis 7-fold smaller than did furosemide. Vasopressin reduced sodium excretion at 1 g/kg but increased it at doses Ͼ5 g/kg, an effect that was abolished by the V1a antagonist. Combined V2 and V1a effects of endogenous vasopressin can be predicted to vary largely according to the respective levels of vasopressin in plasma, renal medulla (acting on interstitial cells), and urine (acting on V1a luminal receptors). In the usual range of regulation, antidiuretic effects of vasopressin may be associated with variable sodium retention. Although V2 antagonists are predominantly aquaretic, their possible effects on sodium excretion should not be neglected. In view of their proposed use in several human disorders, the respective influence of selective (V2) or mixed (V1a/V2) receptor antagonists on sodium handling in humans needs reevaluation. 19: 172119: -173119: , 200819: . doi: 10.1681 The mechanisms by which arginine vasopressin (AVP) exerts its antidiuretic and its pressor effects are relatively well understood. On the one hand, AVP improves water conservation by increasing the permeability to water of the renal collecting duct (CD), an effect mediated by the V2 receptors (V2R) and permitted by the insertion in the luminal membrane of principal cells of preformed aquaporin 2 (AQP2) molecules. This allows more water to be reabsorbed when these ducts traverse the hyperosmotic medulla. On the other hand, AVP increases blood pressure (BP) by inducing a vasoconstriction through its binding to V1a receptors (V1aR) expressed in vascular smooth muscle cells. For these two different effects, in vivo studies are in good agreement with the expectations based on results obtained in vitro. J Am Soc NephrolIn contrast, the experiments intended to study the effects of AVP on sodium handling in vitro or in vivo provide results that are difficult to reconcile. In the isolated microperfused CD, V2R activation increases sodium transport, 1 an effect that should reduce sodium excretion in vivo; however, in a number of studies, AVP infusion in animals and humans

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Vasopressin-V2 Receptor Stimulation Reduces Sodium Excretion in Healthy Humans

Cited by 121 publications

References 41 publications

Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus

Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus

Axial heterogeneity of vasopressin-receptor subtypes along the human and mouse collecting duct

Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists

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