Elevated Arginine Vasopressin Levels Research Articles

Elevated arginine vasopressin levels surrogate acute lung injury in acute decompensated heart failure

Elevated arginine vasopressin levels surrogate acute lung injury in acute decompensated heart failure

Vasopressin but Not Oxytocin Responds to Birth Stress in Infants.

ContextBirth triggers a large fetal neuroendocrine response, which is more pronounced in infants born vaginally than in those born by elective cesarean section (ECS). The two related peptides arginine vasopressin (AVP) and oxytocin (OT) play an essential role in peripheral and central stress adaptation and have a shared receptor mediating their function. Elevated cord blood levels of AVP and its surrogate marker copeptin, the C-terminal part of AVP prohormone, have been found after vaginal delivery (VD) as compared to ECS, while release of OT in response to birth is controversial. Moreover, AVP, copeptin and OT have not yet been measured simultaneously at birth.ObjectiveTo test the hypothesis that AVP but not OT levels are increased in infants arterial umbilical cord blood in response to birth stress and to characterize AVP secretion in direct comparison with plasma copeptin.MethodsIn a prospective single-center cross-sectional study, we recruited healthy women with a singleton pregnancy and more than 36 completed weeks of gestation delivering via VD or ECS (cesarean without prior uterine contractions or rupture of membranes). Arterial umbilical cord blood samples were collected directly after birth, centrifuged immediately and plasma samples were frozen. Concentrations of AVP and OT were determined by radioimmunoassay and that of copeptin by ultrasensitive immunofluorescence assay.ResultsA total of 53 arterial umbilical cord blood samples were collected, n = 29 from VD and n = 24 from ECS. Ten venous blood samples from pregnant women without stress were collected as controls. AVP and copeptin concentrations were significantly higher in the VD group than in the ECS group (both p < 0.001), median (range) AVP 4.78 (2.38–8.66) vs. 2.38 (1.79–3.88) (pmol/L), copeptin 1692 (72.1–4094) vs. 5.78 (3.14–17.97), respectively, (pmol/L). In contrast, there was no difference in OT concentrations (pmol/L) between VD and ECS, 6.00 (2.71–7.69) vs. 6.14 (4.26–9.93), respectively. AVP and copeptin concentrations were closely related (Rs = 0.700, p < 0.001) while OT did not show any correlation to either AVP or copeptin. In linear regression models, vaginal delivery and biochemical stress indicators, base deficit and pH, were independent predictors for both AVP and copeptin. OT was not linked to base deficit or pH.ConclusionVaginal birth causes a profound secretion of AVP and copeptin in infants. Whereas AVP indicates acute stress events, copeptin provides information on cumulative stress events over a longer period. In contrast, fetal OT is unaffected by birth stress. Thus, AVP signaling but not OT mediates birth stress response in infants. This unique hormonal activation in early life may impact neurobehavioral development in whole life.

Psychoendocrinology: arginine vasopressin and resilience in patients with major depressive disorder.

There is a burgeoning body of evidence suggesting that arginine vasopressin (AVP) acts as a neuromodulator of the stress response. AVP stimulates the release of adrenocorticotropic hormone, synergistic to corticotropin-releasing hormone, which might explain AVP's role in resilience. Personal hardiness is the bedrock of resilience. Numerous studies have demonstrated elevated plasma levels of AVP in patients with major depressive disorder (MDD), suggesting an etiopathogenetic role as well as a novel therapeutic target. The aim of this study was to examine the relationship between AVP and resilience in patients with MDD and to determine AVP levels in serum of patients with MDD. Forty patients with MDD and 40 healthy control subjects were studied using the Dispositional Resilience (Hardiness) Scale by Barton, the Quality of Life Scale, the Social Readjustment Rating Scale, and the Beck Depression Inventory. Biochemical analysis of plasma levels of AVP, using the enzyme-linked immunosorbent assay (ELISA), was performed for all participants. Levels of AVP were statistically significantly elevated in patients with MDD compared with healthy controls. Psychological hardiness was decreased in patients with MDD compared with healthy controls, a finding also statistically significant. There was a negative correlation between plasma AVP level and psychological hardiness. AVP and psychological hardiness are negatively correlated, reflecting lower stress resilience. AVP levels are indeed higher in patients struggling with MDD.

Signaling of Phoenixin via GPR173 and the Paradox of Increased Vasopressin Secretion in Preeclampsia

Preterm birth affects over 15 million pregnancies annually worldwide, and is associated with severe health risks for both mother and child. The leading cause of clinically indicated, non-spontaneous preterm delivery is preeclampsia, which can lead to maternal and fetal morbidity and mortality if not appropriately and promptly managed. At this time, the only “cure” for preeclampsia is delivery of the fetus and associated products of conception, which presents the clinical challenge of weighing the risks versus benefits of delivery if the pregnancy is preterm. The etiology of preeclampsia is multifactorial and incompletely understood. However, several carefully conducted studies have implicated the paradoxical secretion of the posterior pituitary hormone, arginine vasopressin (AVP) as a potential causative factor. Women with preeclampsia exhibit elevated plasma levels of AVP even in the face of the ongoing hypertension and hyponatremia, and infusion of AVP into pregnant rodents recapitulated multiple features of preeclampsia. The reason for the inappropriately elevated AVP in preeclampsia is unknown. Using a bioinformatic algorithm, our group identified a novel peptide that is conserved across multiple species, and named it phoenixin (PNX) (PMID 22963497). Our published data demonstrate a reproductive role of the peptide, and indicate that hypothalamic and pituitary PNX expression is modulated by sex hormones (PMID 27440717). Likewise, we recently have demonstrated that cerebroventrcular administration of PNX elevated plasma AVP levels in rats (PMID 29364701). Using the RNAscope approach we have now demonstrated that the receptor for PNX, identified by our group as GPR173 (PMID 27440717), is expressed by AVP neurons. Importantly expression of GPR173 increased across pregnancy in the rat hypothalamus coincident with increased AVP production and release (PMID 27330717). These data strongly suggest that PNX, acting through GPR173, could act as a molecular link between sex hormones and AVP secretion. In addition, we now demonstrate that central injection of PNX increases blood pressure, likely through PNX-induced elevation in AVP secretion. We hypothesize that the paradox of increased AVP secretion in the hyponatremic and hypervolemic state of preeclampsia is due to exaggerated PNX signaling in hypothalamus via GPR173 on AVP neurons and possibly on GPR173 expressing neurons in autonomic centers in hindbrain.

Er Shen Wan extract alleviates polyuria and regulates AQP 2 and AVPR 2 in a rat model of spleen-kidney Yang deficiency–induced diarrhea

Ethnopharmacological relevanceEr Shen Wan (ESW), has been empirically used for treating spleen-kidney Yang deficiency (SKYD) syndrome in Traditional Chinese medicine (TCM) for centuries and shows a variety of activities. The medicinal formula is a mixture of two component herbs, Psoraleae Fructus (PF, Bu-Gu-Zhi in Chinese) and Myristicae Semen (MS, Rou-Dou-Kou in Chinese). The current study was designed to evaluate ESWP antidiuretic treatment of polyuria and to explore potential mechanisms of renal water metabolism in the rat model of SKYD-induced diarrhea. Materials and methodsAn animal model of ‘SKYD–induced diarrhea syndrome’ has been established to evaluate the therapeutic effect and action mechanism according to the clinical syndrome and symptoms. The optimal dose (3.5 g/kg) of ESWP was given to rats by gavage for two weeks. Urinary volumes after 24 h were recorded. After the end of the trial, macroscopic morphological and histological examination of the kidney were conducted. Serum levels of Arginine vasopressin (AVP) and aldosterone (ALD) were also measured. Additionally, quantitative real-time RT-PCR (RT-qPCR) and immunohistochemistry (IHC) analyses were performed to clarify the regulation of aquaporin 2 (AQP 2) and arginine vasopressin type 2 receptor (AVPR 2) in the kidney at the gene and tissue expression levels respectively. ResultsAfter the administration of ESWP, urinary output volume after 24 h was found to be significantly decreased in rats. Elevated plasma levels of AVP and ALD were detected. Histological kidney damage appeared to be impeded, and histological disease scores were reduced. In addition, the expression levels of AQP 2 and AVPR 2 were significantly increased. ConclusionThis study suggests that ESWP may elicit significant effects on the treatment of polyuria. Potential mechanisms at least partially involve hormone regulation, and alleviating renal pathological damage. Simultaneously, ESWP may alter renal water absorption by increasing AQP 2 and AVPR 2 expression levels. Thus, the in vivo experimental evidence indicates that ESWP has a therapeutic effect on the SKYD syndrome, which is consistent with its traditional usage.

Urinary concentrating defect in mice lacking Epac1 or Epac2.

cAMP is a universal second messenger regulating a plethora of processes in the kidney. Two downstream effectors of cAMP are PKA and exchange protein directly activated by cAMP (Epac), which, unlike PKA, is often linked to elevation of [Ca2+]i. While both Epac isoforms (Epac1 and Epac2) are expressed along the nephron, their relevance in the kidney remains obscure. We combined ratiometric calcium imaging with quantitative immunoblotting, immunofluorescent confocal microscopy, and balance studies in mice lacking Epac1 or Epac2 to determine the role of Epac in renal water-solute handling. Epac1-/- and Epac2-/- mice developed polyuria despite elevated arginine vasopressin levels. We did not detect major deficiencies in arginine vasopressin [Ca2+]i signaling in split-opened collecting ducts or decreases in aquaporin water channel type 2 levels. Instead, sodium-hydrogen exchanger type 3 levels in the proximal tubule were dramatically reduced in Epac1-/- and Epac2-/- mice. Water deprivation revealed persisting polyuria, impaired urinary concentration ability, and augmented urinary excretion of Na+ and urea in both mutant mice. In summary, we report a nonredundant contribution of Epac isoforms to renal function. Deletion of Epac1 and Epac2 decreases sodium-hydrogen exchanger type 3 expression in the proximal tubule, leading to polyuria and osmotic diuresis.-Cherezova, A., Tomilin, V., Buncha, V., Zaika, O., Ortiz, P. A., Mei, F., Cheng, X., Mamenko, M., Pochynyuk, O. Urinary concentrating defect in mice lacking Epac1 or Epac2.

GRK2/β-arrestin mediates arginine vasopressin-induced cardiac fibroblast proliferation.

Cardiac fibrosis is a pathological feature commonly found in hearts exposed to haemodynamic orneurohormonal stress. Elevated levels of arginine vasopressin (AVP) are closely associated with the progression of heart failure and could be an underlying cause of cardiac fibrosis. The aim of this study is to characterize the effect of AVP on neonatal rat cardiac fibroblasts (NRCFs) and to illustrate its signalling mechanism. The proliferative effect of AVP was assessed by methylthiazolyldiphenyl-tetrazolium assay and 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, and the amounts of cellular signalling proteins α-smooth muscle actin (α-SMA), matrix metalloproteinase (MMP) 2, MMP9, and phosphorylated ERK1/2 were determined by western blotting. AVP, in a time- and concentration-dependent manner, promoted NRCF proliferation and the expression of MMP2 and MMP9. Inhibition of G protein-coupled receptor kinase2 (GRK2) by the inhibitory peptide GRK2-Ct or knock-down of GRK2 suppressed AVP-induced BrdU incorporation and the expression of MMP2 and α-SMA in NRCFs. Moreover, shRNA-mediated silencing of β-arrestin1 or β-arrestin 2 abolished AVP-induced BrdU incorporation and MMP2 expression. AVP-induced NRCF proliferation depended on the phosphorylation of ERK1/2 , and inhibition of GRK2 or silencing of β-arrestins blocked AVP-induced ERK1/2 phosphorylation. The effects of AVP on NRCF proliferation and α-SMA expression were blocked by SR45059, a vasopressin receptor type1A (V1A R) selective antagonist. In conclusion, AVP promotes NRCF proliferation through V1A R-mediated GRK2/β-arrestin/ERK1/2 signalling.

Vasopressin and Vasopressin Antagonists in Heart Failure.

Despite the introduction of multiple new pharmacological agents over the past three decades in the field of heart failure (HF), overall prognosis remains poor. Hyponatremia is prevalent in HF patients and has been suggested as a contributor to poor response to standard therapy. Elevated levels of arginine vasopressin (AVP), a peptide hormone produced in the hypothalamus, play a role in development of hyponatremia, and AVP and its surrogate, copeptin, are related to changes in osmolality, hemodynamics, neuro-hormones as well as in overall outcome in HF patients. Of current pharmacological interest are the selective and non-selective vasopressin receptor antagonists (VRAs), which inhibit vasoconstriction and cardiac remodeling mediated by the V1a receptors in smooth blood vessels, and water retention (increased urine osmolality and decreased water excretion) by increasing aquaporin-2 water channels mediated by the V2 receptors in the renal collecting tubules. The optimal use of VRAs is yet to be determined, especially in patients with congestive HF. Although long-term effects on improvement in mortality have not been shown in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, the only long-term outcome trial to date, many short-term studies indicate beneficial aquaretic- and hemodynamic-effects of the VRAs. In contrast to loop diuretics, these new agents tend to increase urine flow and the excretion of electrolyte-free water (so-called aquaresis) in patients with HF, without substantial changes in sodium or potassium excretion. This chapter reviews the role of AVP and copeptin in HF, and the treatment potential of VRAs in HF.

Tolvaptan for hyponatremia with preserved sodium pool in critically ill patients.

BackgroundHyponatremia is the most common electrolyte disturbance in hospitalized patients, and it represents a well-established risk factor for ICU/hospital mortality. The majority of hyponatremic states are associated with elevated arginine vasopressin levels and a preserved sodium pool. Conventional treatment is either not pathophysiologically oriented or of limited effectiveness. The aim of the present study is to investigate the use of enteral Tolvaptan in critically ill hyponatremic patients.MethodsThis is a retrospective observational study in a general ICU. Patients with preserved sodium pool hyponatremia refractory to conventional therapy were enrolled. The hemodynamic, renal, and hepatic functions, together with sodium and water balance as close as possible to the drug administration and up to 72 h thereafter, were analyzed. The main outcome was a serum sodium increase of ≥ 4 mmol/L in 24 h; secondary endpoints were the ability to maintain serum sodium at 24 and 72 h, a decrease in urine sodium concentration and an increase in sodium-free diuresis.Results38 patients were enrolled. The average dose of enteral Tolvaptan was 7.5 mg. 31 patients (81.6 %) increased their serum sodium >4 mmol/l/24 h; the average increase was 6.7 ± 3.4 mmol/l during the first 24 h (p < 0.001 vs baseline), and this was sustained at 72 h. No adverse effects were reported. Plasma sodium (R = −0.622, p < 0.001), urine sodium (R = −0.345, p < 0.001), central venous oxygen saturation (R = 0.401, p = 0.013), and BUN (R = −0.416, p = 0.031) before Tolvaptan were all significantly correlated with the absolute increase in serum sodium after the administration.ConclusionsEnteral administration of Tolvaptan seems effective in the treatment of hyponatremia with preserved sodium pool in critically ill patients. Even if the study was underpowered to detect significant side effects or complications of unwarranted fast corrections of hyponatremia, we report no complications.Electronic supplementary materialThe online version of this article (doi:10.1186/s13613-015-0096-2) contains supplementary material, which is available to authorized users.

Differential Regulation of Plasma Copeptin Levels in Patients with Heart Failure: A Single-Center Prospective Study

Elevated levels of arginine vasopressin (AVP) have been reported to be involved in the pathogenesis of heart failure (HF). Recent evidence has shown the role of copeptin, the C-terminal fragment of pro-AVP, as a biomarker in patients with HF. However, the relevant information is still limited. Therefore, we evaluated 39 Japanese patients admitted for HF between 2013 and 2015 (23 males and 16 females with an average age of 79.2 years). They were treated according to the Japanese acute HF guideline. Plasma copeptin levels were measured on admission and about 1 week later. The median plasma copeptin levels on admission were 0.5 (0.1-50.6) pmol/L, higher than the normal values (0.24 ± 0.06 pmol/L). Despite the similar clinical severity on admission, the patients showed great variability in plasma copeptin levels. They were divided into three groups (13 patients/group) according to plasma copeptin levels on admission: highest (> 30.8 pmol/L), midrange, and lowest (< 0.2 pmol/L) groups. Initial treatment improved HF symptoms in 37 of 39 patients, with the two unresponsive patients in the lowest group. Notably, plasma copeptin responses to initial treatment were different, depending on admission copeptin levels. The initial treatment significantly decreased copeptin levels in the highest group, but increased copeptin levels in the lowest group. By contrast, patients in the midrange group showed no significant changes. Thus, the treatment appears to restore the plasma copeptin levels. In conclusion, HF is a complex syndrome with the differential integration of stimulatory and inhibitory inputs to the AVP/copeptin secretory system.

Distinct neurohumoral biomarker profiles in children with hemodynamically defined orthostatic intolerance may predict treatment options.

Studies of adults with orthostatic intolerance (OI) have revealed altered neurohumoral responses to orthostasis, which provide mechanistic insights into the dysregulation of blood pressure control. Similar studies in children with OI providing a thorough neurohumoral profile are lacking. The objective of the present study was to determine the cardiovascular and neurohumoral profile in adolescent subjects presenting with OI. Subjects at 10-18 yr of age were prospectively recruited if they exhibited two or more traditional OI symptoms and were referred for head-up tilt (HUT) testing. Circulating catecholamines, vasopressin, aldosterone, renin, and angiotensins were measured in the supine position and after 15 min of 70° tilt. Heart rate and blood pressure were continuously measured. Of the 48 patients, 30 patients had an abnormal tilt. Subjects with an abnormal tilt had lower systolic, diastolic, and mean arterial blood pressures during tilt, significantly higher levels of vasopressin during HUT, and relatively higher catecholamines and ANG II during HUT than subjects with a normal tilt. Distinct neurohumoral profiles were observed when OI subjects were placed into the following groups defined by the hemodynamic response: postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension (OH), syncope, and POTS/syncope. Key characteristics included higher HUT-induced norepinephrine in POTS subjects, higher vasopressin in OH and syncope subjects, and higher supine and HUT aldosterone in OH subjects. In conclusion, children with OI and an abnormal response to tilt exhibit distinct neurohumoral profiles associated with the type of the hemodynamic response during orthostatic challenge. Elevated arginine vasopressin levels in syncope and OH groups are likely an exaggerated response to decreased blood flow not compensated by higher norepinephrine levels, as observed in POTS subjects. These different compensatory mechanisms support the role of measuring neurohumoral profiles toward the goal of selecting more focused and mechanistic-based treatment options for pediatric patients with OI.

Is the association of serum sodium with mortality in patients with type 2 diabetes explained by copeptin or NT-proBNP? (ZODIAC-46).

Hyponatremia has been associated with an increased mortality risk in the general population. Diabetes is a condition predisposing for elevated levels of arginine vasopressin (AVP) and heart failure, both common causes of hyponatremia. These factors, however, are also associated with an increased mortality risk. We aimed to investigate whether serum sodium is associated with cardiovascular and all-cause mortality in type 2 diabetes and whether these associations could be explained by copeptin, a surrogate for AVP, or NT-proBNP, a marker for heart failure. Patients with type 2 diabetes participating in the observational ZODIAC study were included. Cox regression analyses were used to investigate the association of serum sodium with mortality. We included 1068 patients (age 67 ± 12 years, 45% male, serum sodium 142 ± 3 mmol/L). After 15 years of follow-up, 519 patients (49%) died, with 225 cardiovascular deaths (21%). In univariable analyses, serum sodium, copeptin, and NT-proBNP were all significantly associated with cardiovascular and all-cause mortality. These associations remained significant after combination of these markers in a multivariable model. Serum sodium and NT-proBNP remained significantly associated with mortality after further adjustment for potential confounders, whereas copeptin lost significance after adjustment for SCr and ACR. Low serum sodium was associated with an increased risk of cardiovascular and all-cause mortality in type 2 diabetes. Moreover, these associations were not explained by copeptin and NT-proBNP. Whether low serum sodium itself leads to poor outcome or is a marker for (unidentified) co-morbidity severity or use of specific medications remains to be elucidated.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Vasopressin Antagonists for Patients With Acute Heart Failure: Interpreting New Clinical and Translational Data

Elevated levels of arginine vasopressin (AVP) are associated with a worse prognosis and the development of hyponatremia in patients with heart failure (HF). This observation led to the development of AVP receptor antagonists for the treatment of HF patients. Although AVP receptor antagonists increase serum sodium, their overall benefits in patients with HF have been at best modest, and recent data raise concerns about their safety in patients with acute HF and low serum sodium.

Association of Arginine Vasopressin Levels With Outcomes and the Effect of V2 Blockade in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction

Background— Arginine vasopressin (AVP) levels are elevated in proportion to heart failure severity and are associated with higher cardiovascular mortality in ambulatory patients. However, the relationship between baseline and trends in AVP with outcomes in patients hospitalized for worsening heart failure with reduced ejection fraction is unclear. Methods and Results— The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial investigated the effects of tolvaptan in patients with worsening heart failure and ejection fraction ≤40%. The present analysis examined baseline and follow-up AVP levels in 3196 EVEREST patients with valid AVP measurements. Coprimary end points included all-cause mortality, and the composite of cardiovascular mortality or heart failure hospitalization. Median follow-up was 9.9 months. Times to events were compared with univariate log-rank tests and multivariable Cox regression models, adjusted for baseline risk factors. After adjusting for baseline covariates, elevated AVP levels were associated with increased all-cause mortality (hazard ratio, 1.33; 95% confidence interval, 1.13–1.55) and cardiovascular mortality or heart failure hospitalization (hazard ratio, 1.23; 95% confidence interval, 1.08–1.39). There was no interaction of baseline AVP with treatment assignment in terms of survival ( P =0.515). Tolvaptan therapy increased the proportion of patients with elevated AVP ( P &lt;0.001), but this had no effect on mortality (hazard ratio, 0.95; 95% confidence interval, 0.72–1.24). Conclusions— Elevated baseline AVP level was independently predictive of mortality, but did not identify a group of patients who had improved outcomes with tolvaptan treatment. Tolvaptan treatment increased AVP levels during follow-up, but this incremental increase was not associated with worsened outcomes.

Role of Estrogen in the Urinary Concentrating Mechanism

The anti‐diuretic hormone, arginine vasopressin (AVP) concentrates urine by enhancing water, salt and urea re‐absorption in the renal collecting duct. We hypothesized that estrogen may play a key role in the response of the renal collecting duct to AVP. We used CD1 male and female mice (8‐weeks old, n=8–10) and water restricted (WR, 48 hr) to increase endogenous AVP levels. In another study, we used CD1 female mice which were ovariectomized (OVX) for 5 weeks. Urine osmolality in WR female mice (4874 mOsm/kg.H20) compared to WR males (3962 mOsm/kg.H2O) was significantly higher (25%). Consistent with elevated AVP levels during WR, medullary AQP2 was significantly increased in females (mRNA, 2.12‐fold and protein, 151%). However, following ovariectomy neither AQP2 nor AQP3 mRNA expression levels were altered versus control mice. WR had a similar response in either gender in increasing medullary mRNA expression of the urea transporters (UTA1, UTA3) but decreasing the sodium channels (ENaCβ and ENaCγ). Our data suggests that females are more sensitive to the actions of AVP in the renal medulla which results in higher water re‐absorption from urine possibly through increased expression of AQP2 channels leading to higher urine osmolality. However loss of estrogen (OVX) is not associated with a change in AQP2 expression in females. Support: DK073611 (HLB), NSF ADVANCE (HLB, JF) and HL07249 (SC).

Hyponatremia: a problem-solving approach to clinical cases

Hyponatremia, defined as a serum sodium concentration of <135 mmol/L, often develops as a consequence of elevated levels of arginine vasopressin (AVP) hormone. AVP elevation can occur in a number of common clinical conditions, including syndrome of inappropriate secretion of AVP, volume depletion, postoperative states, heart failure, cirrhosis, neuroendocrine disorders and trauma. A history of concurrent illness and medication use, assessment of extracellular fluid volume as well as measurement of serum and urine osmolality and urine sodium concentration will help to establish the primary underlying causes. Presence or absence of significant neurologic signs and symptoms must guide treatment. Symptomatic hyponatremia must be treated promptly with 3% hypertonic saline to increase the serum sodium by 1-2 mmol/L per hour until symptoms abate, or a total magnitude of correction of 12 mmol/L in 24 hours or 18 mmol/L in 48 hours is achieved. Initial infusion rate (ml/kg per hour) can be estimated by body weight (kg) x desired rate of increase in sodium (mmol/L per hour). An overly rapid increase in sodium (>12 mmol/L per 24 hours) may result in serious neurologic injury. Fluid restriction and loop diuretic are frequently employed to treat volume overload. Vasopressin receptor antagonists provide prompt and effective water diuresis and increase in serum sodium concentration in both euvolemic and hypervolemic hyponatremia. In this review article, the author introduces a problem-solving approach to dissect the different clinical cases with hyponatremia and presents simple algorithms for the evaluation and management of hyponatremia that are useful at the bedside to improve quality, safety and cost-effectiveness of the patient's care.

Hyponatremia in Hospitalized Patients: The Potential Role of Tolvaptan

Hyponatremia (typically defined as serum sodium level < 135 mEq/L) is a common electrolyte abnormality among hospitalized patients. Whether present at admission or acquired during hospitalization, hyponatremia is associated with higher mortality and longer hospital stays. Failure to adequately investigate and treat hyponatremia may also be associated with adverse outcomes. The presence and severity of clinical symptoms largely depend on the rate and extent of the decline in serum sodium; rapid or large decreases may cause serious neurologic complications. The approach to treatment depends on the presence and severity of symptoms, the timing of their onset, the underlying etiology, and the patient's volume status. Patients with euvolemic or hypervolemic hyponatremia usually have inappropriately elevated levels of arginine vasopressin, which stimulates water reabsorption even in the presence of low serum osmolality. Tolvaptan is an orally active, selective V2-receptor antagonist that blocks the effects of arginine vasopressin in the renal collecting duct to promote aquaresis without increasing sodium or potassium excretion; as a result, it increases serum sodium in a controlled manner. Tolvaptan offers a mechanism-based treatment option for patients with euvolemic or hypervolemic hyponatremia who have serum sodium levels < 125 mEq/L or persistent symptoms resistant to fluid restriction.

An Intervention Study of Oral Versus Intravenous Hypertonic Saline Administration in Ultramarathon Runners With Exercise-Associated Hyponatremia: A Preliminary Randomized Trial

To determine whether asymptomatic exercise-associated hyponatremia (EAH) in ultramarathon runners can be corrected with either oral or intravenous (IV) 3% hypertonic saline (HTS). Prospective with randomization into 1 of 2 intervention arms. Western States (161 km) Endurance Run, California. Forty-seven finishers in the event consented to be screened to identify those with EAH, defined as plasma sodium ([Na]p) <135 mmol/L at race end. Participants with EAH but without symptoms were randomized to receive a single 100 mL dose of either oral or IV 3% HTS. Blood was drawn before intervention and at 60 minutes postintervention to measure [Na]p, and concentrations of plasma potassium, proteins, and arginine vasopressin (AVP). Body mass, percent total body water, and percent body fat were measured prerace and postrace using impedance scales. Change in [Na]p. Fourteen of 47 consenting finishers (30%) had EAH. Eight agreed to be randomized into the intervention protocol. Only in the IV group did [Na]p change significantly (from 130.8 to 134.6 mmol/L) over the 60 minutes post-HTS administration. Elevated AVP concentrations were seen at race finish in both the groups and remained so after HTS treatment. In this preliminary trial, prompt administration of a 100 mL bolus of IV 3% HTS was associated with normalization of [Na]p in asymptomatic EAH, but a similar effect was not demonstrated for the same dose orally. Elevated AVP levels were observed and may play a part in the development of EAH but were not suppressed significantly by either intervention.

Clues to renal sodium retention

expansion of extracellular volume manifests as peripheral and pulmonary edema in chronic heart failure (CHF) patients and can lead to hospitalizations and death ([1][1], [10][2]). Stimulation of the autonomic nervous system, elevated levels of arginine vasopressin (AVP), and activation of the renin-