Elevated Vasopressin Levels Research Articles

Neuroendocrinology of bone.

The past decade has witnessed significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone in primary and secondary osteoporosis. Recent breakthroughs have primarily emerged from identifying disease-causing mutations and phenocopying human bone disease in rodents. Notably, using genetically-modified rodent models, disrupting the reciprocal relationship with tropic pituitary hormone and effector hormones, we have learned that pituitary hormones have independent roles in skeletal physiology, beyond their effects exerted through target endocrine glands. The rise of follicle-stimulating hormone (FSH) in the late perimenopause may account, at least in part, for the rapid bone loss when estrogen is normal, while low thyroid-stimulating hormone (TSH) levels may contribute to the bone loss in thyrotoxicosis. Admittedly speculative, suppressed levels of adrenocorticotropic hormone (ACTH) may directly exacerbate bone loss in the setting of glucocorticoid-induced osteoporosis. Furthermore, beyond their established roles in reproduction and lactation, oxytocin and prolactin may affect intergenerational calcium transfer and therefore fetal skeletal mineralization, whereas elevated vasopressin levels in chronic hyponatremic states may increase the risk of bone loss.. Here, we discuss the interaction of each pituitary hormone in relation to its role in bone physiology and pathophysiology.

Congenital nephrogenic diabetes insipidus with a novel variant of AVPR2 gene mutation: A case report

ABSTRACT Congenital nephrogenic diabetes insipidus (CNDI) is a rare genetic disorder characterized by impaired water reabsorption despite normal or elevated levels of antidiuretic hormone. We report a 6-month-old male with classical symptoms of CNDI, such as fever, excessive thirst, polyuria, and failure to thrive. Laboratory investigations revealed hypernatremia, low urine osmolality, and a lack of response to a vasopressin challenge, confirming the diagnosis. Genetic testing identified a hemizygous base pair deletion in the AVPR2 gene, leading to a frameshift mutation and premature protein truncation. Treatment strategies, including hydrochlorothiazide and amiloride therapy, aim to manage symptoms and improve quality of life. Long-term management involves monitoring growth, hydration status, and genetic counseling for affected families. This case highlights the importance of early recognition and management of CNDI to prevent long-term sequelae. Further research into genetic variations and novel therapeutic approaches is warranted to improve outcomes for these children.

Upregulated Angiotensin Ia Receptors in the Hypothalamic Paraventricular Nucleus Sensitize Neuroendocrine Vasopressin Release and Blood Pressure in a Rodent Model of Polycystic Kidney Disease

Introduction: Angiotensin (Ang) II signalling in the hypothalamic paraventricular nucleus (PVN) via Ang type-1a receptors (AT1R) regulates vasopressin release and sympathetic nerve activity – two effectors of blood pressure regulation. We determined the cellular expression and function of AT1R in the PVN of a rodent model of polycystic kidney disease (PKD), the Lewis polycystic kidney (LPK) rat, to evaluate its contribution to blood pressure regulation and augmented vasopressin release in PKD. Methods: PVN AT1R gene expression was quantified with fluorescent in situ hybridization in LPK and control rats. PVN AT1R function was assessed with pharmacology under urethane anaesthesia in LPK and control rats instrumented to record arterial pressure and sympathetic nerve activity. Results: AT1R gene expression was upregulated in the PVN, particularly in corticotrophin-releasing hormone neurons, of LPK versus control rats. PVN microinjection of Ang II produced larger increases in systolic blood pressure in LPK versus control rats (36 ± 5 vs. 17 ± 2 mm Hg; p < 0.01). Unexpectedly, Ang II produced regionally heterogeneous sympathoinhibition (renal: −33%; splanchnic: −12%; lumbar: no change) in LPK and no change in controls. PVN pre-treatment with losartan, a competitive AT1R antagonist, blocked the Ang II-mediated renal sympathoinhibition and attenuated the pressor response observed in LPK rats. The Ang II pressor effect was also blocked by systemic OPC-21268, a competitive V_1A receptor antagonist, but unaffected by hexamethonium, a sympathetic ganglionic blocker. Discussion/Conclusion: Collectively, our data suggest that upregulated AT1R expression in PVN sensitizes neuroendocrine release of vasopressin in the LPK, identifying a central mechanism for the elevated vasopressin levels present in PKD.

Empagliflozin Accelerates Escape from Vasopressin in Rats

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) consists of unregulated, elevated vasopressin levels and can lead to hyponatremia. Vasopressin escape is the body’s defense mechanism to limit hyponatremia. The sodium‐glucose transporter (SGLT‐2) inhibitor, empagliflozin, was identified as a treatment for hyponatremia; however, the mechanism of empagliflozin’s effect is unclear. This project investigates empagliflozin’s impact on vasopressin escape in rats with the hypothesis that empagliflozin accelerates escape via key transport protein alteration. Rats were implanted with vasopressin mini‐pumps to mimic SIADH. The first cohort consisted of male rats and a second cohort compared responses in female rats. On day 2, half the rats were given empagliflozin (~15 mg/kg) via diet. Rats were sacrificed on days 7 or 14. Blood and kidney tissue were collected. Total Aquaporin‐2 (AQP2), pSer‐Aquaporin‐2, and NKCC2 were analyzed by western blot. At day 7, serum sodium levels for the female rats were: empagliflozin 110.1+1.7 mmol/L vs 93.3+1.1 mmol/L for the controls (n=5, p&lt;0.001). Serum sodium levels for the male rats were: empagliflozin 136.0+4.8 mmol/L vs 121.4+3.0 mmol/L for the controls (n=4, p&lt;0.05). NKCC2 abundance in the empagliflozin group was 60% lower than control on day 7 (n=5, p&lt;0.05) for female rats, and 77% lower than control in male rats (n =4, p&lt;0.001). Because changes in the AQP2 levels were similar between the sexes, these data were combined. Total AQP2 abundance was 2.3 fold increased in the empagliflozin group on day 7 and 8 fold greater in the empagliflozin group at day 14 (n=9) compared to the control group. Both pSer256‐AQP2 and pSer261‐AQP2 were increased in the empagliflozin groups at both 7 and 14 days vs their respective control groups. pSer256‐AQP2 increased 2.1 (day 7) and 8.5 fold (day 14); pSer261‐AQP2 increased 3.2 fold (day 7) and 5.0 fold (day 14) (n=9/group). We conclude that empagliflozin accelerates vasopressin escape during SIADH primarily through a decrease in NKCC2 abundance in both male and female rats. This will hasten recovery from hyponatremia in SIADH.

Role of vasopressin signaling in the pathogenesis of diabetic nephropathy

The diabetic kidney disease (also known as diabetic nephropathy) is a major complication of diabetes mellitus and also the most common cause of chronic kidney disease. Elevated plasma levels of vasopressin are consistently observed in patients with either type 1 and type 2 diabetes mellitus and in animal models of diabetes mellitus. A role of enhanced vasopressin signaling in progression of the diabetic nephropathy to chronic kidney disease has been suggested in several epidemiological studies but the underlying pathogenetic mechanisms remain largely unclear and are the subject of current scientific research.

Purinergic signaling is enhanced in the absence of UT-A1 and UT-A3.

ATP is an important paracrine regulator of renal tubular water and urea transport. The activity of P2Y2, the predominant P2Y receptor of the medullary collecting duct, is mediated by ATP, and modulates urinary concentration. To investigate the role of purinergic signaling in the absence of urea transport in the collecting duct, we studied wild‐type (WT) and UT‐A1/A3 null (UT‐A1/A3 KO) mice in metabolic cages to monitor urine output, and collected tissue samples for analysis. We confirmed that UT‐A1/A3 KO mice are polyuric, and concurrently observed lower levels of urinary cAMP as compared to WT, despite elevated serum vasopressin (AVP) levels. Because P2Y2 inhibits AVP‐stimulated transport by dampening cAMP synthesis, we suspected that, similar to other models of AVP‐resistant polyuria, purinergic signaling is increased in UT‐A1/A3 KO mice. In fact, we observed that both urinary ATP and purinergic‐mediated prostanoid (PGE2) levels were elevated. Collectively, our data suggest that the reduction of medullary osmolality due to the lack of UT‐A1 and UT‐A3 induces an AVP‐resistant polyuria that is possibly exacerbated by, or at least correlated with, enhanced purinergic signaling.

An Angiotensin-Responsive Connection from the Lamina Terminalis to the Paraventricular Nucleus of the Hypothalamus Evokes Vasopressin Secretion to Increase Blood Pressure in Mice.

Blood pressure is controlled by endocrine, autonomic, and behavioral responses that maintain blood volume and perfusion pressure at levels optimal for survival. Although it is clear that central angiotensin type 1a receptors (AT1aR; encoded by the Agtr1a gene) influence these processes, the neuronal circuits mediating these effects are incompletely understood. The present studies characterize the structure and function of AT1aR neurons in the lamina terminalis (containing the median preoptic nucleus and organum vasculosum of the lamina terminalis), thereby evaluating their roles in blood pressure control. Using male Agtr1a-Cre mice, neuroanatomical studies reveal that AT1aR neurons in the area are largely glutamatergic and send projections to the paraventricular nucleus of the hypothalamus (PVN) that appear to synapse onto vasopressin-synthesizing neurons. To evaluate the functionality of these lamina terminalis AT1aR neurons, we virally delivered light-sensitive opsins and then optogenetically excited or inhibited the neurons while evaluating cardiovascular parameters or fluid intake. Optogenetic excitation robustly elevated blood pressure, water intake, and sodium intake, while optogenetic inhibition produced the opposite effects. Intriguingly, optogenetic excitation of these AT1aR neurons of the lamina terminalis also resulted in Fos induction in vasopressin neurons within the PVN and supraoptic nucleus. Further, within the PVN, selective optogenetic stimulation of afferents that arise from these lamina terminalis AT1aR neurons induced glutamate release onto magnocellular neurons and was sufficient to increase blood pressure. These cardiovascular effects were attenuated by systemic pretreatment with a vasopressin-1a-receptor antagonist. Collectively, these data indicate that excitation of lamina terminalis AT1aR neurons induces neuroendocrine and behavioral responses that increase blood pressure.SIGNIFICANCE STATEMENT Hypertension is a widespread health problem and risk factor for cardiovascular disease. Although treatments exist, a substantial percentage of patients suffer from "drug-resistant" hypertension, a condition associated with increased activation of brain angiotensin receptors, enhanced sympathetic nervous system activity, and elevated vasopressin levels. The present study highlights a role for angiotensin Type 1a receptor expressing neurons located within the lamina terminalis in regulating endocrine and behavioral responses that are involved in maintaining cardiovascular homeostasis. More specifically, data presented here reveal functional excitatory connections between angiotensin-sensitive neurons in the lamina terminals and vasopressin neurons in the paraventricular nucleus of the hypothalamus, and further indicate that activation of this circuit raises blood pressure. These neurons may be a promising target for antihypertensive therapeutics.

Trust the heart to save the brain: changes in heart rate patterns have the potential to be a biomarker for hypoxic ischaemic brain injury.

Trust the heart to save the brain: changes in heart rate patterns have the potential to be a biomarker for hypoxic ischaemic brain injury.

Early sinusoidal heart rate patterns and heart rate variability to assess hypoxia-ischaemia in near-term fetal sheep.

•Therapeutic hypothermia needs to be started as early as possible in the first 6h after acute injury caused by hypoxia-ischaemia (HI), but the severity and timing of HI are often unclear. In this study we evaluated whether measures of heart rate variability (HRV) might provide early biomarkers of HI. •The duration but not magnitude of suppression of HRV power and conversely increased sample entropy of the heart rate were associated with severity of HI, such that changes in the first 3h did not discriminate between groups. •Relative changes in HRV power bands showed different patterns between groups and therefore may have the potential to evaluate the severity of HI. •Aberrant fetal heart rate patterns and increased arginine vasopressin levels in the first hour after moderate and severe HI were correlated with loss of EEG power after 3days' recovery, suggesting potential utility as early biomarkers of outcome. Therapeutic hypothermia is partially neuroprotective after acute injury caused by hypoxia-ischaemia (HI), likely because the timing and severity of HI are often unclear, making timely recruitment for treatment challenging. We evaluated the utility of changes in heart rate variability (HRV) after HI as biomarkers of the timing and severity of acute HI. Chronically instrumented fetal sheep at 0.85 gestational age were exposed to different durations of umbilical cord occlusion to produce mild (n=6), moderate (n=8) or severe HI (n=8) or to sham occlusion (n=5). Heart rate (HR) and HRV indices were assessed until 72h after HI. All HI groups showed suppressed very low frequency HRV power and elevated sample entropy for the first 3h; more prolonged changes were associated with greater severity of HI. Analysis of relative changes in spectral power showed that the moderate and severe groups showed a shift towards higher HRV frequencies, which was most marked after severe HI. This shift was associated with abnormal rhythmic HR patterns including sinusoidal patterns in the first hour after HI, and with elevated plasma levels of arginine vasopressin, which were correlated with subsequent loss of EEG power by day3. In conclusion, absolute changes in HRV power in the first 3h after acute HI were not significantly related to the severity of HI. The intriguing relative shift in spectral power towards higher frequencies likely reflects greater autonomic dysfunction after severe HI. However, sinusoidal HR patterns and elevated vasopressin levels may have utility as biomarkers of severe HI.

Cardiac hypertrophy elevates serum levels of fibroblast growth factor 23

Several experimental studies have shown that fibroblast growth factor 23 (FGF23) induces left ventricular hypertrophy (LVH). However, the opposite directional relationship, namely a potential effect of LVH on FGF23, remains uncertain. Here we evaluated the effects of LVH on FGF23 using cardiomyocyte-specific calcineurin A transgenic mice. At six weeks, these mice showed severe LVH, with elevated levels of serum intact FGF23. FGF23 levels were elevated in cardiomyocytes, but not osteocytes, of the transgenic animals. Moreover, transverse aortic constriction also upregulated myocardial FGF23 expression in wild type mice. The promoter region of the FGF23 gene contains two putative nuclear factors of activated T cells (NFAT)-binding sites, with NFAT1 activating the promoter in a proximal NFAT-binding site dependent manner. Neither serum, urinary, or fractional excretion values of calcium and phosphate nor serum levels of 1,25(OH)2 vitamin D were different between wild type and transgenic mice. Moreover, the renal expression of FGF receptors and α-Klotho was comparable. However, plasma levels of antidiuretic hormone were significantly increased in the transgenic mice, and aquaporin-2 immunohistochemical staining was mainly positive in the apical membrane of the collecting duct, compared to a primarily cytoplasmic staining in wild type mice. Real-time PCR analyses of kidney CYP27B1 and CYP24A1 expression in wild type mice showed that exogenous antidiuretic hormone blocked FGF23's actions on these vitamin D activating or inactivating enzymes. Finally, the renal resistance of transgenic mice to FGF23 was partly overcome by tolvaptan. Thus, LVH in transgenic mice is associated with an increase in myocardial and serum intact FGF23, with the kidneys being protected against FGF23 excess by elevated antidiuretic hormone levels.

Vasopressin's Role in Stress Response and Glucose Homeostasis in a Pig Model of Endotoxin‐Induced Inflammation

Both acute stress hyperglycemia and uncontrolled hypoglycemia may serve as indices of disease severity in critically ill patients, yet the mechanisms behind altered glucose control in inflammatory diseases such as acute sepsis is poorly understood. Evidence of the ability of vasopressin to mediate central and peripheral glucose regulation via V1b and V1a receptors has mounted over the years, but the role of vasopressin in glucose homeostasis during sepsis, is unclear. We hypothesized that vasopressin is involved in glycemic control in endotoxin‐induced inflammation seen in sepsis but that this role may be overshadowed by vasopressin's primary role of maintaining blood pressure in the face of septic shock. Thus, we used a piglet model of endotoxin‐induced pulmonary hypertension in the absence of systemic shock to better understand the relationship between vasopressin and glucose homeostasis in a hypoxemia‐induced inflammatory state. The intent was to study effects of vasopressin separate from its role in blood pressure regulation.After hemodynamic equilibration following catheterization of anesthetized Yorkshire cross piglets (8 kg body weight), baseline mean arterial pressure, cardiac output, and blood gasses were assessed, and blood was obtained for measurement of glucose (BG), vasopressin, cortisol, insulin, glucagon, and cytokine profiles. Liver and pancreatic blood flows were assessed via colored microsphere method. E. coli endotoxin (7,500–50,000 units) was administered intravenously to achieve pulmonary hypertension (evidenced by a pulmonary to systemic vascular resistance ratio increase of 120%), which decreased arterial oxygenation to a PaO2 of 78 ± 5 mm Hg without systemic hypotension(ETX, n=16). Piglets were followed for 11 hours after endotoxin administration. Results were compared against control piglets who did not receive endotoxin (CON, n=7). In CON group, all hemodynamics and biomarkers measured remained constant. Endotoxin caused an increase in pro‐inflammatory markers TNFα, IL‐1ra, and IL‐6. Blood glucose levels were elevated at baseline in both CON (189±11 mg/dL) and ETX (199±9 mg/dL), with corresponding elevated vasopressin levels (106 ± 17 pg/ml; and 78 ± 9 pg/ml in CON and ETX, respectively) likely due to piglet susceptibility to anesthesia induction stress. Both BG and vasopressin levels decreased over the duration of the experiment, with no significant changes in cortisol. Liver blood flow tended to decrease and pancreatic blood flow to increase with time in both CON and ETX. Interestingly, insulin increased 6‐fold with endotoxin and then returned toward baseline by 2 hours after endotoxin administration. Glucagon increased after endotoxin and remained elevated over baseline 11 hours later.Stepwise multiple regression analysis was used to determine relationships between BG and vasopressin, cortisol, insulin, glucagon, TNFα, IL‐1ra, and IL‐6, liver and pancreatic blood flows, hemodynamics, and blood oxygenation. BG was most strongly positively associated with circulating vasopressin, liver blood flow and insulin, and negatively correlated with glucagon (r= 0.72, p&lt;0.001). Our results support an important role of vasopressin as a stress hormone regulator of glucose homeostasis both in control conditions and in the response to endotoxin‐induced stress.Support or Funding InformationThis project was funded by the US Army Medical Command. The views expressed in this abstract are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hyponatremia in children with acute respiratory infections: A reappraisal.

Hyponatremia (<135 mmol/L), typically associated with an elevated anti-diuretic hormone level, is common among children admitted with bronchiolitis, pneumonia, or pulmonary exacerbation of cystic fibrosis. The main consequences of acute hyponatremia include cerebral edema and Ayus-Arieff pulmonary edema. A widespread belief is that, in children with pneumonia or bronchiolitis, hyponatremia results from inappropriate anti-diuresis. By contrast, the pathogenic role of extracellular fluid volume depletion or decreased effective circulating blood volume is underscored. Considering the prevalence of hyponatremia, sodium determination is advised on admission in children diagnosed with bronchiolitis, pneumonia, or pulmonary exacerbation of cystic fibrosis. There is no necessity to do anything beyond reassessing the appropriateness of fluid therapy in cases with mild (130-134 mmol/L) hyponatremia. In children with sodium <130 mmol/L, the underlying etiology is sometimes evident from history and physical findings. Given that clinical assessment of fluid volume status is difficult in hyponatremia, further laboratory evaluation is often required in these patients. An increase in sodium level ≤6 mmol/L per day is currently considered the therapeutic goal in all cases. Emergency correction with a 2 mL/kg body weight bolus of 3.0% saline over 10-15 min intravenously is advised in cases with severe symptoms due to hyponatremia and in cases with symptoms, even if mild, due to a rapid-onset (<48 h) of hyponatremia (two additional doses are administered if the patient's condition does not improve).

Participation of Antidiuretic Hormone (ADH) in Asthma Exacerbations Induced by Psychological Stress via PKA/PKC Signal Pathway in Airway-Related Vagal Preganglionic Neurons (AVPNs)

Aims: Present study was performed to examine whether ADH was implicated in psychological stress asthma and to explore the underlying molecular mechanism. Methods: We not only examined ADH levels in the cerebrospinal fluid (CSF) via radioimmunoassay, but also measured ADH receptor (ADHR) expression in airway-related vagal preganglionic neurons (AVPNs) through real-time PCR in all experimental mice. Western blotting was performed to evaluate the relationship between ADH and PKA/PKC in psychological stress asthma. Finally, the role of PKA/PKC in psychological stress asthma was analyzed. Results: Marked asthma exacerbations were noted owing to significantly elevated levels of ADH and ADHR after psychological stress induction as compared to OVA alone (asthma group). ADHR antagonists (SR-49095 or SR-121463A) dramatically lowered higher protein levels of PKAα and PKCα induced by psychological stress as compared to OVA alone, suggesting the correlation between ADH and PKA/PKC in psychological stress asthma. KT-5720 (PKA inhibitor) and Go-7874 (PKC inhibitor) further directly revealed the involvement of PKA/PKC in psychological stress asthma. Some notable changes were also noted after employing PKA and PKC inhibitors in psychological stress asthma, including reduced asthmatic inflammation (lower eosinophil peroxidase (EPO) activity, myeloperoxidase (MPO) activity, immunoglobulin E (IgE) level, and histamine release), substantial decrements in inflammatory cell counts (eosinophils and lymphocytes), and decreased cytokine secretion (IL-6, IL-10, and IFN-γ), indicating the involvement of PKA/PKC in asthma exacerbations induced by psychological stress. Conclusion: Our results strongly suggested that ADH participated in psychological stress-induced asthma exacerbations via PKA/PKC signal pathway in AVPNs.

Vasopressin Receptor Regulation in Maintaining Potassium Homeostasis in a Sus scrofa Model of Hemorrhagic Shock

We previously showed that elevated potassium (K)levels seen with severe hemorrhage appear to stimulate enhanced vasopressin(VP) release, and that in turn, elevated VP levels help correct hyperkalemia by increasing renal tubular K secretion. We thus tested whether brain VP receptors controlling vasopressin release were regulated synergistically with kidney VP receptors whichmodulated renal K excretion. We hypothesized that brain VP receptor up‐regulation may enable positive feedback for K‐stimulated augmentation of VP responsiveness in hemorrhage, and that renal VP receptor expression would reflect VP receptor mediated action on renal K excretion. Thus, in anesthetized Yorkshire cross pigs (n=35) we compared plasma VP (pVP) and plasmaK (pK) before, at the end of hemorrhage (30 ml/kg over 20 minutes), and after resuscitation, against mRNA expression of V1aR, V1bR, and V2R receptors in brain and kidney tissues collected after resuscitation. Multiple regression analysis showed that increased pVP at the end of hemorrhage positively correlated (p&lt;0.05) with expression of V1aR and V1bR in the hypothalamus, V1bR in the anterior pituitary, and V2R in the renal cortex. Plasma K levels at the end of resuscitation were negatively correlated (p&lt;0.05) with renalcortex V2R expression. In a different group of control animals that did not undergo hemorrhage, pVP and pK remained unchanged throughout. Results suggest that an up‐regulation of V1a and V1b receptors in the brain contributed to an amplified VP response in hemorrhage. In addition, VP appears to stimulate renal V2R expression to lower pK levels and maintain K homeostasis via a renal V2R‐mediated negative feedback mechanism.Support or Funding InformationThis project was supported by U.S. Army Medical Resarch and Materiel Command Congressionally Directed Medical Research Program grant #DAMD17‐03‐1‐0072. The views expressed in this abstract are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.

Management of hyponatremia in various clinical situations.

Hyponatremia is the most common electrolyte abnormality in both inpatient and outpatient settings. The condition primarily results from the combination of impaired free water excretion due to elevated vasopressin levels in conjunction with a source of free water intake. Recent studies have revealed that even mild and asymptomatic hyponatremia is associated with deleterious consequences. It is an independent risk factor for mortality and is also associated with increased length of hospitalization and hospital costs. Even mild chronic hyponatremia can result in subtle neurologic impairment and bone demineralization, leading to falls and associated bone fractures in the elderly. Hyponatremia can be a difficult condition to treat, with varying therapeutic strategies based on the etiology, severity, duration, and extent of neurologic symptoms. The ideal magnitude of correction is also controversial, as both inadequate therapy and overly aggressive therapy can result in neurologic injury. Formulas that have been devised to aid in the treatment of hyponatremia can be inaccurate in that they fail to adequately account for the renal response to therapy. Hyponatremic encephalopathy is the most serious complication of hyponatremia, and can result in permanent neurologic impairment or death if left untreated. Individuals most at risk for developing hyponatremic encephalopathy are postmenarchal women, children under 16years of age, patients with central nervous system disease or hypoxemia, and patients in the postoperative setting. The preferred therapy for hyponatremic encephalopathy is a 100-ml bolus of 3% sodium chloride (513mEq/L) administered in repeated doses until symptoms reverse, with the goal of increasing the serum sodium 5-6mEq/L. Vasopressin (V2) antagonists (vaptans) are not appropriate for the management of acute hyponatremic encephalopathy, as the onset of action is not sufficiently rapid and the increase in sodium is not predictable. Vaptans are primarily indicated for the treatment of asymptomatic hyponatremia due to SIAD that is refractory to conventional measures.

Hyponatremia and anti-diuretic hormone in Legionnaires’ disease

BackgroundMedical textbooks often list Legionnaires’ disease as a differential diagnosis of the syndrome of inappropriate secretion of anti-diuretic hormone (ADH) (SIADH), but evidence supporting this association is largely lacking. We tested the hypothesis whether hyponatremia in patients with Legionnaires’ disease would be caused by increased CT-ProVasopressin.MethodsWe measured CT-ProVasopressin and sodium levels in a prospective cohort of 873 pneumonia patients from a previous multicentre study with 27 patients having positive antigen tests for Legionella pneumophila.ResultsPatients with Legionnaires’ disease more frequently had low sodium levels (Na < 130 mmol/L) (44.4% vs 8.2%, p < 0.01), but similar mean CT-ProVasopressin levels (pmol/l) (39.4 [±7] vs 51.2 [±2.7], p = 0.43) as compared to patients with pneumonia of other etiologies. In patients with Legionnaires’ disease, CT-ProVasopressin levels showed a positive correlation with sodium (r = 0.42, p < 0.05). Independent of pneumonia etiology, CT-ProVasopressin correlated significantly with the pneumonia severity index (r = 0.56, p < 0.05), ICU admission (adjusted odds ratio per decile, 95% CI) (1.6, 1.2 - 2.0), and 30-day-mortality (1.8, 1.3 - 2.4).ConclusionWhile Legionnaires’ disease was associated with hyponatremia, no concurrent increase in CT-ProVasopressin levels was found, which argues against elevated ADH levels as the causal pathway to hyponatremia. Rather, Vasopressin precursors were upregulated as response to stress in severe disease, which seems to overrule the osmoregulatory regulation of ADH.

Intravenous Maintenance Fluids Revisited

Intravenous maintenance fluid therapy aims to replace daily urinary and insensible losses for ill children in whom adequate enteric administration of fluids is contraindicated or infeasible. The traditional determination of fluid volumes and composition dates back to Holliday and Segar's seminal article from 1957, which describes the relationship between weight, energy expenditure, and physiologic losses in healthy children. Combined with estimates of daily electrolyte requirements, this information supports the use of the hypotonic maintenance fluids that were widely used in pediatric medicine. However, using hypotonic intravenous fluids in a contemporary hospitalized patient who may have complex physiologic derangements, less caloric expenditure, decreased urinary output, and elevated antidiuretic hormone levels is often not optimal; evidence over the last 2 decades shows that it may lead to an increased incidence of hyponatremia. In this review, we present the evidence for using isotonic rather than hypotonic fluids as intravenous maintenance fluid.

Role of vasopressin in maintenance of potassium homeostasis in severe hemorrhage

Uncontrolled elevation in plasma potassium within minutes of rapid blood volume loss is associated with mortality and distinguishes nonsurvivors of severe hemorrhage from survivors. In a pig model of severe hemorrhage, we discovered that along with a sharp increase in plasma potassium coincident with a shut down of urine flow, nonsurvivors also had an insufficient vasopressin response to hemorrhage. In contrast, survivors did have elevated vasopressin levels in response to hemorrhage and maintained plasma potassium within normal limits. While it has been demonstrated for some time that vasopressin can influence secretion of potassium in the distal nephron, the magnitude of this effect and conditions under which this contributes to physiological modulation of potassium excretion has yet to be defined. In this review, we assess the evidence that would suggest that vasopressin plays a key role in modulating potassium excretion and is important in the regulation of potassium homeostasis during hemorrhage.

Controlled and Cardiac-Restricted Overexpression of the Arginine Vasopressin V1A Receptor Causes Reversible Left Ventricular Dysfunction Through Gα q -Mediated Cell Signaling

[Arg8]-vasopressin (AVP) activates 3 G-protein-coupled receptors: V1A, V2, and V1B. The AVP-V1A receptor is the primary AVP receptor in the heart; however, its role in cardiac homeostasis is controversial. To better understand AVP-mediated signaling in the heart, we created a transgenic mouse with controlled overexpression of the V1A receptor. The V1A receptor transgene was placed under the control of the tetracycline-regulated, cardiac-specific α-myosin heavy chain promoter (V1A-TG). V1A-TG mice had a normal cardiac function phenotype at 10 weeks of age; however, by 24 weeks of age, tetracycline-transactivating factor/V1A-TG mouse hearts had reduced cardiac function, cardiac hypertrophy, and dilatation of the ventricular cavity. Contractile dysfunction was also observed in isolated adult cardiac myocytes. When V1A receptor transgene was induced to be expressed in adult mice (V1A-TG(Ind)), left ventricular dysfunction and dilatation were also seen, albeit at a later time point. Because the V1A receptor mediates cell signaling through Gα(q) protein, we blocked Gα(q) signaling by crossing tetracycline-transactivating factor/V1A mice with transgenic mice that expressed a small inhibitory peptide against Gα(q). Gα(q) blockade abrogated the development of the heart failure phenotype in tetracycline-transactivating factor/V1A-TG mice. The heart failure phenotype could be reversed by administration of doxycycline. Our results demonstrate a role for V1A-mediated signaling in the development of heart failure and support a role for V1A blockade in the treatment of patients with elevated levels of vasopressin.

New Options for Old Diseases:Aquaretics (Vasopressin Receptor Antagonists)

There are multiple receptors for vasopressin (ADH) named the V1a, V1b, and V2 receptors. The V2 receptors primarily mediate the antidiuretic response, while V1a and V1b receptors principally cause vasoconstriction and mediate adrenocorticotropin release, respectively. Some oral formulations of vasopressin receptor antogonists tolvaptan, satavaptan, and lixivaptan — are selective for the V2 receptor, while an intravenous agent, conivaptan, blocks both the V2 and V1a receptors and is approved for the management of patients with euvolemic hyponatremia (mostly due to SIADH) and hypervolemic hyponatremia. The vasopressin receptor antagonists produce a selective water diuresis without affecting sodium and potassium excretion. The ensuing loss of free water will tend to correct the hyponatremia in patients with SIADH. Elevated levels of vasopressin may contribute to the increase in systemic vascular resistance in heart failure via stimulation of the V1a receptor, which is found on vascular smooth muscle cells, and also promote renal water retention via the V2 receptor, leading to the development of hyponatremia. At present, conivaptan is the only vasopressin receptor antagonist approved for use. In patients with heart failure, conivaptan both raises the serum sodium concentration and, via blockade of the V1a receptors, diminishes afterload, possibly improving systemic hemodynamics. V2 receptor antagonists (aquaretics) have a critical role in the management of the hyponatremia of SIADH, heart failure, ascites of hepatic failure and they may also diminish the cystogenesis in the early stages of polycystic kidney disease.