Arginine Vasopressin Secretion Research Articles

Diagnosis of central diabetes insipidus using a vasopressin radioimmunoassay during hypertonic saline infusion.

Central diabetes insipidus (CDI) is characterized by polyuria and polydipsia caused by impairment of arginine vasopressin (AVP) secretion. In this study, we evaluated plasma AVP concentrations during a hypertonic saline infusion test using a new AVP radioimmunoassay (RIA) which is now available in Japan. Thirteen control subjects, mostly with hypothalamo-pituitary disease but without CDI, and 13 patients with CDI were enrolled in the study. Whether or not subjects had CDI was determined based on the totality of clinical data, which included urine volumes and osmolality. Regression analysis of plasma AVP and serum Na concentrations revealed that the gradient was significantly lower in the CDI group than in the control group. The area under the receiver-operating-characteristic (ROC) curve was 0.99, and the <0.1 gradient cut-off values for the simple regression line to distinguish CDI from control had a 100% sensitivity and a 77% specificity. The ROC analysis with estimated plasma AVP concentrations at a serum Na concentration of 149 mEq/L showed that the area under the ROC curve was 1.0 and the <1.0 pg/mL cut-off values of plasma AVP had a 99% sensitivity and a 95% specificity. We conclude that measurement of AVP by RIA during a hypertonic saline infusion test can differentiate patients with CDI from those without CDI with a high degree of accuracy. Further investigation is required to confirm whether the cut-off values shown in this study are also applicable to a diagnosis of partial CDI or a differential diagnosis between CDI and primary polydipsia.

Measurement of a Surrogate Biomarker for Arginine Vasopressin Secretion in Association with Physiometric and Molecular Biomarkers of Aging.

A number of physiological changes are known to occur with aging, including increased fat mass, increased insulin resistance, and changes in the levels of circulating biomarkers such as lipids, growth factors, and hormones. Here, we present protocols for physiometric assessments, as well as measurements of circulating biomarkers of hormonal and growth factor function in individuals over the age range of 18-52years. We also test for potential gender differences in the outcome measures.

130: Selective serotonin reuptake inhibitors and vasopressin: an intersection of depression and preeclampsia

High circulating copeptin, a marker for arginine vasopressin (AVP) secretion, is associated with human depression and preeclampsia (PreE). Higher AVP secretion has been shown to be an important etiologic agent in both PreE and depression. Data suggest a lower incidence of PreE in women with depression who are currently taking selective serotonin reuptake inhibitors (SSRIs). While the biomechanism is unknown, SSRIs may decrease copeptin/AVP levels. The objective of this study is to investigate associations among copeptin (vasopressin secretion), depression symptoms, SSRIs, and PreE during pregnancy and postpartum. Overall, we hypothesize that SSRIs may modulate preeclampsia incidence in depressed pregnant women by decreasing vasopressin secretion. In this case-control study, 233 banked clinically annotated maternal plasma samples from the Iowa Maternal Fetal Tissue Bank (IRB #200910784) were used from pregnant women with (PHQ-9 score > 10) and without (PHQ-9 score < 10) depression symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) scores. Copeptin was measured using a commercial enzyme-linked immunosorbent assay. Chi-square, t-tests, and linear regression were performed with alpha=0.05. Thirty-six percent (n=84) of women studied were at risk for depression (PHQ >10). Consistent with previous data, the mean CopeptinLog 10 in women with PreE was significantly higher in comparison to controls (2.1 ± 0.56 vs. 1.93 ± 0.48, p< 0.001). Further, mean CopeptinLog10 is lower in women with a PHQ > 10 (1.77 ± 0.60 vs. 1.94 ± 0.47, p< 0.001). Linear regression demonstrates that copeptin levels decreases for each 0.043 increase of depression symptom score (p< .033). This decrease in copeptin was associated with a higher SSRI usage in PHQ >10 group (25.9% vs. 12.2%, p=008) Further, a lower incidence of PreE was observed in this PHQ >10, higher SSRI group in comparison to the PHQ< 10 group (2.4% vs. 8.8%, p=0.05). Our findings suggest SSRIs could decrease copeptin/AVP secretion levels in pregnancy which in turn may decrease the risk of preeclampsia.

Association of Copeptin With Sense of Coherence in Individuals With Varying Degrees of Glucose Intolerance.

This study aimed to examine the association of serum copeptin levels, a surrogate marker of arginine-vasopressin secretion with sense of coherence (SOC) among individuals with varying degrees of glucose intolerance. The study was conducted in 120 age- and sex-matched individuals who were divided equally into three groups. Group A included individuals with normal glucose tolerance; group B, individuals with prediabetes (impaired glucose tolerance and/or impaired fasting glucose); and group C, individuals with newly detected diabetes mellitus (NDDM). SOC, perceived stress scale (PSS), copeptin, anthropometry, glycated hemoglobin, insulin, and salivary cortisol were measured in all study participants. The SOC score was found to be significantly lower in group C compared with group A (p < .001) and group B (p = .006). The PSS score was found to be significantly higher in group C compared with group A (p = .002). No significant difference was found between PSS scores of groups B and C (p = .25). Copeptin levels were found to be significantly higher in group C compared with group A (p = .016). Copeptin levels in group C did not differ significantly from those in group B (p = .056). There was a significant negative correlation between serum copeptin levels and SOC in the NDDM group C (r = 0.31, p = .048) and overall (r = 0.19, p = .037). In multiple regression analysis, SOC emerged as the variable with the strongest association with 2-hour postprandial plasma glucose and glycated hemoglobin. Individuals with NDDM displayed significantly higher serum copeptin levels that inversely correlated with SOC, a global measure of stress coping ability.

Management of Nocturia and Nocturnal Polyuria

Nocturnal polyuria (NP), characterized by overproduction of urine at night (greater than 20%-33% of total 24-hour urine volume depending on age), is a major contributing factor in most nocturia cases. Nocturia can be caused by intake, urological, nephrological, hormonal, sleep, and cardiovascular factors. It is therefore important to accurately diagnose both the type of nocturia and the potentially associated medical conditions to determine appropriate treatment. Diagnostic tools, in addition to a thorough history and physical examination, include voiding/bladder diary analyses and questionnaires to diagnose nocturia type (NP, diminished nocturnal/global bladder capacity, global polyuria) and causative factors. Lifestyle modifications are the first intervention implemented for the management of nocturia and NP but, as symptoms progress, such measures may be insufficient, and pharmacotherapy may be initiated. While drugs for benign prostatic hyperplasia and overactive bladder have demonstrated statistically significant reductions in nocturnal voids, patients often fail to achieve a clinically meaningful response. Antidiuretic treatment is warranted for patients with nocturia due to NP because, in many patients, it treats the underlying cause (ie, insufficient secretion of antidiuretic hormone arginine vasopressin) that leads to overproduction of urine at night and has been shown to provide statistically significant reductions in nocturnal voids. Desmopressin, a synthetic analog of arginine vasopressin, is the only antidiuretic treatment indicated specifically for nocturia due to NP. Overall, the pathophysiology of NP is complex and differs from that of other types of nocturia. A multidisciplinary approach is necessary to effectively diagnose and manage this bothersome condition.

A PUZZLING DIAGNOSIS: UNUSUAL LARYNGEAL CARCINOMA PRESENTING AS PARANEOPLASTIC SYNDROME

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: The Syndrome of Inappropriate Antidiuretic Hormone (SIADH) is one of the most common causes of euvolemic hyponatremia. The most common malignancy associated with SIADH is small cell lung cancer. We present a case of a patient with SIADH secondary to well differentiated squamous cell carcinoma of the vocal cords. CASE PRESENTATION: A 62-year-old Caucasian male with a history of alcohol abuse and 80 pack-year smoking history presented with recurrent hyponatremia. He was initially admitted to the ICU for altered mental status due to hyponatremia of 111 which was thought to be a combination of beer potomania/SIADH/low solute intake. He required hypertonic saline boluses twice and a one dose of DDAVP to prevent overcorrection, along with fluid restriction with an improvement of Na to 132. (Image 1) Chest CT was obtained that did not reveal any malignancy. He was discharged with fluid restriction and follow up with his PCP. At his follow up, he was found to have again developed severe hyponatremia of 112. He was admitted again to the ICU for appropriate normalization of sodium, required isotonic saline and then fluid restriction. SIADH was confirmed by low Serum Osmolality at 245mosm/kg, high Urine osmolality of 502mosm/kg, Urine sodium of 41mEq/l,and normal serum Potassium of 4.3mEq/l along with low serum uric acid of 3.4mg/dl. Upon review of the CT chest with the radiologist he had some density on his left aryepiglottic fold. Upon closer discussion with him, he endorsed progressive hoarseness for the past year to the point of losing his voice. He also lost about 20 pounds over the last year, with a 10-pound weight loss over the past month. CT neck with IV contrast showed a 4.5cm laryngeal mass (Image 2) and direct laryngoscopy and microscopic laryngoscopy with biopsy of the tumor on the left vocal cord with multiple biopsies taken of the terminal vocal cords finally revealed squamous cell carcinoma. He is scheduled to follow up with oncology, ENT and radiation oncology after a PET scan for tumor staging to decide on further treatment with concurrent chemotherapy and radiation. DISCUSSION: There is a possible relationship between the tumor mass burden and the severity of the hyponatremia. This has been shown in another laryngeal carcinoma but was not seen with recurrence of the tumor.[1] The mechanisms leading to the associated hyponatremia could have been related to tumor ADH productions or other factors yet unknown.[2] CONCLUSIONS: SIADH is well known to occur with squamous cell lung cancer. Other types of squamous cell carcinomas are known to cause SIADH as a paraneoplastic syndrome, particularly squamous cell carcinoma of the tongue.[3] It has not been well documented to be from squamous cell carcinoma of vocal cords. Reference #1: Talmi YP, Hoffman HT, McCabe BF (1992) Syndrome of inappropriate secretion of arginine vasopressin in patients with cancer of the head and neck. Ann Otol Rhinol Laryngol 101:946-949 Reference #2: Roth Y, Lightman SL, Kronenberg J. (1994). Hyponatremia associated with laryngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol 251: 183-185 Reference #3: Zohar Y, Talmi YP, Finkelstein Y, Nobel M, Gafter U (1991) Syndrome of inappropriate antidiuretic hormone secretion in cancer of the head and neck. Ann Otol Rhinol Laryngol 100:341-344 DISCLOSURES: No relevant relationships by Sofia Adamidi, source=Web Response no disclosure on file for Steven Lamontagne; No relevant relationships by Preeyanka Sundar, source=Web Response

Brain-Derived Neurotrophic Factor and Supraoptic Vasopressin Neurons in Hyponatremia

Hyponatremia due to elevated arginine vasopressin (AVP) secretion increases mortality in liver failure patients. The mechanisms causing dysregulation of AVP secretion are unknown. Our hypothesis is that inappropriate AVP release associated with liver failure is due to increased brain-derived neurotrophic factor (BDNF) in the supraoptic nucleus (SON). BDNF diminishes GABA_A inhibition in SON AVP neurons by increasing intracellular chloride through tyrosine receptor kinase B (TrkB) activation and downregulation of K+/Cl– cotransporter 2 (KCC2). This loss of inhibition could increase AVP secretion. This hypothesis was tested using shRNA against BDNF (shBDNF) in the SON in bile duct ligated (BDL) male rats. All BDL rats had significantly increased liver weight (p < 0.05; 6–9) compared to shams. BDL rats with control ­shRNA injections (BDL scrambled [SCR]) developed hyponatremia with increased plasma AVP and copeptin (CPP; all p < 0.05; 6–9) compared to sham groups. This is the first study to show that phosphorylation of TrkB is significantly increased along with significant decrease in phosphorylation of KCC2 in BDL SCR rats compared to the sham rats (p < 0.05;6–8). Knockdown of BDNF in the SON of BDL rats (BDL shBDNF) significantly increased plasma osmolality and hematocrit compared to BDL SCR rats (p < 0.05; 6–9). The BDL shBDNF rats had significant (p < 0.05; 6–9) decreases in plasma AVP and CPP concentration compared to BDL SCR rats. The BDNF knockdown also significantly blocked the increase in TrkB phosphorylation and decrease in KCC2 phosphorylation (p < 0.05; 6–8). The results indicate that BDNF produced in the SON contributes to increased AVP secretion and hyponatremia during liver failure.

Abstract P3038: Reduced Renal Responsiveness and Altered Fluid Volume in an African Green Monkey ( Chlorocebus Aethiops Sabaeus) Preeclampsia Model

Preeclampsia is a prevalent, multi-organ complication of late pregnancy characterized by de novo gestational hypertension (GH) and proteinuria. Our group has demonstrated that arginine vasopressin (AVP) secretion, as measured by copeptin, is predictive of the development of human preeclampsia. Altered regulation of AVP early in gestation has been demonstrated in human preeclampsia. Recently, the nonhuman primate, African Green Monkey (AGM) has been characterized as a spontaneous, translational model of chronic hypertension, GH and preeclampsia. AGMs also have similar gestation and placentation to humans. We hypothesized that the AGM model of preeclampsia would demonstrate similar AVP related plasma and fluid volume changes as humans with preeclampsia. AGMs (n=10) were anesthetized with ketamine during late third trimester of pregnancy to obtain physiologic and obstetric measurements. Compared to normotensive (NT, n=4) third trimester pregnant females, GH females (n=6) had higher systolic and diastolic blood pressures (106 ± 5 vs. 162 ± 11 mmHg; 46 ± 4 vs. 86 ± 12, p=0.01) with no differences in heart rates (158 ± 4 vs. 169 ± 18 bpm, p=0.64). Consistent with other models of GH and preeclampsia, the GH AGM had decreased offspring birthweight in comparison to NT offspring (352 ± 11 vs. 275 ± 12 g, p=0.01). Further, plasma osmolality of GH females was higher in late third trimester compared to NT females (286 ± 11 vs. 312 ± 9 mOsm, p=0.05). This higher plasma osmolality was associated with the GH female’s trend to higher AVP secretion as measured by copeptin (2 ± 2 vs. 4 ± 1 ng/g, p=0.280). In contrast to human pregnancies, late third trimester plasma [Na + ] of GH females was elevated compared to NT females (149 ± 3 vs. 157 ± 2 mMol/L, p=0.04). These data demonstrate that that the AGM model of preeclampsia replicates the plasma volume restricted findings consistent with human preeclampsia and possible insensitivity to control by AVP. Ongoing studies in early pregnancy will quantify changes in renal function during preeclampsia, differences in fluid volumes among NT and GH AGMs, and further the understanding of hormonal regulation of kidney function in the pathogenesis of preeclampsia in this translational AGM nonhuman primate.

Diabetes insipidus.

Diabetes insipidus (DI) is a disorder characterized by excretion of large amounts of hypotonic urine. Central DI results from a deficiency of the hormone arginine vasopressin (AVP) inthe pituitary gland or the hypothalamus, whereas nephrogenic DI results from resistance to AVP in the kidneys. Central and nephrogenic DI are usually acquired, but genetic causes must be evaluated, especially if symptoms occur in early childhood. Central or nephrogenic DI must bedifferentiated from primary polydipsia, which involves excessive intake of large amounts of water despite normal AVP secretion and action. Primary polydipsia is most common in psychiatric patients and health enthusiasts but the polydipsia in a small subgroup of patients seems to be dueto an abnormally low thirst threshold, a condition termed dipsogenic DI. Distinguishing between the different types of DI can be challenging and is done either by a water deprivation test or by hypertonic saline stimulation together with copeptin (or AVP) measurement. Furthermore, a detailed medical history, physical examination and imaging studies are needed toensure an accurate DI diagnosis. Treatment of DI or primary polydipsia depends on the underlying aetiology and differs in central DI, nephrogenic DI and primary polydipsia.

Antidiuretic Hormone and Serum Osmolarity Physiology and Related Outcomes: What Is Old, What Is New, and What Is Unknown?

Although the physiology of sodium, water, and arginine vasopressin (AVP), also known as antidiuretic hormone, has long been known, accumulating data suggest that this system operates as a more complex network than previously thought. English-language basic science and clinical studies of AVP and osmolarity on the development of kidney and cardiovascular disease and overall outcomes. Apart from osmoreceptors and hypovolemia, AVP secretion is modified by novel factors such as tongue acid-sensing taste receptor cells and brain median preoptic nucleus neurons. Moreover, pharyngeal, esophageal, and/or gastric sensors and gut microbiota modulate AVP secretion. Evidence is accumulating that increased osmolarity, AVP, copeptin, and dehydration are all associated with worse outcomes in chronic disease states such as chronic kidney disease (CKD), diabetes, and heart failure. On the basis of these pathophysiological relationships, an AVP receptor 2 blocker is now licensed for CKD related to polycystic kidney disease. From a therapeutic perspective, fluid intake may be associated with increased AVP secretion if it is driven by loss of urine concentration capacity or with suppressed AVP if it is driven by voluntary fluid intake. In the current review, we summarize the literature on the relationship between elevated osmolarity, AVP, copeptin, and dehydration with renal and cardiovascular outcomes and underlying classical and novel pathophysiologic pathways. We also review recent unexpected and contrasting findings regarding AVP physiology in an attempt to explain and understand some of these relationships.

Pathophysiological Mechanisms of Nocturia and Nocturnal Polyuria: The Contribution of Cellular Function, the Urinary Bladder Urothelium, and Circadian Rhythm

Alterations to arginine vasopressin (AVP) secretion, the urinary bladder urothelium (UT) and other components of the bladder, and the water homeostasis biosystem may be relevant to the pathophysiology of nocturia and nocturnal polyuria (NP). AVP is the primary hormone involved in water homeostasis. Disruption to the physiological release of AVP or its target effects may relate to several urinary disturbances. Circadian dysregulation and the effects of aging, for example, the development of oxidative stress and mitochondrial dysfunction, may play a role in nocturia voiding symptoms. The urinary bladder UT not only acts as a highly efficient barrier that is maintained during the filling and voiding of the urinary bladder, but is also capable of sensory and transducer function through a network of functional receptors and ion channels that enable reciprocal communication between UT cells and neighboring elements of the bladder mucosa and wall. Functional components of the UT (eg, claudins and receptors or ion channels) play important roles in AVP-mediated water homeostasis. These components and functions involved in water homeostasis, as well as kidney function, may be affected by the aging process, including age-related mitochondrial dysfunction. The characteristics of NP are discussed and the association between NP and circadian rhythm is examined in light of reports that suggest that nocturia should be considered as a type of circadian dysfunction. Many possible pathologic mechanisms that underlie nocturia and NP have been identified. Future studies may provide further insight into pathophysiology with the hope of identifying new treatment modalities.

NMDA receptor-dependent signalling pathways regulate arginine vasopressin expression in the paraventricular nucleus of the rat

The antidiuretic hormone arginine vasopressin (AVP) regulates water homeostasis, blood pressure and a range of stress responses. It is synthesized in the hypothalamus and released from the posterior pituitary into the general circulation upon a range of stimuli. While the mechanisms leading to AVP secretion have been widely investigated, the molecular mechanisms regulating AVP gene expression are mostly unclear. Here we investigated the neurotransmitters and signal transduction pathways that activate AVP gene expression in the paraventricular nucleus (PVN) of the rat using acute brain slices and quantitative real-time PCR. We show that stimulation with l-glutamate robustly induced AVP gene expression in acute hypothalamic brain slices containing the PVN. More specifically, we show that AVP transcription was stimulated by NMDA. Using pharmacological treatments, our data further reveal that the activation of ERK1/2 (PD184352), CaMKII (KN-62) and PI3K (LY294002; 740 Y-P) is involved in the NMDA-induced AVP gene expression in the PVN. Together, this study identifies NMDA-mediated cell signalling pathways that regulate AVP gene expression in the rat PVN.

OR06-4 Brain Derived Neurotrophic Factor in the Regulation of Supraoptic Vasopressin Neurons in Development of Hyponatremia

Dilutional hyponatremia due to elevated arginine vasopressin (AVP) secretion increases mortality in patients with liver failure. The current conventional therapies are palliative and frequently ineffective. The neural mechanisms causing dysregulation of AVP secretion are not completely understood. Based on previous studies, we hypothesis that inappropriate AVP release associated with liver failure is due to increased Brain Derived Neurotrophic Factor (BDNF) in the supraoptic nucleus (SON). BDNF diminishes GABAA inhibition in SON AVP neurons by increasing intracellular chloride ([Cl]i) through tyrosine receptor kinase B (TrkB) activation and downregulation of K+/Cl- co-transporter 2 (KCC2). This loss of inhibition could increase AVP secretion. To test this hypothesis, chronic bile duct ligated (BDL) rats, a model of dilutional hyponatremia associated with liver failure, were injected with shRNA to prevent increased BDNF in the SON. Adult male Sprague Dawley rats were bilaterally injected in the SON with AAV2- shRNA-BDNF-mCherry or AAV2- shRNA-SCR-mCherry. After two weeks, the rats had BDL or sham ligation surgery. Four weeks later, SON regions were collected by punches for western blot analysis. Fluid accumulation, liver and body weight were recorded to verify if the rats develop liver failure. Blood samples were collected to measure plasma osmolality, hematocrit, and circulating AVP concentration. Data were analyzed by one-way ANOVA with Bonferroni comparisons. The BDL rats had significant increases in liver to body weight ratio (p< 0.05; 6-9) compared to sham rats indicating liver failure and ascites with bile duct ligation. BDL rats with scrambled injections (BDL SCR) developed hyponatremia with significant decrease in plasma osmolality and hematocrit along with significant increase in plasma AVP concentration (all p< 0.05; 6-9) compared to sham groups. This is the first study to show that phosphorylation of TrkB (pTrkBY515) is significantly increased along with significant decrease in phosphorylation of KCC2 (pKCC2S940) in BDL SCR rats compared to the sham rats (p< 0.05; 6-8). Knockdown of BDNF in the SON of BDL rats (BDL shBDNF) prevented the rats from developing hyponatremia and caused significant increase in plasma osmolality and hematocrit compared to BDL SCR rats (p< 0.05; 6-9). The BDL shBDNF rats had significant (p< 0.05; 6-9) decreases in plasma AVP concentration compared to BDL SCR rats. shBDNF injections in the SON of BDL rats significantly blocked the increase in TrkB phosphorylation and decrease in KCC2 phosphorylation (p< 0.05;6-8) associated with bile duct ligation. mCherry expression was used to verify the specificity of stereotaxic injections. Rats that did not had successful virus injections in the SON were analyzed separately. The results indicate that BDNF produced in the SON contributes to increased AVP secretion and hyponatremia during liver cirrhosis.

MON-442 Evaluation of Copeptin as a Surrogate for AVP in the Diagnosis of Water Metabolism Disorders

Arginine vasopressin (AVP) plays a key role in maintaining fluid balance and vascular tone and is useful in diagnosing diabetes insipidus (DI) and polyuria-polydipsia. Central DI is characterized by decreased AVP secretion leading to polyuria and polydipsia caused by diminished renal ability to concentrate urine. Alternatively, nephrogenic DI is characterized by a decrease in the ability to concentrate urine because of resistance of the distal nephron to AVP action. While AVP measurement can be diagnostic, reliable measurement of AVP can be hindered by several factors. AVP is tightly bound to platelets and is influenced by their number and incomplete removal, as well as pre-analytical processing. In addition, AVP is also highly unstable in isolated plasma - even at frozen temperatures. Copeptin comprises the C-terminal portion of the AVP precursor “pre-pro-vasopressin”. Equimolar amounts of AVP and copeptin released from this precursor during prohormone processing. Unlike the AVP molecule, copeptin is stable at room and refrigerated temperatures. In the current study, our objective was to confirm that copeptin can serve as a sensitive surrogate marker for AVP release in diagnosis. Our laboratory validated the B·R·A·H·M·S™ Copeptin proAVP assay on the automated KRYPTOR® platform. The measuring principle of the assay is based on Time-Resolved Amplified Cryptate Emission (TRACE®) technology, which measures the signal that is emitted with time delay from an immunocomplex. The molecules of copeptin present in the patient samples are sandwiched between the antibodies of the immunoassay. The intensity of the signal is proportional to the amount of copeptin. Extensive comparison studies, between AVP and copeptin, were conducted during the assay validation process. Approximately 245 patient samples previously tested for AVP were also tested in the copeptin assay. Using the respective reference intervals (RI) for AVP and copeptin, there was a 78.3% clinical concordance between the 2 assays; 53 samples (21.6%) were clinically discordant. Of the 245 patients, 4.5% (11 ) were above the AVP RI and 22.9% (56) were above the copeptin RI. Correlation plots showed a large degree of scatter between AVP and copeptin, which likely reflects the dissimilar stabilities of the two analytes. In conclusion, validation data suggest that there is clinical concordance for most patients tested using copeptin and AVP assays.

Sex Difference and Hormones in the Regulation of Vasopressin Secretion during Dilutional Hyponatremia

Dilutional hyponatremia due to elevated arginine vasopressin (AVP) secretion increases mortality in patients with liver failure. No previous studies have addressed sex difference in dilutional hyponatremia in animal models of liver failure. The aim of this study is to investigate sex difference in dilutional hyponatremia and the effect of ovarian hormones in AVP secretion. We have used chronic bile duct ligated (BDL) rats, a model of dilutional hyponatremia associated with liver failure.Adult male Sprague Dawley rats, female Sprague Dawley rats and ovariectomized (OVX) female rats were used. After two weeks, the rats had BDL or sham ligation surgery. Four weeks later, the brains were processed for immunohistochemistry analysis of FosB and AVP expression. Blood samples were collected to measure plasma osmolality, hematocrit, circulating estradiol and copeptin concentration. Copeptin was used as biomarker for plasma AVP. Liver weight, body weight, and fluid accumulation were recorded to verify if the rats developed liver failure and ascites. Data were analyzed by one ANOVA with Bonferroni post hoc comparisons.All the BDL rats had significant increase in liver to body weight ratio compared to sham rats indicating liver failure and ascites with bile duct ligation. Male BDL rats had hyponatremia along with significant increases in plasma copeptin and FosB expression in Supraoptic AVP neurons compared to male shams (all p&lt;0.05; 5–7). Unlike male BDL rats, the female BDL rats did not become hyponatremia and did not had increases Supraoptic AVP neuron activation and copeptin secretion compared to female sham.Ovariectomy significantly decreased plasma estradiol concentration in sham rats compared to intact female sham (p&lt; 0.05; 6–10). However, circulating estradiol concentration was significantly elevated in ovariectomized BDL (OVX BDL) rats compared to the ovariectomized sham (OVX sham) and female sham rats (p&lt;0.05; 6–10). To identify the source of estradiol contributing to the observed increase in OVX BDL rats, adrenal glands were collected at the end of protocol. Adrenal gland steroids were extracted to measure estradiol and its precursors, testosterone and DHEA concentration.The OVX BDL rats had significantly increased adrenal estradiol along with significant decrease in adrenal testosterone and DHEA compared to OVX sham rats (all p&lt; 0.05; 6–7). Plasma osmolality, hematocrit and copeptin concentration were not different between OVX BDL and OVX sham rats. Our results show that unlike male BDL rats, female BDL rats did not develop hyponatremia, supraoptic AVP neuron activation, or increased copeptin secretion compared to sham ligated females. Female OVX BDL rats did not become hyponatremia or increased copeptin secretion compared to female OVX sham rats. It is possible that the increase in adrenal estradiol compensated for the lack of ovarian estrogens in OVX BDL rats. Additional experiments will be required to determine the effects of estrogen in this model.Support or Funding InformationSupported by R01 HL119458 and 18PRE34060035This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sex Differences in Expression of Methionine Sulfoxide Reductase A in Hypothalamic Paraventricular Nucleus in Rats with Heart Failure after Myocardial Infarction

Myocardial‐infarction (MI)‐induced heart failure (HF) leads to elevated oxidative stress and proinflammatory cytokine (PIC) expression in the brain and arginine vasopressin (AVP) secretion, contributing to sympathetic excitation and the progression of HF. We recently reported that female rats with HF following MI have less PIC and AVP expression in the hypothalamic paraventricular nucleus (PVN), a key cardiovascular‐related center of the brain that regulates sympathetic nerve activity and extracellular fluid volume. Female animals also exhibited less peripheral sympathetic and vasopressinergic activity and less hemodynamic compromise than male HF rats with the same degree of initial ischemic cardiac injury. The mechanisms responsible for these sex differences remain unclear. Emerging evidence reveals that methionine sulfoxide reductase A (MsrA), an intracellular enzyme that reverses protein methionine oxidation, is protective against brain oxidative stress, neuroinflammation and sympathetic excitation. Here we examined whether MsrA is expressed in the cardiovascular‐related centers of the brain and whether MsrA is altered in HF after MI in male and female rats. Male and female SD rats at ~13 weeks of age underwent MI to induce HF and were euthanized for molecular and immunofluorescent studies 4 weeks later. Age‐matched male and female rats served as controls. There were no differences between male and female rats in ischemic zone or left ventricular ejection fraction at 24 hours and at 4 weeks after MI as assessed by echocardiography. mRNA expression of MsrA in the PVN was significantly higher in female than male control rats (2.06 ± 0.25 vs 1.09 ± 0.16, p &lt; 0.05). mRNA expression of MsrA in the PVN was not affected by HF in female rats (2.12 ± 0.46) but was significantly lower (0.43 ± 0.02, p &lt; 0.01) in male HF rats compared with their age‐matched controls. There was no difference in mRNA expression of MsrA in brain cortex among four experimental groups. Confocal imaging revealed MsrA positive immunofluorescence in the neurons of the PVN, mainly in the magnocellular subdivision, in both male control and female control rats. MsrA positive immunofluorescence was also observed in the subfornical organ, another cardiovascular‐related nucleus, and in the cortex in both male control and female control rats. These results indicate that MsrA is expressed in key cardiovascular‐related centers of the brain, and that there are sex differences in the expression of MsrA in the PVN under physiological conditions and in MI‐induced HF. Whether differences in the expression of MsrA in the PVN play a role in the sex differences in the central and peripheral manifestations of MI‐induced HF deserves further investigation.Support or Funding InformationSupported by NIH grants R01HL073986 and R01HL139521This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Arginine Vasopressin and Posterior Reversible Encephalopathy Syndrome Pathophysiology: the Missing Link?

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological entity characterized by a typical brain edema. Its pathogenesis is still debated through hypoperfusion and hyperperfusion theories, which have many limitations. As PRES occurs almost exclusively in clinical situations with arginine vasopressin (AVP) hypersecretion, such as eclampsia and sepsis, we hypothesize that AVP plays a central pathophysiologic role. In this review, we discuss the genesis of PRES and its symptoms through this novel approach. We theorize that AVP axis stimulation precipitates PRES development through an increase in AVP secretion or AVP receptor density. Activation of vasopressin V1a receptors leads to cerebral vasoconstriction, causing endothelial dysfunction and cerebral ischemia. This promotes cytotoxic edema through hydromineral transglial flux dysfunction and may increase endothelial permeability, leading to subsequent vasogenic brain edema. If our hypothesis is confirmed, it opens new perspectives for better patient monitoring and therapies targeting the AVP axis in PRES.

Association of copeptin, a surrogate marker for arginine vasopressin secretion, with insulin resistance: Influence of adolescence and psychological stress

In middle-aged and elderly individuals, circulating copeptin concentrations, a surrogate marker for arginine vasopressin (AVP) secretion, associates with insulin resistance (IR). Whether this association is present in adolescents and young adults is unclear. Because psychological stress associates with higher circulating copeptin concentrations and IR, it has been speculated that increased AVP secretion could be a link between psychological stress and IR. We measured plasma copeptin concentrations in 351 14–16-year-old adolescents and 617 20–28-year-old young adults from the Danish site of the European Youth Heart Study, a population-based cardiovascular risk factor study in adolescents and young adults. IR was determined by the homeostatic model assessment method. Among the young adults, we used symptoms of depression, evaluated by means of the Major Depression Inventory (MDI) scale, as a measure of psychological stress. We applied linear regressions to examine associations, expressed as unstandardized regression coefficients (B) with 95% confidence intervals (CIs), between variables of interest, stratified by age group and adjusting for age, sex and Tanner stages. Copeptin and IR were log-transformed. Among the young adults, copeptin associated with IR (B (95%CI) = 0.19 (0.11 to 0.27), P < 0.001). This association was not found among the adolescents (B=-0.01 (-0.12 to 0.09), P = 0.78). MDI score associated with IR (B = 0.010 (0.004 to 0.016), P < 0.001) and copeptin (B=0.010 (0.004 to 0.015); P<0.002) in the young adults. Adjusted for copeptin, the strength of the association between MDI score and IR somewhat diminished (to B=0.008). In conclusion, adolescence and psychological stress appear to influence the association between copeptin and IR.

Correlation between Urinary Excretion of Arginine-Vasopressin and Renal Reabsorption of Sodium and Water.

We developed an approach for quantitative assay of injected vasopressin in urine samples by ELISA under conditions of physiological suppression of hormone secretion from the neurohypophysis into the blood. In experiments on unanesthetized rats, water load (5 ml/100 g body weight) almost completely blocked secretion of arginine-vasopressin. Injection of arginine-vasopressin in a dose of 0.1 nmol/100 g body weight after water load enhanced reabsorption of solute-free water and renal excretion of Na+, K+, and Mg2+ by 13.3, 5.5, and 5.0 times, respectively; urinary excretion of Ca2+ remained unchanged. It was found that urinary excretion of arginine-vasopressin directly correlated with reabsorption of solute-free water and renal sodium excretion.

Increased von Willebrand factor parameters in children with febrile seizures.

IntroductionPrimary blood coagulation and wound sealing are orchestrated by von Willebrand factor (VWF), a large multimeric glycoprotein. Upon release of arginine vasopressin (AVP), VWF containing high molecular weight multimers is secreted. By measuring copeptin, the C-terminal part of the AVP prohormone, we recently found strongly increased AVP levels in children with febrile seizures (FS) as compared to children with fever but without seizures. It is unknown if increased AVP levels in FS are of any biological function. Therefore, our a priori hypothesis was that children with FS have increased VWF parameters in parallel with higher AVP levels.MethodsWe conducted a prospective, cross-sectional study of children aged between 6 months and 5 years. Children that presented at our emergency department with fever or a recent FS (within four hours) were evaluated to be included to the study. We measured serum copeptin and VWF parameters, including analyses of VWF:Antigen (WVF:Ag), VWF:collagen binding activity (VWF:CB) and VWF multimers in children with FS, febrile infections without seizures and additionally, in a non-febrile control group.ResultsWe included 54 children in our study, 30 with FS, 10 in the febrile control group, and 14 in the non-febrile control group. Serum copeptin levels were significantly higher in children with FS (median [IQR] 24.73 pmol/l [13.65–68.65]) compared to the febrile control group (5.66 pmol/l [4.15–8.07], p = 0.002) and the non-febrile control group (4.78 pmol/l [3.33–5.3], p<0.001). VWF:CB levels were also significantly higher in children with FS (VWF:CB 2.29 U/ml [1.88–2.97]) as compared to the febrile (VWF:CB 1.41 U/ml [1.27–1.93], p = 0.048) and the non-febrile control group (VWF:CB 1.15 U/ml [0.98–1.21], p<0.001). VWF:Ag tended to be higher in children with FS compared to both control groups. Multivariate regression analysis revealed FS and copeptin as major determinants of VWF:CB.ConclusionsOur results suggest that increased secretion of AVP in children with FS is associated with higher plasma levels of VWF parameters. Especially VWF:CB may serve as additional biomarker in the diagnosis of FS.