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Dilutional hyponatremia associated with liver cirrhosis is due to inappropriate release of arginine vasopressin (AVP). Elevated plasma AVP causes water retention resulting in a decrease in plasma osmolality. Cirrhosis, in this study caused by ligation of the common bile duct (BDL), leads to a decrease in central vascular blood volume and hypotension, stimuli for nonosmotic AVP release. The A1/A2 neurons stimulate the release of AVP from the supraoptic nucleus (SON) in response to nonosmotic stimuli. We hypothesize that the A1/A2 noradrenergic neurons support chronic release of AVP in cirrhosis leading to dilutional hyponatremia. Adult, male rats were anesthetized with 2–3% isoflurane (mixed with 95% O2/5% CO2) and injected in the SON with anti-dopamine β-hydroxylase (DBH) saporin (DSAP) or vehicle followed by either BDL or sham surgery. Plasma copeptin, osmolality, and hematocrit were measured. Brains were processed for ΔFosB, dopamine β-hydroxylase (DBH), and AVP immunohistochemistry. DSAP injection: 1) significantly reduced the number of DBH immunoreactive A1/A2 neurons (A1, P < 0.0001; A2, P = 0.0014), 2) significantly reduced the number of A1/A2 neurons immunoreactive to both DBH and ΔFosB positive neurons (A1, P = 0.0015; A2, P < 0.0001), 3) reduced the number of SON neurons immunoreactive to both AVP and ΔFosB ( P < 0.0001), 4) prevented the increase in plasma copeptin observed in vehicle-injected BDL rats ( P = 0.0011), and 5) normalized plasma osmolality and hematocrit (plasma osmolality, P = 0.0475; hematocrit, P = 0.0051) as compared with vehicle injection. Our data suggest that A1/A2 neurons contribute to increased plasma copeptin and hypoosmolality in male BDL rats.

During development, many aspects of behaviour, including partner preferences and sexual behaviour, are "organized" by neural aromatization of androgen and oestrogen. This study aimed to analyse these processes in the mandarin vole (Microtus mandarinus); this is a novel mammalian model exhibiting strong monogamous pair bonds. Male pups were treated daily with a sesame oil only (MC) or the oestrogen receptor blocker-clomiphene citrate sesame oil mixture (MT) from prenatal day 14 to postnatal day 10. Female pups were treated daily with sesame oil only (FC). Partner preferences, sexual behaviour, and the expression of androgen receptor (AR) and arginine vasopressin (AVP) were examined when animals were 3 months old. The MT and FC groups exhibited male-directed partner preferences and feminized behaviour. AR-immunoreactive neurons (AR-IRs) in the medial preoptic area (mPOA), bed nucleus of stria terminalis (BNST), and medial amygdaloid nucleus (MeA) were reduced in MT males compared to MC males, and there was no significant difference in the number of AR-IRs between MT males and FC females. AVP-immunoreactive neurons (AVP-IRs) in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) were reduced in MT males compared to MC males, and there were no significant differences in the number of AVP-IRs between MT males and FC females. The results indicate a significant role of hormone signalling in the development of male mate preference in the novel monogamous mammal model.

Men with advanced prostate cancer are treated by androgen deprivation therapy but the disease recurs as incurable castration-resistant prostate cancer (CRPC), requiring new treatment options. We previously demonstrated that the G protein–coupled receptor (GPCR) arginine vasopressin receptor type1A (AVPR1A) is expressed in CRPC and promotes castration-resistant growth in vitro and in vivo. AVPR1A is part of a family of GPCR's including arginine vasopressin receptor type 2 (AVPR2). Interrogation of prostate cancer patient sample data revealed that coexpression of AVPR1A and AVPR2 is highly correlated with disease progression. Stimulation of AVPR2 with a selective agonist desmopressin promoted CRPC cell proliferation through cAMP/protein kinase A signaling, consistent with AVPR2 coupling to the G protein subunit alpha s. In contrast, blocking AVPR2 with a selective FDA-approved antagonist, tolvaptan, reduced cell growth. In CRPC xenografts, antagonizing AVPR2, AVPR1A, or both significantly reduced CRPC tumor growth as well as decreased on-target markers of tumor burden. Combinatorial use of AVPR1A and AVPR2 antagonists promoted apoptosis synergistically in CRPC cells. Furthermore, we found that castration-resistant cells produced AVP, the endogenous ligand for arginine vasopressin receptors, and knockout of AVP in CRPC cells significantly reduced proliferation suggesting possible AVP autocrine signaling. These data indicate that the AVP/arginine vasopressin receptor signaling axis represents a promising and clinically actionable target for CRPC. Implications: The arginine vasopressin signaling axis in CRPC provides a therapeutic window that is targetable through repurposing safe and effective AVPR1A and AVPR2 antagonists.

Arginine vasopressin (AVP) is produced in the paraventricular (PVN) and supraoptic nuclei (SON). Peripheral AVP, which is secreted from the posterior pituitary, is produced in the magnocellular division of the PVN (mPVN) and SON. In addition, AVP is produced in the parvocellular division of the PVN (pPVN), where corticotrophin-releasing factor (CRF) is synthesized. These peptides synergistically modulate the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have revealed that the HPA axis was activated by hypovolemia. However, the detailed dynamics of AVP in the pPVN under hypovolemic state has not been elucidated. Here, we evaluated the effects of hypovolemia and hyperosmolality on the hypothalamus, using AVP-enhanced green fluorescent protein (eGFP) transgenic rats. Polyethylene glycol (PEG) or 3% hypertonic saline (HTN) was intraperitoneally administered to develop hypovolemia or hyperosmolality. AVP-eGFP intensity was robustly upregulated at 3 and 6 h after intraperitoneal administration of PEG or HTN in the mPVN. While in the pPVN, eGFP intensity was significantly increased at 6 h after intraperitoneal administration of PEG with significant induction of Fos-immunoreactive (-ir) neurons. Consistently, eGFP mRNA, AVP hnRNA, and CRF mRNA in the pPVN and plasma AVP and corticosterone were significantly increased at 6 h after intraperitoneal administration of PEG. The results suggest that AVP and CRF syntheses in the pPVN were activated by hypovolemia, resulting in the activation of the HPA axis.

The etiology of central diabetes insipidus (DI) is classified into (1) idiopathic, (2) familial, and (3) secondary. Of these, familial central diabetes insipidus shows an autosomal dominant inheritance. We herein report a case in which this disease was diagnosed based on a family history of nocturnal enuresis. A 40-year-old man had had symptoms of polydipsia, polyuria and nocturia since childhood and found that his daughter had the same symptoms. Despite reaching nine years old, his daughter's nocturnal enuresis still had not improved, resulting in her consulting a pediatrician. She was suspected of having familial neurohypophyseal diabetes insipidus (FNDI) based on her family history and was referred along with her father for a detailed examination and treatment. A hypertonic saline load test (HSLT) to evaluate the arginine vasopressin (AVP) reaction was performed in both the proband and his daughter. The results showed no increase in AVP levels in response to high plasma osmolality. The water deprivation test (WDT) revealed he was suffering from partial DI. Based on the above findings and considering the possibility of familial central diabetes insipidus, we performed a gene mutation analysis of AVP-neurophysin II (NPII). Both the father and daughter had an exon 2 abnormality in this gene (c232_234delGAG; pGlu78del), and this gene mutation is known to cause NPII protein abnormality, abolishing the function of AVP as a carrier protein. This case was considered to have provided an opportunity to understand the role of an NPII gene abnormality in familial central diabetes insipidus.

Environmental and hereditary factors play roles in shaping the personality of offspring which are often associated with gene expression alterations. The long-term effects of the environment that are modulated by the epigenetic mechanisms can be even transmitted to the next generations. This study aimed to investigate the effects of paternal stress, such as paternal aggression and food deprivation, on the social interaction behaviors of offspring in adulthood and the expression of genes that are associated with these behaviors.The intruder-resident method, followed by an electric shock, was used to induce aggression in male Wistar rats before mating. To induce food deprivation, father rats were given 10 g pellets every day without restriction on water consumption for 2 weeks before mating. Social interactions of the male offspring were evaluated at the age of 8 weeks using a three-chamber social interaction test. Real-time PCR was applied to quantify the expression levels of oxytocin (OXT), oxytocin receptor (OXTR), and arginine vasopressin (AVP) genes in the amygdala of offspring. One-way analysis of variance was used to compare the means of experimental groups.The results did not show significant changes in the social interaction behaviors for the offspring of aggressive and food-deprived fathers compared to the control group. However, molecular investigations indicated increased levels of OXT, OXTR, and AVP gene expression in the offspring amygdala of aggressive and food-deprived fathers.The results showed that paternal stress, such as aggression and food deprivation, induced gene expression alterations in the offspring, although they did not affect their social interaction behaviors.

Introduction: Exercise becomes a stress when performed at an intensity above the lactate threshold (LT) because at that point the plasma adrenocorticotropic hormone (ACTH), a marker of stress response, increases. It is possible that the exercise-induced ACTH response is regulated at least by arginine vasopressin (AVP) and possibly by corticotropin-releasing hormone (CRH), but this remains unclear. To clarify the involvement of these factors, it is useful to intervene pharmacologically in the regulatory mechanisms, with a physiologically acceptable exercise model. Methods: We used a special stress model of treadmill running (aerobic exercise) for male Wistar rats, which mimic the human physiological response, where plasma ACTH levels increase at just above the LT for 30 min. Animals were administered the AVP V1b receptor antagonist SSR149415 (SSR) and/or the CRH type 1 receptor antagonist CP154526 (CP) intraperitoneally before the exercise, which allowed the monitoring of exercise-induced ACTH response. Immunohistochemical evaluation of activated AVP and CRH neurons with exercise was performed for the animals’ hypothalami. Results: A single injection of either antagonist, SSR or CP, resulted in inhibited ACTH levels after exercise stress. Moreover, the combined injection of SSR and CP strongly suppressed ACTH secretion during treadmill running to a greater extent than each alone. The running-exercise-induced activation of both AVP and CRH neurons in the hypothalamus was also confirmed. Conclusion: These results lead us to hypothesize that AVP and CRH are cooperatively involved in exercise-induced ACTH response just above the LT. This may also reflect the stress response with moderate-intensity exercise in humans.

ObjectiveEarly life trauma (ELT) and HIV are associated with social processing deficits. In people with HIV (PWH), we examined whether facial emotion identification accuracy differs by ELT and whether neuroendocrine factors including cortisol, oxytocin (OT), and arginine vasopressin, and/or immune system measures play a role in the ELT-performance association.MethodsWe used secondary data from the placebo condition of a pharmacologic challenge study in PWH. Presence of ELT was measured with the Childhood Trauma Questionnaire (at least moderate experiences of sexual, physical, and/or emotional abuse). Social processing was measured with the Facial Emotion Perception Test (FEPT). Salivary immune system measures and cortisol were sampled across a 5-hour study session. Blood was collected at study session start (12 pm ) to measure OT and arginine vasopressin. We examined the association of ELT with FEPT and five biological moderators (from principal components analysis of 12 biomarkers) of ELT-FEPT associations.ResultsOf 58 PWH (42 men; mean [standard deviation] age = 33.7 [8.9] years), 50% endorsed ELT. ELT-exposed PWH demonstrated lower identification accuracy across all emotional expressions (unstandardized β [ B ] = 0.13; standard error [SE] = 0.05; p = .021, d = 0.63) and had higher OT levels compared with ELT-unexposed PWH ( t(1,56) = 2.12, p = .039; d = 0.57). For total accuracy, an OT/C-reactive protein factor moderated the ELT-FEPT association ( B = 0.14; SE = 0.05; p = .014); accuracy was lower in ELT-exposed PWH versus ELT-unexposed PWH when the factor was low but not when high. Similar results were obtained for fearful, neutral, and happy faces ( p values < .05). Regardless of ELT, a myeloid migration (MCP-1/MMP-9) factor was associated with reduced accuracy ( p values < .05).ConclusionsOur pilot findings suggest that ELT may alter social processing in PWH, and OT and C-reactive protein may be a target for improving social processing in ELT-exposed PWH, and myeloid migration markers may be a target in PWH more generally.

The roles of oxytocin (OT) and arginine-vasopressin (AVP) as crucial modulators of social cognition and related behaviours have been extensively addressed in the literature. The involvement of these neuropeptides in social cognition in ageing, however, and a potential mediating effect of basic cognitive capacities on this link, are not well understood. To fill these research gaps, this study assessed associations of plasma OT and AVP levels with dynamic emotion identification accuracy in generally healthy older men (aged 55–95 years) and probed the underlying roles of crystallized and fluid cognition in these associations. Higher plasma OT levels were associated with lower accuracy in dynamic emotion identification, with this negative relationship fully mediated by cognition. For plasma AVP levels, in contrast, there was no association with dynamic emotion identification accuracy. Integrated within existing theoretical accounts, results from this study advance understanding of the neuropeptide–social cognition link in ageing and support basic cognitive capacities as mediators in this association. This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.

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 theAgtr1agene) 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 maleAgtr1a-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 STATEMENTHypertension 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.

Early-life adversity impairs neuronal plasticity of the developing brain. In rodents, brain maturation processes, including neuro- and synaptogenesis, myelination, microglial maturation, and hypothalamic-pituitary-adrenal (HPA) axis development continue in the postnatal period. In our study, two models of early-life stress were used: repeated maternal separation (MS) from postnatal day (PND) 2 to PND14 for 3 h daily and single maternal deprivation (MD) on PND9 for 24 h. Effects of each type of early-life stress on neuron density, neurogenesis, microglial morphology, and HPA axis programming were studied in 15-day-old male mice. Neither early-life stress paradigm affected the expression of stress-related genes (Crh, Avp, Crhr1, Crhr2, Nr3c1, and Nr3c2) and the serum level of corticosterone on PND15. Immunohistochemical analysis was performed on slices of the hippocampus and prefrontal cortex (PFC) with antibodies against a marker of mature neurons (NeuN), of microglia (Iba1), proliferating cells (Ki67), and immature neurons (DCX). We found higher density of ameboid microglia and intermediate microglia in the PFC in groups MS and MD, respectively, than in a control group. In both stressed groups, a higher number of Ki67-positive cells was noted in the dentate gyrus. Thus, in mice, the process of transformation of ameboid microglia into ramified ones as well as a neurogenesis reduction take place during the second postnatal week, whereas early-life stress can disturb these processes in a stress- and region-dependent manner.

Aim Abundant evidence indicates that estrogen (E2) plays a protective role against hypertension. Yet, the mechanism underlying the antihypertensive effect of E2 is poorly understood. In this study, we sought to determine the mechanism through which E2 inhibits salt-dependent hypertension. Methods and results To this end, we performed a series of in-vivo and in-vitro experiments employing a rat model of hypertension that is produced by deoxycorticosterone acetate (DOCA)-salt treatment after uninephrectomy. We found that E2 prevented DOCA-salt treatment from inducing hypertension, raising plasma arginine-vasopressin (AVP) level, enhancing the depressor effect of the V1a receptor antagonist (Phenylac1, D-Tyr(Et)2, Lys6, Arg8, des-Gly9)-vasopressin, and converting GABAergic inhibition to excitation in hypothalamic magnocellular AVP neurons. Moreover, we obtained results indicating that the E2 modulation of the activity and/or expression of NKCC1 (Cl- importer) and KCC2 (Cl- extruder) underpins the effect of E2 on the transition of GABAergic transmission in AVP neurons. Lastly, we discovered that, in DOCA-salt-treated hypertensive ovariectomized rats, CLP290 (prodrug of the KCC2 activator CLP257, intraperitoneal injections) lowered blood pressure and plasma AVP level and hyperpolarized GABA equilibrium potential to prevent GABAergic excitation from emerging in the AVP neurons of these animals. Conclusion Based on these results, we conclude that E2 inhibits salt-dependent hypertension by suppressing GABAergic excitation to decrease the hormonal output of AVP neurons. Translational perspective Numerous studies have shown that sex steroids can impact blood pressure (BP) and premenopausal women have a lower incidence of hypertension than age-matched men. Postmenopausal women no longer enjoy this beneficial difference. The causal mechanisms are not clear and hormone replacement therapy with estradiol (E2) does not consistently lower BP in postmenopausal women. In this study we showed that rats treated with CLP290 to control GABAergic excitation in AVP neurons have the same phenotype as E2-supplemented rats in BP and plasma AVP level. This result indicates that CLP290 leverages the same pathway of E2 protective effects against salt-dependent hypertension, and therefore, raises the possibility that classes of drugs like CLP290 may have some utility as alternative antihypertensives in persons resistant to or contraindicated for E2 therapy.

OBJECTIVE Arginine vasopressin (AVP) is released upon osmotic stimulation or hypovolaemia in order to maintain water balance. A recent study showed a role of AVP in haematopoiesis by stimulating red blood cell precursors, suggesting a higher risk of anaemia in patients with AVP deficiency. The objective was to explore the effect of low AVP levels in patients with central diabetes insipidus (cDI) and primary polydipsia (PP) on haemoglobin and the prevalence of anaemia. METHODS A total of 164 patients with either cDI (70, 43%) or PP (94, 57%) and 30 healthy volunteers from two prospective diagnostic studies performed in Switzerland, Germany and Brazil were studied. A standardized clinical and biochemical (eg copeptin, full blood count) assessment was performed. Haemoglobin and haematocrit levels and prevalence of anaemia (defined as haemoglobin values of

The neuropeptide arginine-vasopressin (AVP) has long been implicated in the regulation of social behavior and communication in diverse taxa, but the source of AVP release relevant for behavior has not been precisely determined. Potential sources include hypothalamic cell populations such as the paraventricular (PVN), supraoptic, and suprachiasmatic nuclei, as well as extrahypothalamic cell groups in the extended amygdala. To address if AVP-expressing cells in the PVN are important for mouse social communication, we deleted PVN AVP-expressing cells using viral-mediated delivery of Cre-dependent caspase-9 cell death construct into the PVN of AVP-Cre-positive mice (expressing Cre-recombinase under the control of the AVP promoter) or AVP-Cre-negative littermate controls, and assessed their levels of social investigation, social communication, anxiety, sex behavior, and aggressive behavior. We found that these lesions increased social investigation in females, but not in males. However, in males but not in females, these lesions increased non-social anxiety-related behaviors in the elevated-plus maze. These results therefore point at differential involvement of PVN AVP-expressing cells in the context of social and emotional behavior in the two sexes, which may contribute to sex differences in social communication and anxiety disorders.

Autism spectrum disorder (ASD) is a brain disorder characterized by social impairments. ASD is currently diagnosed on the basis of behavioral criteria because no robust biomarkers have been identified. However, we recently found that cerebrospinal fluid (CSF) concentration of the “social” neuropeptide arginine vasopressin (AVP) is significantly lower in pediatric ASD cases vs. controls. As an initial step in establishing the direction of causation for this association, we capitalized upon a rare biomaterials collection of newborn CSF samples to conduct a quasi-prospective test of whether this association held before the developmental period when ASD first manifests. CSF samples had been collected in the course of medical care of 0- to 3-mo-old febrile infants (n = 913) and subsequently archived at −70 °C. We identified a subset of CSF samples from individuals later diagnosed with ASD, matched them 1:2 with appropriate controls (n = 33 total), and quantified their AVP and oxytocin (OXT) concentrations. Neonatal CSF AVP concentrations were significantly lower among ASD cases than controls and individually predicted case status, with highest precision when cases with comorbid attention-deficit/hyperactivity disorder were removed from the analysis. The associations were specific to AVP, as ASD cases and controls did not differ in neonatal CSF concentrations of the structurally related neuropeptide, OXT. These preliminary findings suggest that a neurochemical marker of ASD may be present very early in life, and if replicated in a larger, prospective study, this approach could transform how ASD is detected, both in behaviorally symptomatic children, and in infants at risk for developing it.

Introduction: Hyponatremia due to elevated arginine vasopressin (AVP) secretion increases mortality in liver failure patients. No previous studies have addressed sex differences in hyponatremia in liver failure animal models. Objective: This study addressed this gap in our understanding of the potential sex differences in hyponatremia associated with increased AVP secretion. Methods: This study tested the role of sex in the development of hyponatremia using adult male, female, and ovariectomized (OVX) female bile duct-ligated (BDL) rats. Results: All BDL rats had significantly increased liver to body weight ratios compared to sham controls. Male BDL rats had hyponatremia with significant increases in plasma copeptin and FosB expression in supraoptic AVP neurons compared to male shams (all p < 0.05; 5–7). Female BDL rats did not become hyponatremic or demonstrate increased supraoptic AVP neuron activation and copeptin secretion compared to female shams. Plasma oxytocin was significantly higher in female BDL rats compared to female sham (p < 0.05; 6–10). This increase was not observed in male BDL rats. Ovariectomy significantly decreased plasma estradiol in sham rats compared to intact female sham (p < 0.05; 6–10). However, circulating estradiol was significantly elevated in OVX BDL rats compared to the OVX and female shams (p < 0.05; 6–10). Adrenal estradiol, testosterone, and dehydroepiandrosterone (DHEA) were measured to identify a possible source of circulating estradiol in OVX BDL rats. The OVX BDL rats had significantly increased adrenal estradiol along with significantly decreased adrenal testosterone and DHEA compared to OVX shams (all p < 0.05; 6–7). Plasma osmolality, hematocrit, copeptin, and AVP neuron activation were not significantly different between OVX BDL and OVX shams. Plasma oxytocin was significantly higher in OVX BDL rats compared to OVX sham. Conclusions: Our results show that unlike male BDL rats, female and OVX BDL rats did not develop hyponatremia, supraoptic AVP neuron activation, or increased copeptin secretion compared to female shams. Adrenal estradiol might have compensated for the lack of ovarian estrogens in OVX BDL rats.

The diagnosis of drowning is considered one of the most difficult in forensic medicine. Due to the paucity of signs, it is a classical diagnosis by exclusion. For this reason, specific immunohistochemical markers would be useful. Far too little has been done to analyze in-depth the differences between SWD and FWD. We focused on the renal immunohistochemical expression of aquaporin 2, AVP, V2R, and renin in cases of drowning. This study has two purposes: (1) to better understand the differences between saltwater drowning (SWD) and freshwater drowning (FWD), which may indicate different pathophysiology and (2) to eventually identify markers useful for the diagnosis of drowning. We retrospectively investigated 10 cases of SWD gathered from the Institute of Legal Medicine in Genoa (Italy), and 10 cases of FWD from the University Center of Legal Medicine in Geneva (Switzerland). As a control group, we investigated 10 cases of death by gunshot to the head. A strong expression of AQP2 and AVP was significantly (p

Sensitive biomarkers are needed to rapidly identify high-risk infants after hypoxia-ischemia for neuroprotective treatment. Hypotension is a key determinant of hypoxic-ischemic neural injury, and a potent stimulus of humoral pressors including angiotensin-II and arginine vasopressin. We therefore aimed to quantify the relationship between vasopressin and angiotensin-II levels in the latent phase after hypoxia-ischemia induced by umbilical cord occlusion (UCO) with both the severity of preceding hypotension and subsequent neuronal injury.Chronically instrumented near-term fetal sheep underwent sham-UCO or UCO for either 15 min or until mean arterial pressure was8 mmHg. Neuronal injury was assessed after 72 h recovery.Umbilical cord occlusion was associated with severe hypotension that recovered after UCO; two fetuses developed profound secondary hypotension within 6 h and died. Vasopressin levels but not angiotensin-II were significantly elevated 1-3 h after UCO and were closely associated with the severity of hypotension during UCO and the subsequent severity of neuronal loss in the parasagittal and lateral cortex, caudate nucleus and putamen. The Youden cut-point for vasopressin at 1 h was 180.0 pmol/L, with sensitivity 100% and specificity 92.3% for severe neuronal injury or death.Vasopressin levels shortly after moderate-severe hypoxia-ischemia may be a useful early biomarker to guide the timely implementation of neuroprotective treatment.It can be difficuIt to rapidly identify infants who might benefit from therapeutic hypothermia. We investigated whether increases in plasma pressor hormones early after hypoxia-ischemia were biomarkers for neonatal hypoxic-ischemic encephalopathy using near-term fetal sheep. Arginine vasopressin levels were elevated at 1-3 h after hypoxia-ischemia and were predictive of the severity of preceding hypotension and subsequent risk of severe neuronal injury or death after hypoxia-ischemia. Arginine vasopressin may help identify neonates at high risk of hypoxic-ischemic encephalopathy early within the therapeutic window for hypothermia.

Maintenance of the volume and osmolality of body fluids is important, and the adaptive responses recruited to protect against osmotic stress are crucial for survival. The objective of this work was to compare the responses that occur in aging male and female rats during water deprivation. For this purpose, groups of male and female Wistar rats aged 3 mo (adults) or 18 mo (old) were submitted to water deprivation (WD) for 48 h. The water and sodium (0.15 M NaCl) intake, plasma concentrations of oxytocin (OT), arginine vasopressin (AVP), corticosterone (CORT), atrial natriuretic peptide (ANP), and angiotensin II (ANG II) were determined in hydrated and water-deprived animals. In response to WD, old male and female rats drank less water and saline than adults, and both adult and old females drank more water and saline than respective males. Dehydrated old animals displayed lower ANG II plasma concentration and CORT response compared with the respective normohydrated rats. Dehydrated adult males had higher plasma ANP and AVP as well as lower CORT concentrations than dehydrated adult females. Moreover, plasma OT and CORT levels of old female rats were higher than those in the dehydrated old male rats. Relative expression of ANG II type 1 receptor mRNA was decreased in the subfornical organ of adult and old male rats as well as adult female rats in response to WD. In conclusion, the study elucidated the effect of sex and age on responses induced by WD, altering the degree of dehydration induced by 48 h of WD.

The precise mechanism of hyponatremia in Kawasaki disease (KD) remains elusive because assessment of volume status based on serial changes in body weight is lacking in previous reports.Seventeen patients who were diagnosed with KD and hyponatremia (serum sodium levels135 mmol/L) were analyzed. Volume status was assessed based on serial changes in body weight. Plasma arginine vasopressin (ADH), urine electrolytes, and serum cytokine levels were measured on diagnosis of hyponatremia. An increase in body weight by3% was defined as hypervolemia and a decrease in body weight by3% was defined as hypovolemia.The volume status was hypervolemic in three patients (18%), euvolemic in 14 (82%), and hypovolemic in none (0%). Five (29%) patients were diagnosed with "syndrome of inappropriate secretion of antidiuretic hormone" (SIADH) and no patients were diagnosed with hypotonic dehydration. The contribution of decreased total exchangeable cations (salt loss) to hyponatremia (5.9% [interquartile range, 4.3%, 6.7%]) was significantly larger than that of increased total body water (-0.7% [-1.8%, 3.1%]) (P = 0.004). Serum interleukin-6 levels were elevated in all of the nine patients who were evaluated. Among the 12 (71%) patients who did not meet the criteria of SIADH and hypotonic dehydration, plasma ADH levels were inappropriately high in ten patients. These patients were also characterized by euvolemic or hypervolemic hyponatremia and salt loss, which might be compatible with a diagnosis of SIADH.Our study shows that hyponatremia in KD is euvolemic or hypervolemic and is associated with nonosmotic secretion of ADH and salt loss in the majority of patients.

There is growing interest in the measurement of plasma levels of arginine vasopressin (AVP) for the assessment of mild dehydration. However, the principles of biological variation have not been applied to the study of AVP and understanding biological variation of AVP may provide insights regarding measurement thresholds. The purpose of this investigation was to determine the biological variation of AVP in healthy euhydrated individuals to understand the potential for establishing both static and/or change thresholds of importance. We studied 29 healthy volunteers (24 men and 5 women) while controlling for hydration and pre-analytical factors. All subjects completed between 2–8 trials where biological variation was determined using widely published methods. We determined the intraindividual, interindividual, and analytical coefficients of variation (CVI, CVG, and CVA, respectively) and subsequently the index of individuality and heterogeneity (II and IH, respectively). AVP did not reach the IH threshold required to be considered useful in the dynamic assessment of physiological deviations from normal. AVP levels approached the II threshold required to be considered useful in the static assessment of physiological deviations from normal. This analysis demonstrates that AVP assessment is unlikely to yield useful information about hydration status.

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

Elabela (ELA) is a newly discovered peptide that acts as a novel endogenous ligand of angiotensin receptor-like 1 (APJ) receptor. This study was designed to evaluate the effects of ELA-21 in paraventricular nucleus (PVN) on blood pressure and sympathetic nerve activity in spontaneously hypertensive rats (SHR). Experiments were performed in male Wistar-Kyoto rats (WKY) and SHR. ELA expression was upregulated in PVN of SHR. PVN microinjection of ELA-21 increased renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), heart rate (HR), plasma norepinephrine, and arginine vasopressin (AVP) levels in SHR. Intravenous injection of ELA-21 significantly decreased MAP and HR in both WKY and SHR, but only induced a slight decrease in RSNA. APJ antagonist F13A in PVN abolished the effects of ELA-21 on RSNA, MAP and HR. Intravenous infusion of both ganglionic blocker hexamethonium and AVP V1a receptor antagonist SR49059 caused significant reduction in the effects of ELA-21 on RSNA, MAP and HR in SHR, while combined administration of hexamethonium and SR49059 abolished the effects of ELA-21. ELA-21 microinjection stimulated Akt and p85α subunit of phosphatidylinositol 3-kinase (PI3K) phosphorylation in PVN, whereas PI3K inhibitor LY294002 or Akt inhibitor MK-2206 almost abolished the effects of ELA-21 on RSNA, MAP, and HR. Chronic PVN infusion of ELA-21 induced sympathetic activation, hypertension, and AVP release accompanied with cardiovascular remodeling in normotensive WKY. In conclusion, ELA-21 in PVN induces exacerbated pressor and sympathoexcitatory effects in hypertensive rats via PI3K-Akt pathway. NEW & NOTEWORTHY We demonstrated that PVN microinjection of ELA-21 increases sympathetic nerve activity and blood pressure, which can be abolished by pretreatment of APJ antagonist. This is the first demonstration that central ELA can induce hypertension. The pressor effects in PVN are mediated by both sympathetic activation and vasopressin release via PI3K-Akt pathway. Our data confirm that ELA is upregulated in the PVN of SHR and so may be involved in the pressor and sympathoexcitatory effects in hypertension.

Circumstantial evidence supports the hypothesis that the sexually dimorphic vasopressin (AVP) innervation of the brain tempers sickness behavior in males. Here we test this hypothesis directly, by comparing sickness behavior in animals with or without ablations of BNST AVP cells, a major source of sexually dimorphic AVP in the brain. We treated male and female AVP-iCre+ and AVP-iCre- mice that had been injected with viral Cre-dependent caspase-3 executioner construct into the BNST with lipopolysaccharide (LPS) or sterile saline, followed by behavioral analysis. In all groups, LPS treatment reliably reduced motor behavior, increased anxiety-related behavior, and reduced sucrose preference and consumption. Male mice, whose BNST AVP cells had been ablated (AVP-iCre+), displayed only minor reductions in LPS-induced sickness behavior, whereas their female counterparts displayed, if anything, an increase in sickness behaviors. All saline-treated mice with BNST AVP cell ablations consumed more sucrose than did control mice, and males, but not females, with BNST AVP cell ablations showed reduced preference for novel conspecifics compared to control mice. These data confirm that BNST AVP cells control social behavior in a sexually dimorphic way, but do not play a critical role in altering sickness behavior.

In the collecting ducts of the kidney, arginine vasopressin (AVP), cyclic adenosine monophosphate (cAMP), and aquaporin 2 (AQP2) play a pivotal role in maintaining fluid volume and serum osmolality in humans. However, their association among those with chronic kidney disease (CKD) remains uncertain.We prospectively included the out-patients with CKD and measured osmolality-related biomarkers including plasma AVP, urine cAMP, urine AQP2, and urine osmolality levels. Association among these parameters at each CKD stage was investigated.A total of 121 patients were included (median age 71 years old [61-78], 89 men, estimated glomerular filtration ratio 28.6 [16.4-45.3] mL/min/1.73 mVasopressin type-2 receptor seems to be particularly impaired in patients with advanced CKD, whereas the signal cascade of the downstream of vasopressin type-2 receptor is relatively preserved. Urine cAMP might be a promising marker to estimate the residual function of the collecting duct.

Sepsis is hallmarked by high plasma cortisol/corticosterone (CORT), low adrenocorticotropic hormone (ACTH), and high pro-opiomelanocortin (POMC). While corticotropin-releasing hormone-(CRH) and arginine-vasopressin (AVP)-driven pituitary POMC expression remains active, POMC processing into ACTH becomes impaired. Low ACTH is accompanied by loss of adrenocortical structure, although steroidogenic enzymes remain expressed. We hypothesized that treatment of sepsis with hydrocortisone (HC) aggravates this phenotype whereas CRH infusion safeguards ACTH-driven adrenocortical structure.In a fluid-resuscitated, antibiotics-treated mouse model of prolonged sepsis, we compared the effects of HC and CRH infusion with placebo on plasma ACTH, POMC, and CORT; on markers of hypothalamic CRH and AVP signaling and pituitary POMC processing; and on the adrenocortical structure and markers of steroidogenesis. In adrenal explants, we studied the steroidogenic capacity of POMC.During sepsis, HC further suppressed plasma ACTH, but not POMC, predominantly by suppressing sepsis-activated CRH/AVP-signaling pathways. In contrast, in CRH-treated sepsis, plasma ACTH was normalized following restoration of pituitary POMC processing. The sepsis-induced rise in markers of adrenocortical steroidogenesis was unaltered by CRH and suppressed partially by HC, which also increased adrenal markers of inflammation. Ex vivo stimulation of adrenal explants with POMC increased CORT as effectively as an equimolar dose of ACTH.Treatment of sepsis with HC impaired integrity and function of the hypothalamic-pituitary-adrenal axis at the level of the pituitary and the adrenal cortex while CRH restored pituitary POMC processing without affecting the adrenal cortex. Sepsis-induced high-circulating POMC may be responsible for ongoing adrenocortical steroidogenesis despite low ACTH.

Hypovolemia induced by hemorrhage is a common clinical complication, which stimulates vasopressin (AVP) secretion by the neurohypophysis in order to retain body water and maintain blood pressure. To evaluate the role of brain L-glutamate and angiotensin II on AVP secretion induced by hypovolemia we induced hemorrhage (∼25% of blood volume) after intracerebroventricular (icv) administration of AP5, NBQX, or losartan, which are NMDA, AMPA, and AT1 receptor antagonists, respectively. Hemorrhage significantly increased plasma AVP levels in all groups. The icv injection of AP5 did not change AVP secretion in response to hemorrhage. Conversely, icv administration of both NBQX and losartan significantly decreased plasma AVP levels after hemorrhage. Therefore, the blockade of AMPA and AT1 receptors impaired AVP secretion in response to hemorrhage, suggesting that L-glutamate and angiotensin II acted in these receptors to increase AVP secretion in response to hemorrhage-induced hypovolemia.

The neuropeptide arginine-vasopressin (AVP) has long been implicated in the regulation of social behaviour and communication, but the sources of AVP release relevant for behaviour have not been precisely determined. Ablations of the sexually dimorphic AVP cells within the bed nucleus of the stria terminalis (BNST), which are more numerous in males, affect social behaviour differently in males and females. However, it is unknown whether these behavioural effects are caused by a reduction of AVP or of other factors associated with these cells. To test the role of AVP specifically, we used an shRNA viral construct to knock down AVP gene expression within the BNST of wild-type male and female mice, using scrambled sequence virus as a control, and evaluated subsequent changes in social behaviours (social investigation, ultrasonic vocalization (USV), scent marking, copulation, and aggression), or anxiety-like behaviours (elevated plus maze). We observed that, in males, knockdown of AVP expression in the BNST strongly reduced investigation of novel males, aggressive signalling towards other males (tail rattling, USV), and copulatory behaviour, but did not alter attack initiation, other measures of social communication, or anxiety-like behaviours. In females, however, BNST AVP knockdown did not alter any of these behaviours. These results point to differential involvement of AVP derived from the BNST in social behaviour.

Social recognition is an essential skill for the expression of appropriate behaviors towards conspecifics in most social species. Several studies point to oxytocin (OT) and arginine vasopressin (AVP) as key mediators of social recognition in males and females. However, sex differences in social cognitive behaviors highlight an important interplay between OT, AVP and the sex steroids. Estrogens facilitate social recognition by regulating OT action in the hypothalamus and that of OT receptor in the medial amygdala. The role of OT in these brain regions appears to be essential for social recognition in both males and females. Conversely, social recognition in male rats and mice is more dependent on AVP release in the lateral septum than in females. The AVP system comprises a series of highly sexually dimorphic brain nuclei, including the bed nucleus of the stria terminalis, the amygdala and the lateral septum. Various studies suggest that testosterone and its metabolites, including estradiol, influence social recognition in males by modulating the activity of the AVP at V1a receptor. Intriguingly, both estrogens and androgens can affect social recognition very rapidly, through non-genomic mechanisms. In addition, the androgen metabolites, namely 3α-diol and 3β-diol, may also have an impact on social behaviors either by interacting with the estrogen receptors or through other mechanisms. Overall, the regulation of OT and AVP by sex steroids fine tunes social recognition and the behaviors that depend upon it (e.g., social bond, hierarchical organization, aggression) in a sex-dependent manner. Elucidating the sex-dependent interaction between sex steroids and neuroendocrine systems is essential for understanding sex differences in the normal and abnormal expression of social behaviors.

Background/Aims: Circadian rhythms in behavior and physiology are programmed by the suprachiasmatic nucleus (SCN) of the hypothalamus. A subset of SCN neurons produce the neuropeptide arginine vasopressin (AVP), but it remains unclear whether AVP signaling influences the SCN clock directly. Methods: Here, we test that AVP signaling acting through V1A and V1B receptors influences molecular rhythms in SCN neurons. V1 receptor agonists were applied ex vivo to PERIOD2::LUCIFERASE SCN slices, allowing for real-time monitoring of changes in molecular clock function. Results: V1A/B agonists reset the phase of the SCN molecular clock in a time-dependent manner, with larger magnitude responses by the female SCN. Further, we found evidence that both Gαq and Gαs signaling pathways interact with V1A/B-induced SCN resetting, and that this response requires vasoactive intestinal polypeptide (VIP) signaling. Conclusions: Collectively, this work indicates that AVP signaling resets SCN molecular rhythms in conjunction with VIP signaling and in a manner influenced by sex. This highlights the utility of studying clock function in both sexes and suggests that signal integration in central clock circuits regulates emergent properties important for the control of daily rhythms in behavior and physiology.

Context Copeptin is the C-terminal fragment of the arginine vasopressin (AVP) prohormone whose measurement is more robust than that of AVP. Similar release and clearance characteristics have been suggested promoting copeptin as a surrogate marker. Objective To characterize the physiology of osmotically regulated copeptin release and its half-life in direct comparison with plasma AVP. Design Ninety-one healthy volunteers underwent a standardized three-phase test protocol including (1) osmotic stimulation into the hypertonic range by hypertonic-saline infusion followed by osmotic suppression via (2) oral water load and (3) subsequent glucose infusion. Plasma copeptin, AVP, serum sodium, and osmolality levels were measured in regular intervals. Results In phase 1, an increase in median osmotic pressure [289 (286; 291) to 311 (309; 314) mOsm/kg H2O] caused similar release kinetics of plasma copeptin [4 (3.1; 6) to 29.3 (18.6; 48.2) pmol/L] and AVP [1 (0.7; 1.6) to 10.3 (6.8; 18.8) pg/mL]. Subsequent osmotic suppression to 298 (295; 301) mOsm/kg at the end of phase 3 revealed markedly different decay kinetics between both peptides—an estimated initial half-life of copeptin being approximately 2 times longer than that of AVP (26 vs 12 minutes). Conclusion Copeptin is released in equimolar amounts with AVP in response to osmotic stimulation, suggesting its high potential as an AVP surrogate for differentiation of osmotic disorders. Furthermore, we here describe the decay kinetics of copeptin in response to osmotic depression enabling to identify a half-life for copeptin in direct comparison with AVP.

Water balance, tracked by extracellular osmolality, is regulated by feedback and feedforward mechanisms. Feedback regulation is reactive, occurring as deviations in osmolality areFine-tuning the amount of water present in the body at any given time is a tight balancing act. The hormone vasopressin helps to ensure that organisms do not get too dehydrated by allowing water in the urine to be reabsorbed into the bloodstream. A group of vasopressin neurons in the brain trigger the release of the hormone if water levels get too low (as reflected by an increase in osmolality, the level of substances dissolved in a unit of blood). However, these cells also receive additional information that allows them to predict and respond to upcoming changes in water levels. For example, drinking water while dehydrated ‘switches off’ the neurons, even before osmolality is restored in the blood to normal levels. Eating, on the other hand, rapidly activates vasopressin neurons before the food is digested and blood osmolality increases as a result. How vasopressin neurons receive this ‘anticipatory’ information remains unclear. Kim et al. explored this question in mice by inhibiting different sets of brain cells one by one, and then examining whether the neurons could still exhibit anticipatory responses. This revealed a remarkable division of labor in the neural circuits that regulate vasopressin neurons: two completely different sets of neurons from distinct areas of the brain are dedicated to relaying anticipatory information about either water or food intake. These findings help to understand how healthy levels of water can be maintained in the body. Overall, they give a glimpse into the neural mechanisms that underlie anticipatory forms of regulation, which can also take place when hunger or thirst neurons ‘foresee’ that food or water will be consumed.

Tolvaptan, a vasopressin type-2 receptor antagonist, is utilized to ameliorate fluid retention following cardiac surgery. However, the optimal timing of tolvaptan administration considering novel biomarkers remains unknown. We prospectively included patients who underwent cardiac surgery between 2016 and 2020. We measured perioperative trends of free water reabsorption mediators including plasma arginine vasopressin and urine aquaporin-2. A total of 20 patients (68 [60, 75] years old, 18 men) were included. Urine volume decreased gradually after the initial 3 hours following cardiac surgery. The plasma arginine vasopressin level increased significantly with a peak at postoperative 6 hours, whereas the urine aquaporin-2 level increased later with a delayed peak at postoperative 12 hours. As a result, urine aquaporin-2 relative to the plasma arginine vasopressin level, which represents the activity of the collecting ducts and indicates predicted responses to tolvaptan, was a minimum at postoperative 6 hours. Tolvaptan administration immediately after cardiac surgery might not be recommended given the transient refractoriness to tolvaptan probably due to the stunning of kidney collecting ducts.

Social recognition is an ability of animals to identify and distinguish conspecifics, which is essential for nearly all social species to establish social relationships. Social recognition provides the basis for a variety of social behaviors. Because of modulated by gonadal hormones, it is possible that social cognition is affected by environmental endocrine disruptors (EEDs). In the present study, after being pubertal exposed to bisphenol A (BPA, 0.04, 0.4, and 4 mg/kg) for 18 days, adult male mice did not show significant dishabituation to a novel female stimulus in habituation-dishabituation task. The capacity for discriminating the odors between familiar and novel female urine or between male and female urine was suppressed in BPA-exposed male. In addition, BPA (0.4, 4 mg/kg) decreased the number of immunoreaction of AVP (AVP-ir) neurons in both the bed nucleus of the stria terminalis (BNST) and the medial amygdala (MeA), and BPA (0.04, 0.4, 4 mg/kg) reduced the level of V1αR in the lateral septum (LS) of adult male. Further, BPA decreased the levels of testosterone (T) in the brain and androgens receptor (AR) in the LS, the amygdala, and BNST, as well the levels of estrogen receptor α and β (ERα/β) in the amygdala and BNST. These results indicate that pubertal exposure to BPA affected the actions of both androgens and estrogens in the brain and inhibited AVP system of social circuits, and these alterations may be associated with impaired social recognition of adult male mice.

Although vasopressin V