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Adipsic diabetes insipidus (ADI) is characterized by central diabetes insipidus and an impaired thirst response to hyperosmolality, leading to hypernatremia. Hyponatremia observed in patients with ADI has been considered a complication of desmopressin therapy. Herein, we present a case of impaired thirst sensation and arginine vasopressin (AVP) secretion without desmopressin therapy, in which hyponatremia developed due to preserved non-osmotic AVP secretion. A 53-year-old woman with hypopituitarism, receiving hydrocortisone and levothyroxine, experienced hyponatremia three times over 5 months without desmopressin treatment. The first hyponatremic episode (120 mEq/L) was complicated by a urinary tract infection with a plasma AVP level of 33.8 pg/mL. Subsequent hyponatremia episodes occurred after administration of antipsychotic (124 mEq/L) and spontaneously (125 mEq/L) with unsuppressed plasma AVP levels (1.3 and 1.8 pg/mL, respectively). Hypertonic saline infusion did not affect AVP or copeptin levels. Regulating water intake using a sliding scale based on body weight prevented the recurrence of hyponatremia without the use of desmopressin. Except during infection, plasma AVP levels (1.3 ± 0.4 pg/mL) were not significantly correlated with serum sodium levels (r s = -0.04, p = 0.85). In conclusion, we present a unique case of impaired thirst sensation and AVP secretion in which hyponatremia developed without desmopressin therapy. Preserved non-osmotic AVP secretion, possibly stimulated by glucocorticoid deficiency, may contribute to the development of hyponatremia in patients with ADI.

Purpose: We recently demonstrated an additional oxytocin (OT) deficiency in patients with arginine vasopressin (AVP) deficiency (central diabetes insipidus) by using 3,4-methylenedioxy-methamphetamine (MDMA) as a novel provocation test. However, the implication of the MDMA provocation test in clinical practice might be challenging. Glucagon effectively stimulates vasopressinergic neurons with a strong increase in plasma copeptin. We therefore hypothesized that this provocation test might also stimulate OT., Methods: This is a predefined secondary analysis of a prospective double-blind, randomised, placebo-controlled cross-over trial involving ten patients with AVP deficiency and ten sex- and body-mass index-matched healthy participants at the University Hospital Basel, Switzerland. Each participant underwent the glucagon test (s.c. injection of 1 mg glucagon) and placebo test (s.c. injection of 0.9% normal saline). Plasma OT levels were measured at baseline, 60, 120 and 180 min after injection. The primary objective was to determine whether glucagon stimulates OT and whether OT levels differ between patients with AVP deficiency and healthy participants. The primary outcome (maximum change in OT within 180 min) was compared between groups and conditions using a linear mixed effects model., Results: In healthy participants, the median OT at baseline was 82.7 pg/ml [62.3-94.3] and slightly increased to a maximum of 93.3 pg/ml [87.2-121.1] after injection of glucagon, resulting in a change increase of 24.9 pg/ml [5.1-27.8]. Similarly, in patients with AVP deficiency, the median OT at baseline was 73.9 pg/ml [65.3-81.6] and slightly increased after glucagon injection to 114.9 pg/ml [70.9-140.9], resulting in a change increase of 36.8 pg/ml [-2.2 to 51.2]. The results from the mixed model showed no effect between glucagon compared to placebo on OT (difference: -0.5 pg/ml; 95%-CI [-25, 24]; p = 0.97) and no significant treatment-by-group interaction effect between patients compared to healthy participants (interaction: 28 pg/ml; 95%-CI [-7, 62]; p = 0.13)., Conclusion: We found no effect of glucagon on plasma OT levels and no difference between patients with AVP deficiency and healthy participants., (© 2024. The Author(s).)

Hyponatremia is the most common electrolyte abnormality encountered in critically ill patients and is linked to heightened morbidity, mortality, and healthcare resource utilization. However, its causal role in these poor outcomes and the impact of treatment remain unclear. Plasma sodium is the main determinant of plasma tonicity; consequently, hyponatremia commonly indicates hypotonicity but can also occur in conjunction with isotonicity and hypertonicity. Plasma sodium is a function of total body exchangeable sodium and potassium and total body water. Hypotonic hyponatremia arises when total body water is proportionally greater than the sum of total body exchangeable cations, that is, electrolyte-free water excess; the latter is the result of increased intake or decreased (kidney) excretion. Hypotonic hyponatremia leads to water movement into brain cells resulting in cerebral edema. Brain cells adapt by eliminating solutes, a process that is largely completed by 48 h. Clinical manifestations of hyponatremia depend on its biochemical severity and duration. Symptoms of hyponatremia are more pronounced with acute hyponatremia where brain adaptation is incomplete while they are less prominent in chronic hyponatremia. The authors recommend a physiological approach to determine if hyponatremia is hypotonic, if it is mediated by arginine vasopressin, and if arginine vasopressin secretion is physiologically appropriate. The treatment of hyponatremia depends on the presence and severity of symptoms. Brain herniation is a concern when severe symptoms are present, and current guidelines recommend immediate treatment with hypertonic saline. In the absence of significant symptoms, the concern is neurologic sequelae resulting from rapid correction of hyponatremia which is usually the result of a large water diuresis. Some studies have found desmopressin useful to effectively curtail the water diuresis responsible for rapid correction., Competing Interests: Declaration of Conflicting InterestsThe author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Differentiating between arginine vasopressin deficiency (AVP-D) and primary polydipsia (PP) requires a copeptin stimulation test. We aimed to characterize changes in apelin, an endogenous hormone antagonizing AVP, upon copeptin stimulation tests., Design: Post hoc secondary analysis of a multi-centric cross-over diagnostic study (NCT03572166)., Setting: Outpatients included at the University Hospital Basel., Participants: Patients with AVP-D and PP., Interventions: Copeptin stimulation tests with hypertonic saline and arginine infusion., Outcomes and Measures: The primary outcome was the absolute difference in apelin between baseline and peak of copeptin stimulation tests. Secondary objectives included the diagnostic ability of apelin., Results: Thirty-eight patients were analysed, 23 (60%) had PP and 15 (40%) had AVP-D. No difference was seen between baseline median (IQR) apelin levels in PP and AVP-D (1079 [912, 1225] and 910 [756, 1039] pmol/L, respectively). Upon hypertonic saline, apelin decreased by -241 (-326, -124) pmol/L in PP and -47.2 (-198, 5.86) pmol/L in AVP-D (P = .022). The area under the curve (AUC) to differentiate PP from AVP-D was 97.1% (95% CI, 90.5-100) for copeptin and 49.3% (95% CI, 30.4-68.1) for apelin (P < .001). Upon arginine, apelin decreased by -39.2 (-96.4, 39.8) pmol/L in PP and increased by 25.8 (2.8, 113.0) pmol/L in AVP-D (P = .1). The AUC was 97.1% (95% CI: 79.6-98.0) for copeptin and 60.5% (95% CI: 39.8-80.0) for apelin (P = .007)., Conclusions and Relevance: Our findings suggest that apelin decreases to a greater extent in PP compared with AVP-D upon copeptin stimulation tests. However, copeptin remains the best marker to differentiate AVP-D from PP., Competing Interests: Conflict of interest: Thermo Fisher Scientific provided the copeptin assays (BRAHMS Copeptin proAVP assay). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The authors declare that there is no further conflict of interest that could be perceived as prejudicing the impartiality of the research reported. The co-author M.C.-C. is on the editorial board of EJE. She was not involved in the review or editorial process for this paper, on which she is listed as author., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

This study aimed to predict arginine vasopressin deficiency (AVP-D) following transsphenoidal pituitary adenoma surgery using machine learning algorithms. We reviewed 452 cases from December 2013 to December 2023, analyzing clinical and imaging data. Key predictors of AVP-D included sex, tumor height, preoperative and postoperative changes in sellar diaphragm height and pituitary stalk length, preoperative ACTH levels, changes in ACTH levels, and preoperative cortisol levels. Six machine learning algorithms were tested: logistic regression (LR), support vector classification (SVC), random forest (RF), decision tree (DT), k-nearest neighbors (KNN), and extreme gradient boosting (XGBoost). After cross-validation and parameter optimization, the random forest model demonstrated the highest performance, with an accuracy (ACC) of 0.882 and an AUC of 0.96. The decision tree model followed, achieving an accuracy of 0.843 and an AUC of 0.95. Other models showed lower performance: LR had an ACC of 0.522 and an AUC of 0.54; SVC had an ACC of 0.647 and an AUC of 0.67; KNN achieved an ACC of 0.64 and an AUC of 0.70; and XGBoost had an ACC of 0.794 and an AUC of 0.91. The study found that a shorter preoperative pituitary stalk length, significant intraoperative stretching, and lower preoperative ACTH and cortisol levels were associated with a higher likelihood of developing AVP-D post-surgery., (© 2024. The Author(s).)

Background & Aims: Athletes are commonly exposed to exercise-induced dehydration. However, the best method to detect dehydration under this circumstance is not clear. This study aimed to analyze pre- and post-dehydration measurements of biomarkers, including saliva osmolality (SOsm), urine osmolality (UOsm), urine-specific gravity (USG), urine color (Ucolor), serum osmolality (SeOsm), serum arginine vasopressin (AVP), serum sodium (Na + ), and thirst sensation in underhydrated athletes, using the body mass loss (BML) as the reference method., Methods: In this clinical trial (NCT05380089), a total of 38 athletes (17 females) with a regular low water intake (<35 mL/kg/day) were submitted to exercise-induced dehydration with a heat index of 29.8 ± 3.1 °C and an individualized running intensity (80-90% of first ventilatory threshold)., Results: ROC curve analysis revealed significant discriminative abilities of SOsm, with AUC values of 0.76 at 1.5% BML, 0.75 at 1.75% BML, and 0.87 at 2% BML, while Na + and SeOsm showed the highest AUC of 0.87 and 0.91 at 2% BML, respectively. SOsm showed high sensitivity at 1.5% of BML, while SeOsm and Na + demonstrated high sensitivity at 2% of BML., Conclusion: This study highlights SOsm as a potential indicator of hydration status across different levels of BML. Additionally, Na + and SeOsm emerged as accurate dehydration predictors at 1.75% and 2% of BML. Notably, the accuracy of urinary indices and thirst sensation for detecting hydration may be limited., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Vasopressin or arginine-vasopressin (AVP) is a neuropeptide molecule known for its antidiuretic effects and serves to regulate plasma osmolality and blood pressure. The existing literature suggests that AVP plays a multifaceted-though less well-known-role in the central nervous system (CNS), particularly in relation to the pathophysiology and treatment of mood disorders. Animal models have demonstrated that AVP is implicated in regulating social cognition, affiliative and prosocial behaviors, and aggression, often in conjunction with oxytocin. In humans, AVP is implicated in mood disorders through its effects on the hypothalamic-pituitary-adrenal (HPA) axis as well as on the serotoninergic and glutamatergic systems. Measuring plasma AVP has yielded interesting but mixed results in mood and stress-related disorders. Recent advances have led to the development of copeptin as a stable and reliable surrogate biomarker for AVP. Another interesting but relatively unexplored issue is the interaction between the osmoregulatory system and mood disorder pathophysiology, given that psychotropic medications often cause dysregulation of AVP receptor expression or signaling that can subsequently lead to clinical syndromes like syndrome of inappropriate diuresis and diabetes insipidus. Finally, pharmaceutical trials of agents that act on V1a and V1b receptor antagonists are still underway. This narrative review summarizes: (1) the neurobiology of the vasopressinergic system in the CNS; (2) the interaction between AVP and the monoaminergic and glutamatergic pathways in the pathophysiology and treatment of mood disorders; (3) the iatrogenic AVP dysregulation caused by psychotropic medications; and (4) the pharmaceutical development of AVP receptor antagonists for the treatment of mood disorders., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Environmental exposures may have endocrine disruptor (ED) effects, e.g., a role for halogenated hydrocarbon chlorobenzenes in increasing vasopressin (AVP), oxytocin (OT) secretion and, in association, anxiety and aggression in male rats has been shown. Our aim is to investigate whether 1,2,4-trichlorobenzenehexachlorobenzene= 1:1 (mClB) treatment of female rats also shows ED effects and reproductive biology differences, and whether AVP may have a mediator role in this? Female Wistar rats were treated (0.1; 1.0; 10.0 μg/bwkg/day) with mClB (by gastrictube) and then 30; 60; 90 days after treatment anxiety (open field test) and aggressive (resident intruder test) behaviors AVP, OT concentrations from blood plasma samples were detected by radioimmunoassay on 30; 60; 90 days. Treated female rats were mated with untreated males. Mating success, number of newborn and maternal aggression on the neonates were monitored. Results showed that AVP, OT levels; and anxiety, aggressive behaviors; and mothers' aggression towards their offspring increased significantly in relation to the duration and the dose of mClB treatment. But mating propensity and number of offspring decreased. Patterns of AVP, OT release and anxiety, aggression behaviors, and reproductive-related behaviors were correlated. Consistent with the literature, our studies confirmed the role of AVP and OT in different behavioral effects., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The neurohormones oxytocin (OT) and arginine vasopressin (AVP) are involved in social behaviors and psychiatric conditions. However, more research on nonhuman primates with complex social behaviors is needed. We studied two closely-related primate species with divergent social and mating systems; hamadryas baboons (Papio hamadryas, n=38 individuals) and anubis baboons (Papio anubis, n=46). We measured OT in cerebrospinal fluid (CSF, n=75), plasma (n=81) and urine (n=77), and AVP in CSF (n=45), and we collected over 250 hours of focal behavioral observations. Using Bayesian multivariate models, we found no clear species difference in hormone levels; the strongest support was for hamadryas having higher CSF OT levels than anubis (posterior probability [PP] for females = 0.75, males = 0.84). Looking at nine specific behaviors, OT was associated with affiliative behaviors (approach, proximity, grooming, PP ∼ 0.85 - 1.00), albeit inconsistently across sources of measurement (CSF, plasma, and urine, which were uncorrelated with each other). Most behaviors had low repeatability (R ∼ 0 - 0.2), i.e. they did not exhibit stable between-individual differences (or "personality"), and different behaviors did not neatly coalesce into higher-order factors (or "behavioral syndromes"), which cautions against the use of aggregate behavioral measures and highlights the need to establish stable behavioral profiles when testing associations with baseline hormone levels. In sum, we found some associations between peptides and social behavior, but also many null results, OT levels from different sources were uncorrelated, and our behavioral measures did not indicate clear individual differences in sociability., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

When a naïve observer meets with a familiar conspecific in pain, mice may have a myriad of social (sniffing, allolicking, allogrooming, huddling) and non-social (self-grooming) behaviors under dyadic social interaction (DSI) paradigm. Unlike male, female observers express more allolicking behavior toward injury site of a familiar female in pain, but with less body allogrooming. In current study, we investigated roles of natural estrus cycle phases and ovarian estrogen in these behaviors and results showed that: (1) there was no changes in above behaviors in terms of latency, time and bouts across different natural estrus cycle phases in intact female. (2) however, ovariectomy (OVX) changed estrus cycle phases, lowered circulating level of ovarian estrogen, reduced time and bouts of allolicking behavior and increased time of self-grooming without affecting other behaviors. Moreover, OVX in observers decreased social buffering effect of DSI on spontaneous pain-related behavior in demonstrator relative to naïve and sham controls. (3) treatment of OVX-female with β-estradiol (E 2 ) or progesterone (PROG) as replacement therapies, only E 2 reversed impairment of allolicking behavior. (4) Additionally, socially transferred pain could be identified in intact female across all estrus cycle phases post-DSI, but disappeared in OVX-female, which could be reversed completely by E 2 but not by PROG. (5) Finally, serum levels of estrogen, PROG, oxytocin, arginine vasopressin (AVP), prolactin, norepinephrine and 5-HT were examined by ELISA after E 2 , results showed only AVP level was significantly increased. These results suggest both injury site-targeted caring behavior and socially transferred pain are selectively dependent on ovarian estrogen. This article is part of the Special Issue on "Empathic Pain"., Competing Interests: Declaration of competing interest The authors hereby declare that there are no conflicts of interest, financial or otherwise, that could have influenced the integrity and objectivity of the research conducted and presented in this paper. This includes, but is not limited to, the following aspects: 1. Financial Conflicts of Interest: All authors affirm that they have not received any direct or indirect financial support that could influence the outcomes of this research. Furthermore, no author is employed by, consults for, owns shares in, or receives funding from any company or organization that would benefit from the results of this study. 2. Personal and Academic Relationships: All authors declare that they have no personal relationships or academic competition related to the subject matter of this research that could interfere with the objectivity or fairness of the research. 3. Transparency in Data and Methods: To ensure transparency, the data and methodologies used in this study are openly available for peer review and public scrutiny. 4. Other Potential Conflicts: All authors confirm that there are no other potential conflicts of interest, beyond those disclosed, that could undermine the integrity of this research., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The elucidation of the underlying cause of polyuria-polydipsia syndrome (PPS) is a challenging-especially in the differentiation of partial defects of arginine vasopressin (AVP) secretion or action from primary polydipsia. The water deprivation test has been utilized for many decades, and its application in the paediatric population has been applied using parameters predominantly established in adult cohorts. In more recent times, the development of automated commercial assays for copeptin, a surrogate marker for AVP, has represented a significant advancement in the diagnostic approach to PPS. Measurement of copeptin concentrations has major advantages and has essentially superseded measurement of AVP in diagnostic protocols for PPS. Additionally, stimulated-copeptin protocols utilizing hypertonic saline infusion, arginine, and glucagon have been investigated, and are promising. However, further studies are required in the population-incorporating the differences in physiological regulation of water homeostasis, and safety requirements-before there is widespread adoption into clinical practice., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Polyuria-polydipsia syndrome can be caused by central diabetes insipidus, nephrogenic diabetes insipidus or primary polydipsia. To avoid confusion with diabetes mellitus, the name 'central diabetes insipidus' was changed in 2022 to arginine vasopressin (AVP) deficiency and 'nephrogenic diabetes insipidus' was renamed as AVP resistance. To differentiate the three entities, various osmotic and non-osmotic copeptin-based stimulation tests have been introduced in the past decade. The hypertonic saline test plus plasma copeptin measurement emerged as the test with highest diagnostic accuracy, replacing the water deprivation test as the gold standard in differential diagnosis of the polyuria-polydipsia syndrome. The mainstay of treatment for AVP deficiency is AVP replacement with desmopressin, a synthetic analogue of AVP specific for AVP receptor 2 (AVPR2), which usually leads to rapid improvements in polyuria and polydipsia. The main adverse effect of desmopressin is dilutional hyponatraemia, which can be reduced by regularly performing the so-called desmopressin escape method. Evidence from the past few years suggests an additional oxytocin deficiency in patients with AVP deficiency. This potential deficiency should be further evaluated in future studies, including feasible provocation tests for clinical practice and interventional trials with oxytocin substitution., (© 2024. Springer Nature Limited.)

Plasma copeptin is a biomarker that reflects arginine vasopressin (AVP) secretion. In this study we measured copeptin during insulin tolerance test (ITT) in 65 patients referred to our department for evaluation of anterior pituitary function. Plasma for measurements of copeptin were collected at the start of the test and regurarly up to 120 minutes thereafter. Of 60 patients who developed significant hypoglycemia and were included in the analyses, 13 (22%) had corticotropic deficiency, 11 (18%) had thyreotropic deficiency, 33 (55%) had growth hormone deficiency and 4 (6%) had AVP deficieny (AVPD). Thirty-seven (62%) patients had at least one anterior pituitary deficiency. In patients without AVPD, median (range) copeptin increased from 4.5 pmol/L (1.3-33.0) to a maximum of 6.2 pmol/L (2.0-34.4; p<0.001). Baseline copeptin was similar in men and women, but maximal copeptin during ITT was higher in men. Copeptin concentrations were not affected by age, BMI, somatotropic, or corticotropic function. Copeptin concentrations were lower in patients with AVPD than patiets without AVPD, and in patients with thyrotropic deficiency, compared to patients with intact thyrotropic function, both at baseline and during ITT. In conclusion, copeptin increases significantly during insulin induced hypoglycemia but is of limited value in predicting anterior pituitary hormonal function., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Arginine-vasopressin (AVP), a cyclic peptide hormone composed of nine amino acids, regulates water reabsorption by increasing intracellular cyclic adenosine monophosphate (cAMP) concentrations via the vasopressin V2 receptor (V2R). Plasma AVP is a valuable biomarker for the diagnosis of central diabetes insipidus (CDI) and is commonly measured using radioimmunoassay (RIA). However, RIA has several drawbacks, including a long hands-on time, complex procedures, and handling of radioisotopes with special equipment and facilities. In this study, we developed a bioassay to measure plasma AVP levels using HEK293 cells expressing an engineered V2R and a cAMP biosensor. To achieve high sensitivity, we screened V2R orthologs from 11 various mammalian species and found that the platypus V2R (pV2R) responded to AVP with approximately six-fold higher sensitivity than that observed by the human V2R. Furthermore, to reduce cross-reactivity with desmopressin (DDAVP), a V2R agonist used for CDI treatment, we introduced a previously described point mutation into pV2R, yielding an approximately 20-fold reduction of responsiveness to DDAVP while maintaining responsiveness to AVP. Finally, a comparison of plasma samples from 12 healthy individuals demonstrated a strong correlation (Pearson's correlation value: 0.90) between our bioassay and RIA. Overall, our assay offers a more rapid and convenient method for quantifying plasma AVP concentrations than existing techniques., (© 2024. The Author(s).)

Objectives: Arginine-stimulated serum copeptin has been proposed as a new method to diagnose arginine vasopressin (AVP) deficiency in children and adolescents. Herein we investigated the secretagogic potential of clonidine or L-Dopa on the copeptin serum levels in children., Methods: Eight stimulation tests (4 with clonidine and 4 with L-Dopa) were performed in eight children (5 boys and 3 girls) with a median age of 6.5 years-old, evaluated for short stature due to possible growth hormone deficiency. Serum copeptin levels were measured at 30, 60, 90, and 120 min after administration of clonidine or L-Dopa., Results: Copeptin levels in serum did not show any significant change in either test (clonidine or L-Dopa). The values of copeptin levels compared to the baseline value did not deviate more than 5 % in the clonidine arm (p=0.60) or 8 % in the L-Dopa arm (p=0.75) respectively., Conclusions: Data do not support the use of L-Dopa or clonidine as stimulants for evaluating AVP relating disorders in clinical pediatric practice., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background/aim: Nocturnal enuresis can be frustrating for children and their families as the child ages. Our aim is to evaluate urine aquaporin 2 (AQP-2) as a noninvasive biomarker of water balance in children with primary monosymptomatic nocturnal enuresis (PMNE)., Material and Methods: The study included 90 children; sixty-eight children suffering from PMNE aged (9.57 ± 2.16) years and 22 healthy children with good toilet control, matched sex and age. All enuretic children were subjected to complete history taking, clinical evaluation, and bed wetting diary. Serum arginine vasopressin (AVP) and urine AQP-2 were tested in the morning (at 9-11 am) and evening (at 9-11 pm). Blood urea, creatinine, Na, glucose, urine osmolality, Ca/Cr, Alb/Cr and specific gravity were tested simultaneously., Results: Serum AVP, urine AQP-2, and urine osmolality were statistically lower in patients than controls. Patients had a significantly lower level of night serum AVP concentrations, urine AQP-2, and urine osmolality than the corresponding morning level. Urine AQP-2 was significantly correlated with urine osmolality (p < 0.05). AQP-2 had a sensitivity of 90% and a specificity of 70%. However, no statistically significant correlation was found between serum AVP and urine AQP-2., Conclusion: Primary monosymptomatic nocturnal enuresis in children could be associated with reduction of urine excretion of AQP-2 at night. Urine AQP-2 is significantly correlated with urine osmolality. Therefore, it may be a noninvasive biomarker of hydration status in children with PMNE, with good sensitivity and specificity., Competing Interests: Conflict of interest: No potential conflict of interest was reported by the author(s)., (© TÜBİTAK.)

Objective: Arginine vasopressin deficiency (AVD) following neurosurgical procedures for pituitary disorders is common and can delay discharge. Copeptin, a stable surrogate marker of arginine vasopressin, may predict postoperative AVD. The authors' aim was to assess the optimal postoperative sampling time and cut-point concentration of copeptin to predict the development of postsurgical AVD., Methods: Adults without preexisting AVD who were undergoing surgery for a pituitary lesion between February 2020 and April 2022 were eligible for study inclusion. Two samples were drawn from each patient postoperatively to assess the copeptin concentration using an immunofluorescent assay. Samples were denoted as "early" (within 6 hours of extubation) or "postoperative day 1" (POD1; within 10-30 hours of extubation). Patients were evaluated for the development of AVD., Results: One hundred ninety-two patients (54.2% female) with a median age of 54.5 years (IQR 39.8-67.0 years) were included in the study. The median copeptin concentration at both time points was significantly lower in those with AVD (transient or permanent; n = 22, 11.5%) than in those without (early: 4.9 vs 18.7 pmol/L, p < 0.001; POD1: 3.4 vs 4.9 pmol/L, p < 0.001) but did not differ in those who developed transient versus permanent AVD. The optimal copeptin cut point for the prediction of AVD was < 8.5 pmol/L for early samples (sensitivity 0.70, specificity 0.80, positive predictive value [PPV] 0.29, negative predictive value [NPV] 0.96) and < 4.3 pmol/L for POD1 samples (sensitivity 0.82, specificity 0.63, PPV 0.22, NPV 0.96). In early samples, a copeptin cutoff of 22.9 pmol/L increased the sensitivity for the detection of AVD to 95% with an NPV of 99%. The proportion of patients who had AVD was higher (60.0% vs 8.8%, p < 0.001) and the copeptin concentration lower (early: 4.3 vs 17.0 pmol/L, p < 0.001; POD1: 2.7 vs 4.9 pmol/L, p < 0.001) among those who had undergone surgery for a craniopharyngeal duct pathology versus a pituitary adenoma. Although copeptin was lower in patients with persistent Cushing's disease than in those in remission, the difference did not reach statistical significance (early p = 0.11, POD1 p = 0.52). Furthermore, the copeptin concentration could not predict the development of syndrome of inappropriate secretion of antidiuretic hormone. Patients without AVD who had received stress dose steroids intraoperatively had lower median early copeptin (11.7 vs 19.1 pmol/L, p = 0.027)., Conclusions: In early postoperative copeptin samples, the optimal copeptin cut point for AVD diagnosis was < 8.5 pmol/L, and a level > 22.9 pmol/L had predicative utility in excluding AVD. Caution should be used when interpreting copeptin results, as patients administered glucocorticoids intraoperatively without AVD had lower median copeptin concentrations.

Background: The clinical utility of tolvaptan in chronic kidney disease (CKD) patients with heart failure remains uncertain. The level of urine cyclic adenosine monophosphate (AMP) relative to plasma arginine vasopressin (AVP) indicates the residual function of the collecting ducts in response to AVP stimulation and might be a key to predicting response of tolvaptan., Methods: CKD patients who were hospitalized to treat their congestive heart failure refractory to conventional loop diuretics were considered to receive tolvaptan and included in this prospective study. The impact of urine cyclic AMP/plasma AVP ratio for prediction of response to tolvaptan, which was defined as any increase in urine volume at day 7 from day 0, was investigated., Results: A total of 30 patients (median 75 years old, 24 men, and median estimated glomerular filtration rate 14.4 mL/min/1.73 m 2 ) were included. As compared to baseline, urine volume increased at day 7 in 17 responders, whereas urine volume decreased at day 7 in 13 non-responders. Baseline urine cyclic AMP/plasma AVP ratio distributed between 0.25 and 4.01 with median 1.90. The urine cyclic AMP/plasma AVP ratio was a significant predictor of response to tolvaptan, which was adjusted for 6 potential confounders with a cutoff of 1.24., Conclusions: Baseline urine cyclic AMP/plasma AVP ratio is an independent predictor of response to tolvaptan in advanced CKD patients with heart failure., Clinical Trial Registration: UMIN000022422., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

Liver diseases, including cirrhosis, viral hepatitis, and hepatocellular carcinoma, account for approximately two million annual deaths worldwide. They place a huge burden on the global healthcare systems, compelling researchers to find effective treatment for liver fibrosis-cirrhosis. Portacaval anastomosis (PCA) is a model of liver damage and fibrosis. Arginine vasopressin (AVP) has been implicated as a proinflammatory-profibrotic hormone. In rats, neurointermediate pituitary lobectomy (NIL) induces a permanent drop (80%) in AVP serum levels. We hypothesized that AVP deficiency (NIL-induced) may decrease liver damage and fibrosis in a rat PCA model. Male Wistar rats were divided into intact control (IC), NIL, PCA, and PCA+NIL groups. Liver function tests, liver gene relative expressions (IL-1, IL-10, TGF- β , COLL-I, MMP-9, and MMP-13), and histopathological assessments were performed. In comparison with those in the IC and PCA groups, bilirubin, protein serum, and liver glycogen levels were restored in the PCA+NIL group. NIL in the PCA animals also decreased the gene expression levels of IL-1 and COLL-I, while increasing those of IL-10, TGF- β , and MMP-13. Histopathology of this group also showed significantly decreased signs of liver damage with lower extent of collagen deposition and fibrosis. Low AVP serum levels were not enough to fully activate the AVP receptors resulting in the decreased activation of cell signaling pathways associated with proinflammatory-profibrotic responses, while activating cell molecular signaling pathways associated with an anti-inflammatory-fibrotic state. Thus, partial reversion of liver damage and fibrosis was observed. The study supports the crucial role of AVP in the inflammatory-fibrotic processes and maintenance of immune competence. The success of the AVP deficiency strategy suggests that blocking AVP receptors may be therapeutically useful to treat inflammatory-fibrotic liver diseases., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Martín Muñoz-Ortega et al.)

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.

Background and Aims: Direct measurement of arginine vasopressin (AVP) via immunoassays is not widely conducted, mainly because of technical constraints. Liquid chromatography-tandem mass spectrometry (LC/MS/MS) has been widely used as the gold standard in clinical chemistry. Here, we aimed to develop an MS-based assay to determine human plasma AVP and compare the results with those obtained using a conventional immunoassay., Materials and Methods: We developed a protocol using triple quadrupole MS coupled with LC for the measurement of human plasma AVP. Analytical evaluations of the method were performed, and the results obtained using LC/MS/MS and radioimmunoassay (RIA) were compared., Results: The lower limit of quantification (LLOQ) for plasma AVP obtained using LC/MS/MS and RIA were 0.2 and 0.4 pg/mL, respectively. Although there was a weak overall correlation between the results obtained using the two different methods, the RIA results did not agree with the LC/MS/MS results, particularly at low concentrations., Conclusions: AVP detection through RIA is not satisfactory compared with that using LC/MS/MS. Diagnostic values of direct AVP measurements must be evaluated based on the results obtained via sensitive and accurate MS-based methods rather than those obtained through RIA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder leading to deterioration of kidney function and end stage kidney disease (ESKD). A number of molecular processes are dysregulated in ADPKD but the exact mechanism of disease progression is not fully understood. We measured protein biomarkers being linked to ADPKD-associated molecular processes via ELISA in urine and serum in a cohort of ADPKD patients as well as age, gender and eGFR matched CKD patients and healthy controls. ANOVA and t -tests were used to determine differences between cohorts. Spearman correlation coefficient analysis was performed to assess coregulation patterns of individual biomarkers and renal function. Urinary epidermal growth factor (EGF) and serum apelin (APLN) levels were significantly downregulated in ADPKD patients. Serum vascular endothelial growth factor alpha (VEGFA) and urinary angiotensinogen (AGT) were significantly upregulated in ADPKD patients as compared with healthy controls. Arginine vasopressin (AVP) was significantly upregulated in ADPKD patients as compared with CKD patients. Serum VEGFA and VIM concentrations were positively correlated and urinary EGF levels were negatively correlated with urinary AGT levels. Urinary EGF and AGT levels were furthermore significantly associated with estimated glomerular filtration rate (eGFR) in ADPKD patients. In summary, altered protein concentrations in body fluids of ADPKD patients were found for the mechanistic markers EGF, APLN, VEGFA, AGT, AVP, and VIM. In particular, the connection between EGF and AGT during progression of ADPKD warrants further investigation.

Previously, we found that basal corticosterone pulsatility significantly impacts the vulnerability for developing post-traumatic stress disorder (PTSD). Rats that exhibited PTSD-phenotype were characterized by blunted basal corticosterone pulsatility amplitude and a blunted corticosterone response to a stressor. This study sought to identify the mechanisms underlining both the loss of pulsatility and differences in downstream responses. Serial blood samples were collected manually via jugular vein cannula at 10-min intervals to evaluate suppression of corticosterone following methylprednisolone administration. The rats were exposed to predator scent stress (PSS) after 24 h, and behavioral responses were assessed 7 days post-exposure for retrospective classification into behavioral response groups. Brains were harvested for measurements of the glucocorticoid receptor, mineralocorticoid receptor, FK506-binding protein-51 and arginine vasopressin in specific brain regions to assess changes in hypothalamus-pituitary-adrenal axis (HPA) regulating factors. Methylprednisolone produced greater suppression of corticosterone in the PTSD-phenotype group. During the suppression, the PTSD-phenotype rats showed a significantly more pronounced pulsatile activity. In addition, the PTSD-phenotype group showed distinct changes in the ventral and dorsal CA1, dentate gyrus as well as in the paraventricular nucleus and supra-optic nucleus. These results demonstrate a pre-trauma vulnerability state that is characterized by an over-reactivity of the HPA and changes in its regulating factors.

Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.

Arginine vasopressin (AVP), which is also called antidiuretic hormone (ADH), is a neurohormone synthetized from a pre-pro-hormone precursor in the supraoptic and paraventricular nuclei of the hypothalamus in response to increased plasma osmolality and decreased blood volume. AVP exerts several effects by binding to three different receptors: V1aR, V1bR, and V2R. In recent years, it has been suggested that increased plasma concentration of AVP may play a causal role in the development of type 2 diabetes, the metabolic syndrome, renal dysfunction and cardiovascular disease by influencing glucose homeostasis and lipid metabolism through several possible mechanisms involving V1aR and V1bR. V1aR located in the liver is involved in hepatic glycogenolysis and gluconeogenesis. V1bR, found in the pituitary gland and pancreas, mediates secretion of adrenocorticotrophic hormone (ACTH), insulin, and glucagon. However, AVP's clinical use as a biomarker is limited due to its short half-life in plasma (16-20 minutes), small size, and poor stability, which make direct measurement difficult. Copeptin, the biologically inactive, stable, C-terminal part of pro-vasopressin, is co-secreted with AVP in equimolar amounts and thus is considered an adequate and clinically useful surrogate marker of AVP. The aim of this review is to assess the current state of knowledge about the potential role of copeptin as a novel biomarker of cardiometabolic syndrome on the basis of recent scientific literature published up to December 2020 and searches of the PubMed, Google Scholar, and Web of Science databases.

Rates of delivery by caesarean section (CS) are increasing around the globe and, although several epidemiological associations have already been observed between CS and health outcomes in later life, more are sure to be discovered as this practice continues to gain popularity. The components of vaginal delivery that protect offspring from the negative consequences of CS delivery in later life are currently unknown, although much attention to date has focused on differences in microbial colonisation. Here, we present the case that differing hormonal experiences at birth may also contribute to the neurodevelopmental consequences of CS delivery. Levels of each of the 'birth signalling hormones' (oxytocin, arginine vasopressin, epinephrine, norepinephrine and the glucocorticoids) are lower following CS compared to vaginal delivery, and there is substantial evidence for each that manipulations in early life results in long-term neurodevelopmental consequences. We draw from the research traditions of neuroendocrinology and developmental psychobiology to suggest that the perinatal period is a sensitive period, during which hormones achieve organisational effects. Furthermore, there is much to be learned from research on developmental programming by early-life stress that may inform research on CS, as a result of shared neuroendocrine mechanisms at work. We compare and contrast the effects of early-life stress with those of CS delivery and propose new avenues of research based on the links between the two bodies of literature. The research conducted to date suggests that the differences in hormone signalling seen in CS neonates may produce long-term neurodevelopmental consequences., (© 2020 British Society for Neuroendocrinology.)

Purpose: The physiological role of arginine vasopressin (AVP) in the acute stress response in humans and especially in children is unclear. The aim of this study was to explore the interaction between copeptin, a well-established surrogate marker of AVP release, and anterior pituitary hormone activation in response to acute hypoglycemic stress in children and adolescents., Methods: We conducted an exploratory single center study involving 77 children and adolescents undergoing insulin-induced hypoglycemia. Blood levels of copeptin, ACTH, cortisol, GH, prolactin, interleukin-6 (IL-6), adrenaline and noradrenaline were determined at baseline and after insulin-induced hypoglycemia., Results: Basal plasma levels of copeptin (median: 5.2 pmol/L) increased significantly after hypoglycemia (median 9.7 pmol/L; P < 0.0001). Subjects with insufficient HPA axis response or severe GH deficiency had lower hypoglycemia-induced copeptin increase (median: 2.3 pmol/L) compared with individuals with intact pituitary response (median: 5.2 pmol/L, P = 0.02). Copeptin increase correlated significantly with the maximal increase of ACTH (r s  = 0.30; P = 0.010), cortisol (r s  = 0.33; P = 0.003), prolactin (r s  = 0.25; P = 0.03), IL-6 (r s  = 0.35; P = 0.008) and with BMI-SDS (r s  = - 0.28, P = 0.01). In multivariate regression analysis, prolactin increase was the only independent variable associated with copeptin increase (P = 0.0004)., Conclusion: Our data indicate that: (1) hypoglycemic stress elicits a marked copeptin response in children and adolescents, pointing out its role as an acute stress marker in this population; (2) stress-induced AVP/copeptin release is associated with anterior pituitary activation, mainly a prolactin response.

Context: Copeptin is a surrogate marker for arginine vasopressin (AVP) release in response to hyperosmolal stimuli such as diabetic ketoacidosis (DKA)., Objective: The objective of this work is to characterize kinetics of copeptin and osmolality, and their dynamic relationship during rehydration and insulin therapy in children with type 1 diabetes (T1D) and DKA., Design and Setting: A prospective, observational, multicenter study was conducted., Patients and Intervention: Children with T1D admitted for DKA underwent serial serum copeptin and osmolality measurements from start of rehydration at 14 time points during 72 hours., Main Outcome Measures: Measurements included temporal course of copeptin and osmolality (kinetics), relationship between both (dynamics), and association between-subject variability (BSV) (coefficient of variation, CV%)., Results: Twenty-eight children (20 newly diagnosed T1D) aged 1 to 16 years were included. Copeptin decreased from 95 pmol/L (95% CI, 55-136 pmol/L) (CV%, 158%) to 9.7 pmol/L (95% CI, 8.1-11.4 pmol/L) (CV%, 31%) with a 50% recovery time (t1/2) of 7.1 hours (range, 5.1-11.5 hours) (114%). Serum osmolality decreased from 321 mOsm/kg (range, 315-327 mOsm/kg) (4%) to 294 mOsm/kg (range, 292-296 mOsm/kg) (1%) with a t1/2 of 4.3 hours (range, 3.0-5.6 hours) (64%). Copeptin levels doubled with each osmolality increase by 15 mOsm/kg (range, 10-21 mOsm/kg) (59%), from 9.8 pmol/L (range, 7.3-12.3 pmol/L) (48%) to 280 mOsm/kg. Copeptin kinetics differed between newly diagnosed and known T1D patients (P = .001), and less between mild vs moderate-severe DKA (P = .04)., Conclusions: First, this study characterized for the first time copeptin kinetics and dynamics in the high hyperosmolar range in children with DKA. Second, it revealed significant differences in copeptin kinetics between newly diagnosed and known T1D patients that may be explained by changes at the osmoreceptor and renal AVP receptor level due to longstanding osmotic diuresis and DKA., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cancer immunotherapy is a breakthrough strategy entwined with toxicity. Immune-related hypophysitis is conventionally considered distinctive of cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors. Immune-related central diabetes insipidus (CDI) is exceptional. CDI rarely manifests as hypernatremia, which is almost always euvolemic. We report a 71-years-old male patient with advanced lung cancer who experienced severe chronic hypernatremia presented as alterations in mental status five months after initiation of treatment with the anti-PD-1 checkpoint inhibitor nivolumab. Combination of persistenthypernatremia, polyuria, high plasma osmolality and hyposthenuria raised suspicion of diabetes insipidus, prompting measurement of serum concentration of arginine vasopressin(AVP). The inappropriately undetectable serum levels of AVP confirmed central diabetes insipidus (CDI). Nivolumab-related hypophysitis was recognized as possible cause of CDI. Further hormonal assessment excluded any endocrinopathy indicating disorder of posterior pituitary. Pituitary MRI was normal with persistence of hyperintensity of posterior pituitary on T1-weighted images (bright spot). The patient was scheduled to receive 1-deamino-8-D-arginine vasopressin (DDAVP), but he died suddenly due to cardiac arrest before initiation of treatment. Our report describes the first case of nivolumab related CDI, building on existing literature through: (I) underscoring hypovolemic hypernatremia as CDI manifestation; (ii) bringing into spotlight the rare anti-PD-1 treatment related hypophysitis; (iii) enriching the limited evidence on immune-related CDI. Increased awareness of nivolumab related CDI will enable prompt recognition and therapeutic intervention., (Copyright © 2020 Elsevier B.V. All rights reserved.)

It has been identified that arginine vasopressin (AVP), vasopressin receptor 2(V2R), and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist, could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R downregulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training, V2R antagonist mozavaptan, or PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reducing rotatory stimulus- or DDAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness; thus, mozavaptan targeting AVP V2Rs in the inner ear may provide us with a new application option to reduce motion sickness. SIGNIFICANCE STATEMENT: Motion sickness affects many people traveling or working. In the present study our results showed that activation of the inner ear arginine vasopressin-vaspopressin receptor 2 (V2R)-aquaporin 2 signaling pathway was potentially involved in the development of motion sickness and that blocking V2R with mozavaptan, a V2R antagonist, was much more effective in reducing motion sickness in both rat and dog; therefore, we demonstrated a new mechanism to underlie motion sickness and a new candidate drug to reduce motion sickness., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

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.

A long-standing body of clinical observations associates low 24-h total water intake (TWI = water + beverages + food moisture) with acute renal disorders such as kidney stones and urinary tract infections. These findings prompted observational studies and experimental interventions comparing habitual low volume (LOW) and high volume (HIGH) drinkers. Investigators have learned that the TWI of LOW and HIGH differ by 1-2 L·d -1 , their hematological values (e.g., plasma osmolality, plasma sodium) are similar and lie within the laboratory reference ranges of healthy adults and both groups appear to successfully maintain water-electrolyte homeostasis. However, LOW differs from HIGH in urinary biomarkers (e.g., reduced urine volume and increased osmolality or specific gravity), as well as higher plasma concentrations of arginine vasopressin (AVP) and cortisol. Further, evidence suggests that both a low daily TWI and/or elevated plasma AVP influence the development and progression of metabolic syndrome, diabetes, obesity, chronic kidney disease, hypertension and cardiovascular disease. Based on these studies, we propose a theory of increased disease risk in LOW that involves chronic release of fluid-electrolyte (i.e., AVP) and stress (i.e., cortisol) hormones. This narrative review describes small but important differences between LOW and HIGH, advises future investigations and provides practical dietary recommendations for LOW that are intended to decrease their risk of chronic diseases.

Protein-arginine methyltransferases catalyze the methylation of the guanidine (N G ) group of proteinic L-arginine (Arg) to produce monomethyl and dimethylarginine proteins. Their proteolysis releases the free amino acids monomethylarginine (MMA), symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA), respectively. MMA, SDMA and ADMA are inhibitors of the nitric oxide synthase (NOS) activity. High circulating and low urinary concentrations of ADMA and SDMA are considered risk factors in the cardiovascular and renal systems, mainly due to their inhibitory action on NOS activity. Identity, biological activity and concentration of N G -methylated proteins are largely unknown. The present study addressed these issues by using GC-MS and LC-MS/MS approaches. GC-MS was used to quantify free ADMA released by classical HCl-catalyzed hydrolysis of three synthetic Arg-vasopressin (V) peptides and of unknown endogenous N G -dimethylated proteins. The cyclic (c) disulfide forms of Arg-vasopressin analogs, i.e., Arg-vasopressin (cV-Arg-Gly-NH 2 ), asymmetrically N G -dimethylated vasopressin (cV-ADMA-Gly-NH 2 ) and symmetrically N G -dimethylated vasopressin (cV-SDMA-Gly-NH 2 ) were used as model peptides in quantitative GC-MS analyses of ADMA, SDMA and other expected amino acids from the hydrolyzed Arg-vasopressin analogs. cV-ADMA-Gly-NH 2 and cV-SDMA-Gly-NH 2 were discriminated from cV-Arg-Gly-NH 2 by LC-MS and LC-MS/MS, yet they were indistinguishable from each other. The same applies to the respective open (o) reduced and di-S-acetamide forms of oV-ADMA-Gly-NH 2 , oV-SDMA-Gly-NH 2 and oV-Arg-Gly-NH 2 . Our LC-MS and LC-MS/MS studies suggest that the Arg-vasopressin analogs form [(M-H)] + and [(M-H)+H] + in the positive ESI mode and undergo in part conversion of their terminal Gly-NH 2 (NH 2 , 16 Da) group to Gly-OH (OH, 17 Da). The product ion mass spectra of the di-S-acetamide forms are complex and contain several intense mass fragments differing by 1 Da. cV-ADMA-Gly-NH 2 and cV-SDMA-Gly-NH 2 induced platelet aggregation in platelet-rich human plasma with moderately different initial velocity and maximal aggregation rates compared to cV-Arg-Gly-NH 2 . Previous studies showed that human red blood cells are rich in large (>50 kDa) ADMA-containing proteins of unknown identity. Our LC-MS/MS proteomic study identified several membrane and cytosolic erythrocytic N G -dimethylated proteins, including spectrin-α (280 kDa), spectrin-β (247 kDa) and protein 4.1 (80 kDa). Being responsible for the stability of the erythrocyte membrane, the newly identified main targets for N G -dimethylation in human erythrocytes should be given a closer look in erythrocytic diseases like hereditary spherocytosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: 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., Methods: 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 (CV I , CV G , and CV A , respectively) and subsequently the index of individuality and heterogeneity (II and IH, respectively)., Results: 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., Conclusions: This analysis demonstrates that AVP assessment is unlikely to yield useful information about hydration status.

Background: 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., Methods: Seventeen patients who were diagnosed with KD and hyponatremia (serum sodium levels <135 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 by >3% was defined as hypervolemia and a decrease in body weight by >3% was defined as hypovolemia., Results: 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., Conclusions: 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., (© 2019 Japan Pediatric Society.)

Various types of acute/chronic nociceptive stimuli cause neuroendocrine responses such as activation of the hypothalamo-neurohypophysial [oxytocin (OXT) and arginine vasopressin (AVP)] system and hypothalamo-pituitary adrenal (HPA) axis. Chronic multiple-arthritis activates the OXT/AVP system, but the effects of acute mono-arthritis on the OXT/AVP system in the same animals has not been simultaneously evaluated. Further, AVP, not corticotropin-releasing hormone (CRH), predominantly activates the HPA axis in chronic multiple-arthritis, but the participation of AVP in HPA axis activation in acute mono-arthritis remains unknown. Therefore, we aimed to simultaneously evaluate the effects of acute mono-arthritis on the activity of the OXT/AVP system and the HPA axis. In the present study, we used an acute mono-arthritic model induced by intra-articular injection of carrageenan in a single knee joint of adult male Wistar rats. Acute mono-arthritis was confirmed by a significant increase in knee diameter in the carrageenan-injected knee and a significant decrease in the mechanical nociceptive threshold in the ipsilateral hind paw. Immunohistochemical analysis revealed that the number of Fos-immunoreactive (ir) cells in the ipsilateral lamina I-II of the dorsal horn was significantly increased, and the percentage of OXT-ir and AVP-ir neurons expressing Fos-ir in both sides of the supraoptic (SON) and paraventricular nuclei (PVN) was increased in acute mono-arthritic rats. in situ hybridization histochemistry revealed that levels of OXT mRNA and AVP hnRNA in the SON and PVN, CRH mRNA in the PVN, and proopiomelanocortin mRNA in the anterior pituitary were also significantly increased in acute mono-arthritic rats. Further, plasma OXT, AVP, and corticosterone levels were significantly increased in acute mono-arthritic rats. These results suggest that acute mono-arthritis activates ipsilateral nociceptive afferent pathways at the spinal level and causes simultaneous and integrative activation of the OXT/AVP system. In addition, the HPA axis is activated by both AVP and CRH in acute mono-arthritis with a distinct pattern compared to that in chronic multiple-arthritis., (Copyright © 2020 Nishimura, Kawasaki, Matsuura, Suzuki, Motojima, Baba, Ohnishi, Yamanaka, Fujitani, Yoshimura, Maruyama, Ueno, Sonoda, Nishimura, Tanaka, Sanada, Onaka, Ueta and Sakai.)

Rapid detection of physiological changes of neuropeptides is of great importance as they are involved in a wide range of physiological processes and behaviors. Abnormalities in their expression level are correlated with various neurological diseases. However, current methods such as radioimmunoassay, enzyme-linked immunosorbent assays and liquid chromatography tandem mass spectrometry relied on cumbersome operation steps and could not rapidly provide the information of their concentration fluctuations. Thus motivated, we developed a target-driven DNA-based molecular machine that could be triggered only in the presence of a specific target neuropeptide. Using arginine-vasopressin (AVP) as a model neuropeptide, we integrated the DNA-based molecular machine with fluorescence signal transduction and amplification technology. The assay was rapid and homogeneous, which offered a linear range of 75-700 pM and a limit-of-detection as low as 75 pM. It holds great potential for further applications in real-time monitoring of the variations of the AVP level in biological samples.

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.

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 18-52 years. We also test for potential gender differences in the outcome measures.

Purpose: The aims of our study were to determine first circadian influences on central concentrations of the neuropeptides oxytocin and arginine-vasopressin and second to investigate if these central concentrations are associated with those in the peripheral compartments blood and saliva in neurocritical care patients. We therefore included patients with external ventricular drain who attended a neurosurgical intensive care unit and were not exposed to painful or stressful stimuli during the sampling period. For this purpose, blood, cerebrospinal fluid and saliva were collected in a 24-hour-interval at the timepoints 06:00, 12:00, 18:00 and 24:00., Results: In none of the three body fluids examined, significant time-dependent fluctuations of oxytocin and arginine-vasopressin concentrations could be detected during the 24-hour sampling period. The only exception was the subgroup of postmenopausal women whose oxytocin concentrations in cerebrospinal fluid at 12:00 were significantly higher than at 18:00. Correlations of blood and cerebrospinal fluid and blood and saliva neuropeptide levels were very weak to weak at each timepoint. Cerebrospinal fluid and saliva oxytocin levels showed a moderate correlation at 06:00 but did correlate very weak at the other timepoints., Conclusions: Central as well as peripheral oxytocin and arginine-vasopressin concentrations in neurocritical care patients did not show significant diurnal fluctuations. No strong correlations between central and peripheral neuropeptide concentrations could be detected under basal conditions. If investigators even though decide to use saliva concentrations as surrogate parameter for central neuropeptide activity, they have to consider that correlations of cerebrospinal fluid and saliva oxytocin seem to be highest in the early morning., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: To explore the association of plasma copeptin, the C-terminal portion of provasopressin and a stable surrogate marker for arginine vasopressin secretion, with plasma glucagon in obese men and men of normal weight., Methods: We measured fasting blood concentrations of copeptin and glucagon in 102 healthy obese men (mean ± sd age 49.4 ± 10.2 years) and a control group 27 healthy men of normal weight (mean ± sd age 51.5 ± 8.4 years). Differences between groups were evaluated using t-tests, and multiple linear regression analysis, adjusting for age and weight status (normal weight vs obese), was used to calculate unstandardized regression coefficients (β) with 95% CIs between copeptin and glucagon. Copeptin was (natural) log-transformed., Results: The obese men had higher [median (interquartile range)] plasma copeptin concentrations [6.6 (4.6-9.5) vs 4.9 (3.5-6.8) pmol/l; P = 0.040] and higher mean ± sd plasma glucagon concentrations (8.5 ± 3.8 vs 5.3 ± 1.4 pmol/l; P < 0.001) than the normal-weight men. Adjusted for age and weight status, copeptin was significantly associated with glucagon (β = 1.35, 95% CI 0.13-2.57; P = 0.031). No significant interaction effect between copeptin and weight status on glucagon was found (P = 0.81)., Conclusions: Obese men had higher concentrations of copeptin and glucagon than men of normal weight. Copeptin was positively associated with glucagon. Our data suggest that increased arginine vasopressin-stimulated glucagon secretion might contribute to higher glucagon concentrations; therefore, increased arginine vasopressin secretion, in addition to other factors, could further aggravate the hyperglucagonaemic state found in obese individuals., (© 2018 Diabetes UK.)

Perioperative stress provides not only physical, but also psychic and emotional aspects, which may influence the hypothalamic neuropeptide system. Studies investigating the perioperative course of central neuropeptide activity are missing. Therefore, the present study aimed to determine perioperative fluctuations in central and concomitant peripheral concentrations of the hypothalamic neuropeptides oxytocin (OXT) and arginine-vasopressin (AVP), as well as their impact on perioperative anxiety and depression. Cerebrospinal fluid (CSF), blood and saliva were collected from 12 patients who underwent elective endovascular aortic repair with a routinely inserted spinal catheter. AVP and OXT concentrations were analysed at four timepoints: (i) the evening before the operation; (ii) the operation day immediately before anaesthesia induction; (iii) intraoperatively after the stent was placed; and (iv) on day 1 after the operation. Patients completed the Hospital Anxiety and Depression Scale (HADS) at timepoints 1 and 4. For CSF OXT, the present study showed a significant intraoperative decline, accompanied by a decrease in saliva. OXT blood concentrations before anaesthesia induction were higher than at the evening before the operation. OXT concentrations in CSF and saliva correlated well at timepoints 2-4. AVP concentrations in CSF, blood and saliva did not show any significant changes perioperatively. However, postoperative AVP blood concentrations showed a significant negative correlation with anxiety and depression scores according to the HADS. This pilot study demonstrates perioperative fluctuations in central OXT concentrations, which are better reflected by saliva than by blood. Further studies are required to determine whether OXT and AVP can predict postoperative post-traumatic stress disorder., (© 2019 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Context: Oxytocin (OT) and vasopressin share anatomical pathways of synthesis and secretion, and patients with central diabetes insipidus (CDI) presumably are at risk for OT deficiency. However, an OT-deficient state in hypopituitary patients has not been established., Objectives: We hypothesized that men with CDI compared to patients with similar anterior pituitary deficiencies (APD) but no CDI and healthy controls (HC) of similar age and body mass index, would have lower plasma OT levels, associated with increased psychopathology., Design: Cross-sectional., Setting: Clinical research center., Participants: Sixty-two men (20 CDI, 20 APD, 22 HC), age 18 to 60 years., Interventions: Frequent sampling of blood every 5 minutes for OT over 1 hour and validated questionnaires to assess psychopathology., Main Outcomes: Pooled plasma OT levels; depressive, anxiety, and alexithymia symptoms; and quality of life., Results: The mean 1-hour pool of fasting OT levels was lower in CDI compared with APD and HC (P = 0.02 and P = 0.009, respectively), with no differences between APD and HC (P = 0.78). Symptoms of depression, anxiety, and alexithymia were more pronounced in CDI than in HC (P = 0.001, P = 0.004, and P = 0.02, respectively). Although CDI and APD reported worse physical health compared with HC (P = 0.001 and P = 0.005) with no differences between APD and CDI, only CDI reported worse mental health compared with HC (P = 0.009)., Conclusions: We have demonstrated low plasma OT levels and increased psychopathology in hypopituitary men with CDI, suggestive of a possible OT-deficient state. Larger studies of both sexes are required to confirm these findings and clinically characterize hypopituitary patients with OT deficiency., (Copyright © 2019 Endocrine Society.)

Objective: Acyl ghrelin, which is the endogenous ligand for the growth hormone secretagogue receptor, potently stimulates pituitary growth hormone release, and to some degree adrenocorticotropic hormone and prolactin. Ghrelin is also orexigenic and has recently been shown to stimulate renal sodium absorption in rodent models. Increased thirst sensation has been observed as a side effect of acyl ghrelin administration in some human studies. The objective of this clinical trial was to investigate the direct effects of acyl ghrelin on thirst sensation and sodium excretion in hypopituitary patients., Design: Hypopituitary patients on stable replacement with hydrocortisone and growth hormone were investigated in two double-blind and placebo-controlled crossover studies. The patients received a 5-h intravenous infusion of acyl ghrelin (5 pmol/kg/min in the first study and 1 pmol/kg/min in the second study). Thirst sensation was measured on a Visual Analog Scale (VAS). In the second study plasma osmolality, vasopressin, copeptin, water intake, diuresis and urinary excretion of sodium and creatinine were measured., Results: In the initial study, acyl ghrelin (5 pmol/kg/min) increased thirst sensation (time × treatment analysis of variance for the effect of acyl ghrelin infusion P = 0.003). In the second study acyl ghrelin (1 pmol/kg/min) also increased thirst (P = 0.04) but did not affect urinary excretion of either sodium or water., Conclusions: We demonstrate that acyl ghrelin infusion increases thirst sensation, without affecting sodium excretion or diuresis in human subjects.

Objective: Studies have suggested that arginine vasopressin (AVP) and its surrogate marker copeptin increase during exercise, independently of serum sodium and/or osmolality. In extreme cases, this can lead to runners-induced hyponatremia. Interleukin-1 (IL-1) increases during exercise and induces AVP in animal models. We here therefore investigate whether copeptin (a surrogate marker for AVP) increases upon exercise in young and healthy males, and whether this increase is regulated by IL-1., Design: In a randomized, placebo-controlled, double-blind, crossover trial in 17 healthy male volunteers, the effect of the IL-1 receptor antagonist anakinra on exercise-induced copeptin was compared with placebo., Methods: Participants exercised for one hour at 75% of VO2max and were not allowed to drink/eat 6 hours before and during the study. Participants received either 100 mg of anakinra or placebo 1h before exercise. Blood was drawn at certain time intervals., Results: In both groups, copeptin levels were induced by 2.5-fold upon exercise (p<0.001), from 4.5-10.6 pmol/l in the placebo, and 4.3-11.3 pmol/l in the anakinra group, (p = 0.38). One hour after exercise, copeptin levels dropped to 7.7 and 7.9 pmol/l in the placebo and anakinra group, respectively (p = 0.58). The increase of copeptin levels was not explained by sodium concentrations., Conclusions: Exercise induces a continuous rise of plasma copeptin levels in healthy male volunteers independently of sodium levels and fluid intake. This increase is not regulated by the IL-1 pathway., Competing Interests: The authors have declared that no competing interests exist.

Arginine vasopressin (AVP), which induces vasoconstriction and conserves solute-free water when released during high plasma osmolality, is secreted through 2 mechanisms: osmoregulation and baroregulation. This study aims to clarify the mechanisms and influencing factors for non-osmotic AVP secretion in adult patients with congenital heart disease (CHD). AVP levels were measured in 74 adults with CHD. Non-osmotic AVP secretion was defined as excessive AVP secretion relative to the AVP level inferred from plasma osmolality. Accordingly, 10 patients (13.5%) demonstrated non-osmotic AVP secretion, with AVP levels higher than those in patients without non-osmotic AVP secretion (6.4 ± 3.1 vs. 1.6 ± 0.9 pg/ml; p < 0.0001). Non-osmotic AVP secretion was significantly correlated with diuretic use [odds ratio (OR) 7.227; confidence interval (CI) 1.743-29.962; p = 0.0006], HbA1c level (OR 11.812; CI 1.732-80.548; p = 0.012), and B-type natriuretic peptide (BNP) level (OR 1.007; CI 1.001-1.012; p = 0.022). Multiple logistic regression analysis revealed that there was a significant association between non-osmotic AVP secretion and HbA1c level (OR 9.958; 1.127-87.979; p = 0.0039), and a nearly significant relationship between non-osmotic AVP secretion and BNP (OR 1.006; CI 1.000-1.012; p = 0.056). In conclusion, this study showed that 13.5% of adult patients with CHD demonstrated non-osmotic AVP secretion, which could be correlated with heart failure and insulin resistance. The AVP system might be one of the mechanisms linking heart failure and the onset of type 2 diabetes mellitus in adults with CHD.

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., (Copyright © 2019. Published by Elsevier Inc.)

Introduction: Supra-clinical doses of clonidine appear beneficial in experimental sepsis, but there is limited understanding of the effects of clonidine at clinically relevant doses., Methods: In conscious sheep, with implanted renal and pulmonary artery flow probes, sepsis was induced by infusion of live Escherichia coli. At 24 h, a high clinical dose of clonidine (HCDC) [1.0 μg/kg/h], a low clinical dose of clonidine (LCDC) [0.25 μg/kg/h] or vehicle, was infused for 8 h., Results: Animals developed hyperdynamic, hypotensive sepsis with acute kidney injury. The HCDC decreased heart rate (153 ± 6 to 119 ± 7 bpm) and cardiac output (5.6 ± 0.4 to 5.0 ± 0.4 L/min), with no reduction in mean arterial pressure (MAP). In contrast, LCDC increased cardiac output with peripheral vasodilatation. Both doses induced a large transient increase in urine output, an increase in plasma osmolality and, with the high dose, an increase in plasma arginine vasopressin. Sepsis increased plasma interleukin-6 (IL-6) and IL-10 and clonidine further increased IL-10 (1.6 ± 0.1 to 3.3 ± 0.7 ng/mL), but not IL-6. Clonidine reduced rectal temperature. During recovery from sepsis, MAP returned to baseline values more rapidly in the HCDC group (P < 0.001)., Conclusions: In hyperdynamic, hypotensive sepsis, the effects of clonidine at clinically relevant doses are complex and dose dependent. HCDC attenuated sepsis-related increases in heart rate and cardiac output, with little effect on arterial pressure. It also induced a water diuresis, increased AVP, reduced body temperature, and had an anti-inflammatory action. Low-dose clonidine had similar but less pronounced effects, except that it induced moderate vasodilatation and increased cardiac output.