Arginine Vasopressin Group Research Articles

Impact of arginine-vasopressin on regional perfusions in a porcine model of post-resuscitation syndrome

BackgroundPost-cardiac arrest (CA) shock is associated with multiple organ failure, including acute kidney injury, and is the leading cause of early death among patient successfully resuscitated from CA. Arginine-vasopressin (AVP) may be an interesting therapeutic alternative or complement to noradrenaline (NAD) to both control shock and preserve regional, especially renal, organ perfusions. Methods18 swine (24–39 kg) were submitted to 14 min of ventricular fibrillation and cardio-pulmonary resuscitation. After return of spontaneous circulation (ROSC), animals randomly received either AVP, NAD or AVP-NAD combination for maintaining a targeted mean arterial pressure of 70 ± 5 mmHg for 6 h. Haemodynamic and biological parameters, including kidney function biomarkers and diuresis, were monitored throughout the follow-up. ResultsTargeted mean arterial pressure was successfully obtained in the NAD (n = 6) and the AVP-NAD (n = 6) groups, but not in the AVP group (n = 6), where 4 animals died. As compared to NAD alone, renal blood flow (2.9 ± 1.15 vs 4.36 ± 0.64 mL//kg/min in NAD and AVP-NAD groups) and diuresis were higher in the AVP-NAD group. This was associated with a reduction of carotid blood flow and a more severe metabolic acidosis during the first 3 h of follow-up in the AVP-NAD group as compared to NAD group. ConclusionCombination of AVP and NAD improved renal perfusion and diuresis but reduced carotid blood flow as compared to NAD alone in a porcine model of post-resuscitation syndrome. AVP alone failed to manage shock and led to mortality.

Hesperidin improves physiological outcomes in an arginine vasopressin rat model of pre-eclampsia.

Hesperidin, a flavanone commonly found in citrus fruits and herbal formulations, has emerged as a potential new therapeutic agent for modulating several diseases. Since pre-eclampsia is a growing public health threat, it may negatively impact the economy and increase the disease burden of South Africa. Phytocompounds are easily accessible, demonstrate minimal side effects, and may confer novel medicinal options as a treatment and preventive preference. To investigate the physiological, biochemical, and hematological outcomes of hesperidin in an arginine vasopressin (AVP)-induced rodent model of pre-eclampsia. Female Sprague-Dawley rats were surgically implanted with mini-osmotic pumps to deliver AVP (200 ng/h) subcutaneously. Animals were treated with hesperidin at 200 mg/kg.b.w via oral gavage for 14 days. Systolic and diastolic blood pressures were measured on GD 7, 14, and 18 using a non-invasive tail-cuff method and were euthanized on GD 21. The findings showed that hesperidin administration significantly decreased blood pressure (P < 0.05) and urinary protein levels in pregnant rats (P < 0.001). Placental and individual pup weight also increased significantly in the pregnant hesperidin-treated groups compared to AVP untreated groups (P < 0.001). Biochemical and hematological markers such as white blood cell count and lymphocyte levels differed significantly (P < 0.05) in AVP groups treated with and without hesperidin. Our results suggest that hesperidin is an antihypertensive agent with modes of action associated with its diuretic and blood pressure lowering effects and reduction of proteinuria in AVP-induced pre-eclamptic rats.

PS-BPB06-6: RENAL INJURY ASSOCIATED WITH ARGININE VASOPRESSIN INDUCTION IN A RAT MODEL OF PREECLAMPSIA

Objective: Worldwide, preeclampsia (PE) accounts for 2–8% of pregnancies and is a main cause of maternal and fetal morbidity and mortality. In vivo murine studies confirm the use of arginine vasopressin (AVP) in replicating the clinical symptoms of PE development, suggestive of a role for PE prediction. The renal effects that AVP may have in PE remains elusive, hence this study aimed to explore the physiological effects of AVP on the kidneys of pregnant rats in an effort to determine its role in PE development. Design and method: Twenty-four female Sprague Dawley rats (non-pregnant saline, pregnant saline, non-pregnant AVP and pregnant AVP) were surgically implanted with ALZET mini osmotic pumps infusing with either saline or AVP for 18 days. Blood pressure measurements and urine samples were taken on gestational days (GD) 8, 14 and 18. Placental and fetal weights were recorded following sacrifice on GD18. Urinary levels of kidney injury molecule-1 (KIM-1) were determined using the rat kidney toxicity immunoassay panel 1 (#RKTX1MAG-37K). Immunohistochemistry was used to determine the expression of KIM-1 in rat kidney tissue. Results: Systolic [143.00 (139.67–144.00) mmHg vs 125.00 (124.00–127.00) mmHg; p &lt; 0.05] and diastolic blood pressures [103.50 (100.33–106.88) mmHg vs 81.00 (80.00–87.00) mmHg; p &lt; 0.001] were significantly higher in the pregnant AVP vs pregnant saline group. Urinary protein levels in pregnant AVP rats [0.45 (0.42–0.48) g/L] were significantly elevated in comparison to pregnant saline rats [0.24 (0.21–0.32) g/L; p &lt; 0.05]. Pregnant AVP rats also demonstrated a significant decrease in individual placental [0.39 (0.31–0.46) g vs 0.59 (0.55–0.63) g; p &lt; 0.05] and pup weights [1.57 (1.45–1.67) g vs 1.79 (1.70–1.85) g; p &lt; 0.05] in comparison to pregnant saline rats. Urinary KIM-1 levels are significantly elevated in the pregnant AVP (0.53 ± 0.05 ng/mL) vs pregnant saline group (0.17 ± 0.02 ng/mL; p &lt; 0.001). Qualitative analysis revealed that KIM-1 expression is markedly upregulated on the apical membrane surface of epithelial cells of the proximal convoluted tubules in AVP treated rats. Conclusions: AVP infusion increases blood pressure, urine protein levels and urinary and tissue expression of KIM-1. Our findings indicate that there is significant kidney injury associated with AVP treatment, indicative of the utility of this model in studying the mechanisms driving renal damage in PE.

The Changes of Amygdala Transcriptome in Autism Rat Model After Arginine Vasopressin Treatment

BackgroundSome studies have shown that arginine vasopressin (AVP) can significantly improve the social interaction disorder of autism, but the mechanism remains unclear.MethodsFemale Wistar rats were intraperitoneally injected with VPA or normal saline at embryonic day 12.5 to establish an autism model or normal control in their offspring. Male offspring prenatally exposed to VPA were randomly assigned to two groups: the VPA-induced autism model group and the AVP group. The rats in the AVP group were treated with intranasal AVP at postnatal day (PND) 21 and for 3 weeks. The VPA-induced autism model group was given the same dose of normal saline in the same way. Behavioral responses were evaluated in the open field and three-chambered social test apparatus; the expression levels of AVP in serum were detected by enzyme-linked immunosorbent assay kit, and the gene expression levels on the amygdala were measured by RNA-seq at PND42.ResultsIntranasal administration of AVP can significantly improve the social interaction disorder and elevate the levels of AVP in serum. Transcriptome sequencing results showed that 518 differently expressed genes (DEGs) were identified in the VPA-induced autism model group compared with the control in this study. Gene Ontology biological process enrichment analysis of DEGs showed that the VPA-induced autism model group had significant nervous system developmental impairments compared with the normal group, particularly in gliogenesis, glial cell differentiation, and oligodendrocyte differentiation. Gene Set Enrichment Analysis (GSEA) enrichment analysis also showed that biological process of oligodendrocyte differentiation, axoneme assembly, and axon ensheathment were inhibited in the VPA-induced autism model group. Pathway enrichment analysis of DEGs between the control and VPA-induced autism model group showed that the PI3K/AKT and Wnt pathways were significantly dysregulated in the VPA-induced autism model group. Few DEGs were found when compared with the transcriptome between the VPA-induced autism model group and the AVP treatment group. GSEA enrichment analysis showed deficits in oligodendrocyte development and function were significantly improved after AVP treatment; the pathways were mainly enriched in the NOTCH, mitogen-activated protein kinase, and focal adhesion signaling pathways, but not in the PI3K/AKT and Wnt pathways. The expression patterns analysis also showed the same results.ConclusionAVP can significantly improve the social interaction disorder of VPA-induced autism model, and AVP may target behavioral symptoms in autism by modulating the vasopressin pathways, rather than primary disease mechanisms.

Physiological characterization of an arginine vasopressin rat model of preeclampsia

ABSTRACT Rodent models have contributed greatly to our understanding of preeclampsia (PE) progression in humans, however to-date no model has been able to effectively replicate the clinical presentation of the disease. This study aimed to provide a thorough physiological characterization of the arginine vasopressin (AVP)-induced rat model of PE to determine its applicability in studying the pathophysiology of PE. Female Sprague Dawley rats (n = 24) were separated into four groups (n = 6 per group) viz., pregnant AVP, pregnant saline, non-pregnant AVP, and non-pregnant saline. All animals received a continuous dose of either AVP (150 ng/h) or saline via subcutaneous mini osmotic pumps for 18 days. Full physiological characterization of the model included measuring systolic and diastolic blood pressure, and collecting urine and blood samples for biochemical analysis. AVP infusion significantly increased blood pressure and urinary protein levels in the pregnant rats (p < 0.05). Biochemical markers measured, differed significantly in the AVP-treated vs the pregnant saline groups (p < 0.05). Placental and individual pup weight decreased significantly in the pregnant AVP vs pregnant saline group (p < 0.05). The physiological and hematological data confirm the usefulness of this rat model in the study of PE, since AVP-induced vasoconstriction increases peripheral resistance and successfully mimics the pathological changes associated with PE development in humans. Abbreviations: PE: preeclampsia; AVP: arginine vasopressin; ISSHP: International Society for the Study of Hypertension in Pregnancy; ACOG: American College of Obstetricians and Gynecologists; RUPP: reduced uterine perfusion pressure; sFlt-1: soluble fms-like tyrosine kinase; VEGF: vascular endothelial growth factor; PlGF: placental growth factor; AVP: arginine vasopressin; PAVP: pregnant AVP-treated; PS: pregnant saline; GD: gestational day; ALT: alanine transaminase; NAVP: non-pregnant AVP-treated; NS: non-pregnant saline; AST: aspartate aminotransferase; HDL: high-density lipoprotein; RBC: red blood cell; RAAS: renin-angiotensin aldosterone system; HELLP: hemolysis, elevated liver enzymes, low platelet.

Does Arginine Vasopressin Reflect HPA-axis Activation in Major Depressive Disorder?

Researchers have endeavored to subclassify depressive illness based on pathophysiological mechanism. One model relates to hypothalamic-pituitary-adrenal (HPA) axis overactivation with a shift from corticotropin-releasing hormone (CRH) driven regulation to arginine vasopressin (AVP) driven regulation. Given the mixed literature, we compared plasma AVP levels in healthy controls to patients with major depressive disorder (MDD). Plasma samples from 33 patients and 12 controls were collected at baseline, 8 weeks, and 12 weeks of treatment and measured by immunochemical assay. Patients who were treatment responders trended toward lower AVP levels than non-responders. Patients were stratified into low and high AVP groups based on median split. Within the low AVP group, patients whose current episode lasted longer than a year had significantly higher baseline AVP levels than patients whose current episode was less than 6 months. Female patients in the low AVP group had significantly higher baseline AVP levels than male patients. Given the association between stress, HPA axis activation, immune dysregulation, and depression, we also measured concentrations of inflammatory biomarkers. We found a significant negative correlation between IL-10 and baseline AVP levels, within the low AVP subgroup. Given inconsistent data, HPA axis overactivation may be present within a subset of depressed patients.

Peroxynitrite decomposition catalyst reduces vasopressin requirement in ovine MRSA sepsis

BackgroundSepsis is one of the most frequent causes of death in the intensive care unit. Host vascular hypo-responsiveness to vasopressors during septic shock is one of the challenging problems. This study tested the hypothesis that adjunct therapy with peroxynitrite decomposition catalyst (WW-85) would reduce arginine vasopressin (AVP) requirements during sepsis resuscitation, using ovine sepsis model.MethodsThirteen adult female Merino sheep, previously instrumented with multiple vascular catheters, were subjected to “two-hit” (cotton smoke inhalation and intrapulmonary instillation of live methicillin-resistant Staphylococcus aureus; 3.5 × 1011 colony-forming units) injury. Post injury, animals were awakened and randomly allocated to the following groups: (1) AVP: injured, fluid resuscitated, and titrated with AVP, n = 6 or (2) WW-85 + AVP: injured, fluid resuscitated, treated with WW-85, and titrated with AVP, n = 7. One-hour post injury, a bolus intravenous injection of WW-85 (0.1 mg/kg) was followed by a 23-h continuous infusion (0.02 mg/kg/h). Titration of AVP started at a dose of 0.01 unit/min, when mean arterial pressure (MAP) decreased by 10 mmHg from baseline, despite aggressive fluid resuscitation, and the rate was further adjusted to maintain MAP. After the injury, all animals were placed on a mechanical ventilator and monitored in the conscious state for 24 h.ResultsThe injury induced severe hypotension refractory to aggressive fluid resuscitation. High doses of AVP were required to partially attenuate the sepsis-induced hypotension. However, the cumulative AVP requirement was significantly reduced by adjunct treatment with WW-85 at 17–24 h after the injury (p < 0.05). Total AVP dose and the highest AVP rate were significantly lower in the WW-85 + AVP group compared to the AVP group (p = 0.02 and 0.04, respectively). Treatment with WW-85 had no adverse effects. In addition, the in vitro effects of AVP on isolated artery diameter changes were abolished with peroxynitrite co-incubation.ConclusionsThe modulation of reactive nitrogen species, such as peroxynitrite, may be considered as a novel adjunct treatment option for septic shock associated with vascular hypo-responsiveness to vasopressors.

Effect of Low-Dose Supplementation of Arginine Vasopressin on Need for Blood Product Transfusions in Patients With Trauma and Hemorrhagic Shock

Current therapies for traumatic blood loss focus on hemorrhage control and blood volume replacement. Severe hemorrhagic shock, however, is associated with a state of arginine vasopressin (AVP) deficiency, and supplementation of this hormone may decrease the need for blood products in resuscitation. To determine whether low-dose supplementation of AVP in patients with trauma (hereinafter referred to as trauma patients) and with hemorrhagic shock decreases their need for transfused blood products during resuscitation. This randomized, double-blind placebo-controlled clinical trial included adult trauma patients (aged 18-65 years) who received at least 6 U of any blood product within 12 hours of injury at a single urban level 1 trauma center from May 1, 2013, through May 31, 2017. Exclusion criteria consisted of prehospital cardiopulmonary resuscitation, emergency department thoracotomy, corticosteroid use, chronic renal insufficiency, coronary artery disease, traumatic brain injury requiring any neurosurgical intervention, pregnancy, prisoner status, or AVP administration before enrollment. Data were analyzed from May 1, 2013, through May 31, 2017, using intention to treat and per protocol. After administration of an AVP bolus (4 U) or placebo, participants received AVP (≤0.04 U/min) or placebo for 48 hours to maintain a mean arterial blood pressure of at least 65 mm Hg. The primary outcome was total volume of blood product transfused. Secondary end points included total volume of crystalloid transfused, vasopressor requirements, secondary complications, and 30-day mortality. One hundred patients underwent randomization (49 to the AVP group and 51 to the placebo group). Patients were primarily young (median age, 27 years [interquartile range {IQR}, 22-25 years]) and male (n = 93) with penetrating trauma (n = 79). Cohort characteristics before randomization were well balanced. At 48 hours, patients who received AVP required significantly less blood products (median, 1.4 [IQR, 0.5-2.6] vs 2.9 [IQR, 1.1-4.8] L; P = .01) but did not differ in requirements for crystalloids (median, 9.9 [IQR, 7.9-13.0] vs 11.0 [8.9-15.0] L; P = .22) or vasopressors (median, 400 [IQR, 0-5900] vs 1400 [IQR, 200-7600] equivalent units; P = .22). Although the groups had similar rates of mortality (6 of 49 [12%] vs 6 of 51 [12%]; P = .94) and total complications (24 of 44 [55%] vs 30 of 47 [64%]; P = .37), the AVP group had less deep venous thrombosis (5 of 44 [11%] vs 16 of 47 [34%]; P = .02). Low-dose AVP during the resuscitation of trauma patients in hemorrhagic shock decreases blood product requirements. Additional research is necessary to determine whether including AVP improves morbidity or mortality. ClinicalTrials.gov identifier: NCT01611935.

Arginine vasopressin improves cerebral perfusion following controlled haemorrhage in adult ewes.

Traumatic haemorrhagic shock carries significant morbidity and mortality related to the severity and duration of tissue hypoperfusion, much of which occurs in the pre-hospital environment where therapy must be easy to use and would augment, not replace, local haemorrhage control measures. Vasopressor therapy use in haemorrhagic shock remains controversial. Potential benefits from improved blood pressure and tissue perfusion need to be weighed against possible harm from increased blood loss if haemorrhage is uncontrolled. We demonstrate that 20 IU I.M. vasopressin produces a progressive, sustained and clinically significant increase in blood pressure and carotid blood flow compared to 1mg I.M. adrenaline or placebo in an animal model of controlled haemorrhagic shock. I.M. vasopressin may play a role in the early management of haemorrhagic shock by improving cerebral perfusion and haemodynamic stability; however, further studies are required to establish the potential benefit against the risk of exacerbating haemorrhage, if it is uncontrolled. Haemorrhagic shock causes significant morbidity and mortality. Novel pre-hospital therapy to improve haemodynamic stability and cerebral perfusion may improve outcomes but remains controversial. In an ovine model of controlled haemorrhagic shock, the effects of early intramuscular arginine vasopressin (AVP), adrenaline or placebo on haemodynamic stability and cerebral perfusion were compared. Carotid pressure and flow catheters were placed in healthy, anaesthetized adult ewes. Frontal cortex cerebral oxygenation was measured using near infrared spectroscopy. Controlled, rapid, haemorrhage (∼30% estimated blood volume) was induced. Five minutes post-bleed a 1ml intramuscular dose of 0.9% saline, adrenaline 1mg or AVP 20IU was administered. Carotid blood pressure and flow improved significantly in the AVP group over the first 30min post-intervention. To emulate standard trauma care, 1L of 0.9% saline was infused 30min post-bleed followed by re-transfusion of the sheep's own blood at 60min post-bleed. Carotid blood pressure and flow in the AVP group remained significantly higher post-crystalloid infusion, but this difference was lost post-blood transfusion. Data were analysed by two-way ANOVA with time, group as the main factors. When compared to saline or adrenaline, a single dose of intramuscular AVP resulted in a progressive and sustained increase in carotid artery blood pressure and flow with commensurate increase in cerebral oxygenation. Intramuscular AVP has potential as an emergency pre-hospital therapy following exsanguinating haemorrhage; however, further studies are required to investigate whether the benefit of improved perfusion pressure outweighs the risks of exacerbating ongoing bleeding.

Vasopressin in Septic Shock; Assessment of Sepsis Biomarkers: A Randomized, Controlled Trial.

Background and Aims:Vasopressin (VP) in sepsis apart from vasoconstrictive effect may have some immunomodulatory effects. The aim of this study was to evaluate the effect of VP on different aspect of sepsis by measuring of sepsis biomarkers.Materials and Methods:In this trial, a total number of 42 septic shock patients were included. The first group received norepinephrine (NE) infusion to reach the target mean arterial pressure (MAP) of ≥ 65 mm Hg and the second group received arginine vasopressin (AVP) infusion in addition to NE. Serum lactate, C-reactive protein (CRP), interleukin-6 (IL-6), IL-10, pentraxin 3 (PTX3), angiopoietin 1 and 2 (Ang 1 and 2) levels were assessed.Results:Level of IL-6 and IL-10 decreased, but there was no significant difference between the two groups after 48 h. CRP and PTX3 levels were not also significantly different between groups. Although Angs were not statistically different, there was a trend toward higher Ang-1 in and lower Ang 2 in AVP group after 24 and 48 h. In addition, lactate level did not differ between NE and AVP groups. There was no interaction between VP and hydrocortisone use on IL-6, IL-10, and PTX3, but a significant statistical interaction on Ang 1 and Ang 2 were observed.Conclusions:Although analysis of sepsis biomarkers showed no significant difference between two groups, no immunomodulatory effect for VP alone, subgroup analysis of hydrocortisone used in this study showed that the combination of glucocorticoids and AVP had a significant effect on Angs level which eventually causes less endothelial permeability and higher MAP in this group of patients.

Hypotensive resuscitation in combination with arginine vasopressin may prolong the hypotensive resuscitation time in uncontrolled hemorrhagic shock rats.

The optimal resuscitation strategy for traumatic hemorrhagic shock is not completely determined. The objective of the present study was to investigate whether hypotensive resuscitation in combination with arginine vasopressin (AVP) can prolong the hypotensive resuscitation time by minimizing blood loss and stabilizing hemodynamics for uncontrolled hemorrhagic shock. With an established rat model of uncontrolled hemorrhagic shock, we compared the beneficial effects of hypotensive resuscitation in combination with AVP to maintain blood pressure at 50 mm Hg for 3 hours to hypotensive resuscitation alone on animal survival, blood loss, and vital organ functions. Hypotensive resuscitation in combination with AVP maintenance for 3 hours significantly reduced total blood loss and fluid requirement during hypotensive resuscitation period and significantly improved the survival of shock rats as compared with hypotensive resuscitation alone. Among the four concentrations of AVP, 5 × 10 U/mL had the best effect: it significantly improved hemodynamics and increased cardiac function, oxygen delivery, as well as hepatic blood flow and hepatic function in the shock rats. However, renal blood flow in the hypotensive resuscitation + AVP group was lower than that in the hypotensive resuscitation alone group. Hypotensive resuscitation in combination with early application of AVP could prolong the tolerance time of hypotensive resuscitation and "buy" longer safe prehospital transport time by reducing blood loss and stabilizing hemodynamics. This strategy may be a promising strategy for the early management of trauma patients with active bleeding.

Under General Anesthesia Arginine Vasopressin Prevents Hypotension but Impairs Cerebral Oxygenation During Arthroscopic Shoulder Surgery in the Beach Chair Position

Patients undergoing surgery in the beach chair position (BCP) are at a risk of cerebral ischemia. We evaluated the effect of arginine vasopressin (AVP) on hemodynamics and cerebral oxygenation during surgery in the BCP. Thirty patients undergoing shoulder surgery in BCP under propofol-remifentanil anesthesia were randomly allocated either to receive IV AVP 0.07 U/kg (AVP group, N = 15) or an equal volume of saline (control group, N = 15) 2 minutes before taking BCP. Mean arterial blood pressure (MAP), heart rate (HR), jugular venous bulb oxygen saturation (SjvO2), and regional cerebral tissue oxygen saturation (SctO2) were measured after induction of anesthesia and before (presitting in supine position) and after patients took BCP. AVP itself given before the positioning increased MAP and decreased SjvO2 and SctO2 (P < 0.0001), with HR unaffected. Although MAP was decreased by BCP in both groups, it was higher in the AVP group (P < 0.0001). While in BCP, HR remained unaltered in the control and decreased in the AVP group. SjvO2 in BCP did not differ between the groups. SctO2 was decreased by BCP in both groups, which was more pronounced in the AVP group until the end of study. The incidence of hypotension (13% vs 67%; P = 0.003) was less frequent, and that of cerebral desaturation (>20% SctO2 decrease from presitting value) (80% vs 13%; P = 0.0003) was higher in the AVP group. The incidence of jugular desaturation (SjvO2 <50%) was comparable between the groups. A prophylactic bolus administration of AVP prevents hypotension associated with BCP in patients undergoing shoulder surgery under general anesthesia. However, it was associated with regional cerebral but not jugular venous oxygen desaturation on upright positioning.

Actions of intravenous injections of AVP and oxytocin on plasma ACTH, GH, insulin and glucagon concentrations in goats

This study was conducted to investigate the arginine-vasopressin (AVP)- and oxytocin-induced changes in plasma adrenocorticotropic hormone (ACTH), growth hormone (GH), insulin and glucagon levels and their metabolite concentrations in goats. In this study, five goats were intravenously injected with either AVP (0.3 nmol/kg body weight (BW)) or oxytocin (0.7 IU/kg BW). AVP injection significantly increased ACTH and GH secretions compared to controls, although insulin and glucagon concentrations were not altered. The incremental areas (ICAs) of the ACTH and GH concentrations were higher in the AVP group than in the saline group. Oxytocin injections increased insulin and glucagon secretions, while ACTH level was not altered. GH levels became elevated 30 min after the oxytocin injection. The ICAs of insulin and glucagon after oxytocin was injected were higher than those of the control. Results indicate that AVP is a potent stimulant of ACTH and GH secretions, while oxytocin uses different pathways to regulate insulin and glucagon secretions in goats.

The Effects of Acute Arginine Vasopressin Administration on Social Cognition in Healthy Males

The structurally similar neuropeptides and hormones oxytocin (OT) and arginine vasopressin (AVP) play significant and complex roles in modulating a range of social behaviours, including social recognition and bond formation. Although OT has well-known roles in facilitating prosocial behaviors and enhancing emotion recognition, AVP has received increasing interest for diverging effects on social cognition behaviour most notably in males. The current study aimed to determine whether AVP also modulates the ability to understand emotion. Using a randomised double blind procedure, 45 healthy young males received either an AVP or placebo nasal spray and completed the Reading the Mind in the Eyes Test (RMET). In contrast to previous findings, there were no significant differences observed in performance on the RMET between AVP and placebo groups, even after examining items separated by task difficulty, emotional valence, and gender. This study provides diverging evidence from previous findings and adds to the growing body of research exploring the influence of neuropeptide hormones in social behaviour. It demonstrates that in this sample of participants, AVP does not enhance the ability to understand higher order emotion from others. Implications and suggestions for future AVP administration studies are discussed.

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Introduction: The selective vasopressin V1a-receptor agonist selepressin has been shown to decrease platelet activating factor (PAF)-induced capillary leakage and to reverse hypotension in rat and ovine sepsis.Hypothesis: Our hypothesis was that early administration of selepressin (formerly FE 202158) might reduce mortality and organ dysfunction when compared to arginine vasopressin (AVP) or norepinephrine (NE) in the treatment of septic shock.Methods: Twenty-eight fasted, anesthetized, invasively monitored, mechanically ventilated female sheep (28.9 +/- 3.5 kg) received 1.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. Ringer's lactate and hydroxyethyl starch (volume ratio = 1:1) were titrated to maintain pulmonary artery occlusion pressure at baseline level throughout the experimental period. When mean arterial pressure (MAP) decreased by 10% from baseline, animals were randomized to receive 0.9% saline (control group, n = 7), 0.25 pmol/kg/min AVP (n = 7), 1 pmol/kg/min selepressin (SEL, n = 7) or 0.5 mcg/kg/min NE (n = 7). In the absence of a response to fluid challenge, all vasopressors were titrated to keep MAP > 70 mmHg. The experiment was continued until death or for a maximum of 30 hours. After death, lung wet/dry ratio was measured.Results: The mean time to start therapy was similar (2.5 hrs) in all four groups. Compared with the other groups, SEL significantly prolonged time to develop hypotension. Both SEL and AVP groups had higher renal blood flow compared with NE and control groups, but only SEL had a significant delay in the development of oliguria. Fluid balance was significantly lower and colloid oncotic pressure higher in the SEL group than in the others. Hypoxemia was significantly delayed in the SEL group as was lactate increase when compared to the other groups. Post-mortem lung wet/dry ratio was significantly lower in the SEL group than in the others. Median survival was significantly prolonged in the SEL group compared with other groups (26 vs 19-23 hours, p

Unlike arginine vasopressin, the selective V1a receptor agonist FE 202158 does not cause procoagulant effects by releasing von Willebrand factor.

To compare the effects on von Willebrand factor release of the mixed vasopressin type 1a and type 2 receptor agonist arginine vasopressin and the selective vasopressin type 1a receptor agonist FE 202158, [Phe2,Ile3,Hgn4,Orn(iPr)8]vasopressin, at doses required for the treatment of septic shock. Prospective, randomized, controlled laboratory experiment. University animal research facility. Twenty-four chronically instrumented sheep. After a 5-day recovery from instrumentation, sheep were randomly assigned to receive a single intravenous bolus of the selective vasopressin type 2 receptor agonist desmopressin (1 nmol·kg(-1)) or continuous intravenous infusions of arginine vasopressin (3 pmol·kg(-1)·min(-1)), the selective vasopressin type 1a receptor agonist FE 202158 (10 pmol·kg(-1)·min(-1)), or vehicle (0.9% NaCl) (n = 6 each). The von Willebrand factor antigen activity relative to hemoglobin concentration (vWF:Ag/Hb ratio) was measured at different time points during the 120-min study period. Maximal vWF:Ag/Hb ratio expressed as percentage of baseline level was significantly increased compared to vehicle-infused animals (3 ± 2%) in the desmopressin (40 ± 6%, p < .001) and arginine vasopressin groups (25 ± 4%, p < .001). The ratio for the FE 202158 group was not statistically different from the sham group (9 ± 2%, p = .208). Notably, maximal vWF:Ag/Hb ratio was lower in the FE 202158 than the arginine vasopressin group (p < .005). Unlike the mixed vasopressin type 1a receptor/vasopressin type 2 receptor agonist arginine vasopressin, the selective vasopressin type 1a receptor agonist FE 202158 does not release von Willebrand factor. Because von Willebrand factor is involved in coagulatory and inflammatory pathways during septic shock, future studies should clarify the role of the vasopressin type 2 receptor-mediated von Willebrand factor increase by arginine vasopressin and the potential benefit of selective vasopressin type 1a receptor-agonists like FE 202158.

Experimental sepsis in pigs—effects of vasopressin on renal, hepatic, and intestinal dysfunction

Introduction. Low-dose arginine vasopressin (AVP) has been proposed as an adjunctive vasopressor for the treatment of advanced vasodilatory shock. However, its effects on renal, hepatic, and intestinal dysfunction during sepsis remain controversial.Methods. Fecal peritonitis was induced in 20 anesthetized, invasively monitored, mechanically ventilated female pigs. Following the time point of septic shock (defined as mean artery pressure (MAP) ≤65 mmHg), animals were randomly assigned to the following groups (n = 10): 1) a norepinephrine group with MAP between 65 and 75 mmHg; and 2) an AVP group with a constant infusion rate of 0.5 mU.kg-1.min-1.Results. MAP, pulmonary capillary wedge pressure, hematocrit, TNF-α, IL-6, and IL-10 were similar in the two groups during the 28-h observation period. Infusion of AVP was associated with lower total norepinephrine and fluid requirements. There was a statistically significant improvement in renal function as assessed by increased urine output and renal blood flow, and decreased serum creatinine, in the AVP group when compared with the norepinephrine group (P < 0.05). Histological analyses of the intestine, liver, and kidney showed similar light microscopical appearance of the two groups. Apoptotic cells in the liver were significantly fewer in the AVP group when compared with the norepinephrine group (P < 0.05).Conclusion. An adjunctive AVP to norepinephrine infusion exhibits a favorable impact on renal function without deleterious effects on the liver and intestine in a porcine model of experimental sepsis when compared with norepinephrine infusion alone.

Vasopressin-dependent coupling between sodium transport and water flow in a mouse cortical collecting duct cell line

Water balance is achieved through the ability of the kidney to control water reabsorption in the connecting tubule and the collecting duct. In a mouse cortical collecting duct cell line (mCCD(c11)), physiological concentrations of arginine vasopressin increased both electrogenic, amiloride-sensitive, epithelial sodium channel (ENaC)-mediated sodium transport measured by the short-circuit current (Isc) method and water flow (Jv apical to basal) measured by gravimetry with similar activation coefficient K(1/2) (6 and 12 pM, respectively). Jv increased linearly according to the osmotic gradient across the monolayer. A small but highly significant Jv was also measured under isoosmotic conditions. To test the coupling between sodium reabsorption and water flow, mCCD(c11) cells were treated for 24 h under isoosmotic condition with either diluent, amiloride, vasopressin or vasopressin and amiloride. Isc, Jv, and net chemical sodium fluxes were measured across the same monolayers. Around 30% of baseline and 50% of vasopressin-induced water flow is coupled to an amiloride-sensitive, ENaC-mediated, electrogenic sodium transport, whereas the remaining flow is coupled to an amiloride-insensitive, nonelectrogenic sodium transport mediated by an unknown electroneutral transporter. The mCCD(c11) cell line is a first example of a mammalian tight epithelium allowing quantitative study of the coupling between sodium and water transport. Our data are consistent with the 'near isoosmotic' fluid transport model.

Role of selective V2-receptor-antagonism in septic shock: a randomized, controlled, experimental study

IntroductionV2-receptor (V2R) stimulation potentially aggravates sepsis-induced vasodilation, fluid accumulation and microvascular thrombosis. Therefore, the present study was performed to determine the effects of a first-line therapy with the selective V2R-antagonist (Propionyl1-D-Tyr(Et)2-Val4-Abu6-Arg8,9)-Vasopressin on cardiopulmonary hemodynamics and organ function vs. the mixed V1aR/V2R-agonist arginine vasopressin (AVP) or placebo in an established ovine model of septic shock.MethodsAfter the onset of septic shock, chronically instrumented sheep were randomly assigned to receive first-line treatment with the selective V2R-antagonist (1 μg/kg per hour), AVP (0.05 μg/kg per hour), or normal saline (placebo, each n = 7). In all groups, open-label norepinephrine was additionally titrated up to 1 μg/kg per minute to maintain mean arterial pressure at 70 ± 5 mmHg, if necessary.ResultsCompared to AVP- and placebo-treated animals, the selective V2R-antagonist stabilized cardiopulmonary hemodynamics (mean arterial and pulmonary artery pressure, cardiac index) as effectively and increased intravascular volume as suggested by higher cardiac filling pressures. Furthermore, left ventricular stroke work index was higher in the V2R-antagonist group than in the AVP group. Notably, metabolic (pH, base excess, lactate concentrations), liver (transaminases, bilirubin) and renal (creatinine and blood urea nitrogen plasma levels, urinary output, creatinine clearance) dysfunctions were attenuated by the V2R-antagonist when compared with AVP and placebo. The onset of septic shock was associated with an increase in AVP plasma levels as compared to baseline in all groups. Whereas AVP plasma levels remained constant in the placebo group, infusion of AVP increased AVP plasma levels up to 149 ± 21 pg/mL. Notably, treatment with the selective V2R-antagonist led to a significant decrease of AVP plasma levels as compared to shock time (P < 0.001) and to both other groups (P < 0.05 vs. placebo; P < 0.001 vs. AVP). Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 (vs. placebo) and lower 3-nitrotyrosine concentrations (vs. AVP) in the V2R-antagonist group. In addition, the selective V2R-antagonist slightly prolonged survival (14 ± 1 hour) when compared to AVP (11 ± 1 hour, P = 0.007) and placebo (11 ± 1 hour, P = 0.025).ConclusionsSelective V2R-antagonism may represent an innovative therapeutic approach to attenuate multiple organ dysfunction in early septic shock.

Low-dose vasopressin infusion results in increased mortality and cardiac dysfunction following ischemia-reperfusion injury in mice

IntroductionArginine vasopressin is a vasoactive drug commonly used in distributive shock states including mixed shock with a cardiac component. However, the direct effect of arginine vasopressin on the function of the ischemia/reperfusion injured heart has not been clearly elucidated.MethodsWe measured left ventricular ejection fraction using trans-thoracic echocardiography in C57B6 mice, both in normal controls and following ischemia/reperfusion injury induced by a one hour ligation of the left anterior descending coronary artery. Mice were treated with one of normal saline, dobutamine (8.33 μg/kg/min), or arginine vasopressin (0.00057 Units/kg/min, equivalent to 0.04 Units/min in a 70 kg human) delivered by an intraperitoneal micro-osmotic pump. Arterial blood pressure was measured using a micromanometer catheter. In addition, mortality was recorded and cardiac tissues processed for RNA and protein.ResultsBaseline left ventricular ejection fraction was 65.6% (60 to 72). In normal control mice, there was no difference in left ventricular ejection fraction according to infusion group. Following ischemia/reperfusion injury, AVP treatment significantly reduced day 1 left ventricular ejection fraction 46.2% (34.4 to 52.0), both in comparison with baseline and day 1 saline treated controls 56.9% (42.4 to 60.2). There were no significant differences in preload (left ventricular end diastolic volume), afterload (blood pressure) or heart rate to account for the effect of AVP on left ventricular ejection fraction. The seven-day mortality rate was highest in the arginine vasopressin group. Following ischemia/reperfusion injury, we found no change in cardiac V1 Receptor expression but a 40% decrease in Oxytocin Receptor expression.ConclusionsArginine vasopressin infusion significantly depressed the myocardial function in an ischemia/reperfusion model and increased mortality in comparison with both saline and dobutamine treated animals. The use of vasopressin may be contraindicated in non-vasodilatory shock states associated with significant cardiac injury.