ABSTRACT
INTRODUCTION: Dimenhydrinate and scopolamine are frequently used drugs, but they cause drowsiness and performance decrement. Therefore, it is crucial to find peripheral targets and develop new drugs without central side effects. This study aimed to investigate the anti-motion sickness action and inner ear-related mechanisms of atrial natriuretic peptide (ANP). METHODS: Endolymph volume in the inner ear was measured with magnetic resonance imaging and expression of AQP2 and p-AQP2 was detected with Western blot analysis and immunofluorescence method. RESULTS: Both rotational stimulus and intraperitoneal arginine vasopressin (AVP) injection induced conditioned taste aversion (CTA) to 0.15% sodium saccharin solution and an increase in the endolymph volume of the inner ear. However, intraperitoneal injection of ANP effectively alleviated the CTA behaviour and reduced the increase in the endolymph volume after rotational stimulus. Intratympanic injection of ANP also inhibited rotational stimulus-induced CTA behaviour, but anantin peptide, an inhibitor of ANP receptor A (NPR-A), blocked this inhibitory effect of ANP. Both rotational stimulus and intraperitoneal AVP injection increased the expression of AQP2 and p-AQP2 in the inner ear of rats, but these increases were blunted by ANP injection. In in vitro experiments, ANP addition decreased AVP-induced increases in the expression and phosphorylation of AQP2 in cultured endolymphatic sac epithelial cells. CONCLUSION: Therefore, the present study suggests that ANP could alleviate motion sickness through regulating endolymph volume of the inner ear increased by AVP, and this action of ANP is potentially mediated by activating NPR-A and antagonising the increasing effect of AVP on AQP2 expression and phosphorylation.
Subject(s)
Arginine Vasopressin , Atrial Natriuretic Factor , Endolymph , Motion Sickness , Animals , Atrial Natriuretic Factor/pharmacology , Atrial Natriuretic Factor/metabolism , Atrial Natriuretic Factor/administration & dosage , Arginine Vasopressin/pharmacology , Arginine Vasopressin/administration & dosage , Arginine Vasopressin/metabolism , Motion Sickness/drug therapy , Male , Endolymph/drug effects , Endolymph/metabolism , Ear, Inner/drug effects , Rats, Sprague-Dawley , Aquaporin 2/metabolism , RatsABSTRACT
Introducción: Se ha postulado que el uso de vasopresina tendría efectos beneficiosos en el postoperatorio de cirugía cardiovascular. Objetivo: Evaluar la respuesta a la vasopresina en el postoperatorio (POP) de cirugía de Fontan de nuestra población. Métodos: Estudio de casos y controles anidados en una cohorte retrospectiva. Se incluyeron pacientes con cirugía de Fontan entre 2014 y 2019. Se registraron variables demográficas, datos del cateterismo pre-Fontan, días de asistencia respiratoria mecánica (ARM), necesidad de inotrópicos, diuréticos, diálisis, dieta hipograsa, octreotide, sildenafil y nutrición parenteral total (NPT); balance de fluidos al primer y segundo día POP, necesidad de cateterismo en el POP, días de permanencia de tubo pleural, días de internación, necesidad de reinternación y mortalidad. Se compararon los grupos con y sin vasopresina utilizando la prueba de Mann- Whitney-Wilcoxon test. Se consideró significativa una p < 0.05. Resultados: Del total analizado, 35 pacientes recibieron vasopresina. En el grupo control fueron 58 pacientes con características similares de gravedad sin vasopresina. No se encontraron diferencias en la evolución postoperatoria entre ambos grupos. El grupo con vasopresina recibió en mayor proporción dieta hipograsa. Conclusiones: En nuestra serie el uso de vasopresina no marcó diferencias significativas en términos de morbimortalidad con relación al grupo control (AU)
Introduction: The use of vasopressin has been suggested to have beneficial effects in the postoperative period after cardiovascular surgery. Objective: To evaluate the response to vasopressin in the postoperative period (POP) of Fontan surgery in our population. Methods: Nested case-control study in a retrospective cohort. Patients who underwent Fontan surgery between 2014 and 2019 were included. Demographic variables, pre-Fontan catheterization data, days of mechanical ventilation (MRA), need for inotropics, diuretics, dialysis, low-fat diet, octreotide, sildenafil and total parenteral nutrition (TPN); fluid balance at first and second day POP, need for catheterization at POP, duration of chest tube drainage, days of hospitalization, need for readmission, and mortality were recorded. Groups with and without vasopressin were compared using the Mann-Whitney- Wilcoxon test. A p < 0.05 was considered significant. Results: Of all patients analyzed, 35 received vasopressin. The control group consisted of 58 patients with similar severity characteristics who did not receive vasopressin. No differences were found in the postoperative outcome between the two groups. The vasopressin group received a higher proportion of low-fat diet. Conclusions: In our series the use of vasopressin did not show significant differences in terms of morbidity and mortality compared to the control group (AU)
Subject(s)
Humans , Infant , Child, Preschool , Postoperative Complications/drug therapy , Arginine Vasopressin/administration & dosage , Arginine Vasopressin/therapeutic use , Fontan Procedure/adverse effects , Antidiuretic Agents/administration & dosage , Antidiuretic Agents/therapeutic use , Indicators of Morbidity and Mortality , Retrospective Studies , Treatment Outcome , HemodynamicsABSTRACT
RATIONALE: Arginine vasopressin (AVP) has dose- and sex-specific effects on social behavior, and variation in social responses is related to variation in the V1a receptor gene in animals. Whether such complexity also characterizes AVP effects on anxiety in humans, or whether V1a genotype is related to anxiety and/or AVP's ability to affect it, remains to be determined. OBJECTIVE: To test if AVP has dose-dependent effects on anxiety in men and/or women and if a particular allele within the RS3 promoter region of the V1a receptor gene is associated with anxiety and/or AVP effects on anxiety. METHOD: Men and women self-administered 20 IU or 40 IU intranasal arginine vasopressin (AVP) and placebo in a double-blind, within-subjects design, and State (SA) and Trait (TA) anxiety were measured 60 min later. PCR was used to identify allelic variation within the RS3 region of the V1a receptor gene. RESULTS: AVP decreased SA in men across both doses, whereas only the lower dose had the same effect, across sexes, in individuals who carry at least one copy of a previously identified "risk" allele in the RS3 promoter of the V1a receptor gene. Additionally, after placebo, women who carried a copy of the allele displayed lower TA than women who did not, and AVP acutely increased TA scores in those women. CONCLUSIONS: Exogenous AVP has modest sex- and dose-dependent effects on anxiety/affect in humans. Further, allelic variation in the V1a promoter appears associated with responsiveness to AVP's effects and, at least in women, to stable levels of anxiety/affect.
Subject(s)
Anxiety , Arginine Vasopressin , Dose-Response Relationship, Drug , Genotype , Receptors, Vasopressin , Humans , Male , Receptors, Vasopressin/genetics , Female , Arginine Vasopressin/genetics , Arginine Vasopressin/pharmacology , Arginine Vasopressin/administration & dosage , Double-Blind Method , Anxiety/genetics , Anxiety/drug therapy , Adult , Young Adult , Sex Factors , Promoter Regions, Genetic , Administration, Intranasal , AllelesABSTRACT
Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.
Subject(s)
Arginine Vasopressin/metabolism , Diabetes Mellitus, Type 1/metabolism , Glucagon/metabolism , Adult , Animals , Arginine Vasopressin/administration & dosage , Diabetes Mellitus, Type 1/physiopathology , Female , Humans , Male , Mice , Young AdultABSTRACT
The respective roles of the neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) in modulating social cognition and for therapeutic intervention in autism spectrum disorder have not been fully established. In particular, while numerous studies have demonstrated effects of oxytocin in promoting social attention the role of AVP has not been examined. The present study employed a randomized, double-blind, placebo (PLC)-controlled between-subject design to explore the social- and emotion-specific effects of AVP on both bottom-up and top-down attention processing with a validated emotional anti-saccade eye-tracking paradigm in 80 healthy male subjects (PLC = 40, AVP = 40). Our findings showed that AVP increased the error rate for social (angry, fearful, happy, neutral and sad faces) but not non-social (oval shapes) stimuli during the anti-saccade condition and reduced error rates in the pro-saccade condition. Comparison of these findings with a previous study (sample size: PLC = 33, OXT = 33) using intranasal oxytocin revealed similar effects of the two peptides on anti-saccade errors, although with some difference in effects of specific face emotions, but a significantly greater effect of AVP on pro-saccades. Both peptides also produced a post-task anxiolytic effect by reducing state anxiety. Together these findings suggested that both AVP and OXT decrease goal-directed top-down attention control to social salient stimuli but that AVP more potently increased bottom-up social attentional processing.
Subject(s)
Arginine Vasopressin , Attention , Oxytocin , Administration, Intranasal , Arginine Vasopressin/administration & dosage , Arginine Vasopressin/pharmacology , Attention/drug effects , Attention/physiology , Autism Spectrum Disorder/therapy , Humans , Male , Oxytocin/administration & dosage , Oxytocin/pharmacologyABSTRACT
PURPOSE: To compare patient outcomes based on management of arginine vasopressin (AVP) during the recovery phase of septic shock (abrupt vs. tapering discontinuation). PATIENTS AND METHODS: Multicenter, retrospective cohort study of patients receiving AVP with concomitant norepinephrine for septic shock. Primary outcome measure was time to intensive care unit (ICU) discharge (from decision to titrate or stop AVP). Secondary outcomes included ICU and hospital mortality, and incidence of hypotension. RESULTS: A total of 958 (73%) abrupt discontinuation and 360 (27%) down-titration patients were included. Patient characteristics and septic shock treatment courses were similar between groups. Median time to ICU discharge was similar between abrupt discontinuation (7.9 days, 95% CI 7.2-8.7 days) and tapered patients (7.3 days, 95% CI 6.3-9.3 days, Pâ=â0.60). After controlling for baseline discrepancies, down-titration was not an independent predictor of time to ICU discharge (HRâ=â0.99, 95% CI: 0.85-1.15, Pâ=â0.91). There was no difference in ICU mortality (21.8% vs. 18.0%, Pâ=â0.13) or hospital mortality (28.9% vs. 31.1%, Pâ=â0.44). Although incidence of hypotension was similar (39.7% vs. 41.7%, Pâ=â0.53), patients in the down-titration group more frequently required an escalation of AVP dose (5.7% vs. 11.1%, Pâ<â0.001). Median AVP duration was shorter in the abrupt discontinuation group (1.4 days [IQR: 0.6-2.6 days] vs. 1.8 days [IQR: 1.1-3.2 days], Pâ<â0.001). CONCLUSIONS: A difference in time to ICU discharge was not detected between abrupt AVP discontinuation and down-titration in patients recovering from septic shock. In patients recovering from septic shock, abrupt discontinuation of AVP appears to be safe and may lead to shortened AVP duration.
Subject(s)
Arginine Vasopressin/administration & dosage , Shock, Septic/drug therapy , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Retrospective Studies , Treatment Outcome , Withholding TreatmentABSTRACT
OBJECTIVE: In this study, we examined the effect of acute hyponatremia associated with vasopressin (AVP) on the responses of the isolated rat's MCAs and PAs to acidosis, nitric oxide donor (SNAP) and to endothelium-dependent vasodilator ATP. METHODS: The studies were performed on isolated, perfused and pressurized MCAs and PAs in control conditions and during AVP-associated hyponatremia. Hyponatremia was induced in vitro by lowering Na+ concentration from 144 to 121 mmol/L in intra- and extravascular fluid in the presence of AVP. RESULTS: Parenchymal arterioles showed greater response to an increase in H+ and K+ ions concentration and to ATP in comparison with MCAs in control normonatremic conditions. Both PAs and MCAs constricted in response to acute hyponatremia associated with AVP. Interestingly, disordered regulation of vascular tone was observed in PAs but not in MCAs. The abnormalities in the regulation comprised a significant reduction of PA response to acidosis and the absence of the response to the administration of SNAP or ATP. CONCLUSIONS: Arginine vasopressin-associated hyponatremia leads to constriction and dysregulation of PAs which may impair neurovascular coupling.
Subject(s)
Arterioles/physiopathology , Brain/blood supply , Brain/physiopathology , Hyponatremia/physiopathology , Acidosis/physiopathology , Acute Disease , Adenosine Triphosphate/pharmacology , Animals , Arginine Vasopressin/administration & dosage , Arginine Vasopressin/physiology , Arterioles/drug effects , Disease Models, Animal , Humans , Hyponatremia/etiology , In Vitro Techniques , Male , Middle Cerebral Artery/drug effects , Middle Cerebral Artery/physiopathology , Nitric Oxide Donors/pharmacology , Rats , Rats, Wistar , S-Nitroso-N-Acetylpenicillamine/pharmacology , Vasoconstriction/drug effects , Vasoconstriction/physiologyABSTRACT
BACKGROUND: Arginine-vasopressin (AVP) is a neuropeptide and provides learning and memory modulation. The AVP (4-5) dipeptide corresponds to the N-terminal fragment of the major vasopressin metabolite AVP (4-9), has a neuroprotective effect and used in the treatment of Alzheimer's and Parkinson's disease. METHODS: The main objective of the present study is to evaluate the molecular mechanism of AVP (4-5) dipeptide and to develop and synthesize chitosan nanoparticle formulation using modified version of ionic gelation method, to increase drug effectiveness. For peptide loaded chitosan nanoparticles, the synthesized experiment medium was simulated for the first time by molecular dynamics method and used to determine the stability of the peptide, and the binding mechanism to protein (HSP70) was also investigated by molecular docking calculations. A potential pharmacologically features of the peptide was also characterized by ADME (Absorption, Distribution, Metabolism and Excretion) analysis. The characterization, in vitro release study, encapsulation efficiency and loading capacity of the peptide loaded chitosan nanoparticles (CS NPs) were performed by Dynamic Light Scattering (DLS), UV-vis absorption (UV), Scanning Electron Microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy techniques. Additionally, in vitro cytotoxicity of the peptide on human neuroblastoma cells (SH-SY5Y) was examined with XTT assay and the statistical analysis was evaluated. RESULTS: The results showed that; hydrodynamic size, zeta potential and polydispersity index (PdI) of the peptide-loaded CS NPs were 167.6 nm, +13.2 mV, and 0.211, respectively. In vitro release study of the peptide-loaded CS NPs showed that 17.23% of the AVP (4-5)-NH2 peptide was released in the first day, while 61.13% of AVP (4-5)-NH2 peptide was released in the end of the 10th day. The encapsulation efficiency and loading capacity were 99% and 10%, respectively. According to the obtained results from XTT assay, toxicity on SHSY-5Y cells in the concentration from 0.01 µg/µL to 30 µg/µL were evaluated and no toxicity was observed. Also, neuroprotective effect was showed against H2O2 treatment. CONCLUSION: The experimental medium of peptide-loaded chitosan nanoparticles was created for the first time with in silico system and the stability of the peptide in this medium was carried out by molecular dynamics studies. The binding sites of the peptide with the HSP70 protein were determined by molecular docking analysis. The size and morphology of the prepared NPs capable of crossing the blood-brain barrier (BBB) were monitored using DLS and SEM analyses, and the encapsulation efficiency and loading capacity were successfully performed with UV Analysis. In vitro release studies and in vitro cytotoxicity analysis on SHSY-5Y cell lines of the peptide were conducted for the first time. Grapical abstract.
Subject(s)
Arginine Vasopressin , Chitosan , Nanoparticles , Neuroprotective Agents , Peptides , Arginine Vasopressin/administration & dosage , Arginine Vasopressin/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Chitosan/administration & dosage , Chitosan/chemistry , Drug Design , Humans , Hydrogen Peroxide/toxicity , Molecular Docking Simulation , Molecular Dynamics Simulation , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/chemistry , Peptides/administration & dosage , Peptides/chemistryABSTRACT
Objective: To summarize literature evaluating vasopressin use, focusing on clinical controversies regarding initiation, dosing, and discontinuation and interaction of vasopressin with other therapies in septic shock patients. Data Sources: A PubMed English-language literature search (January 2008 to December 2019) was performed using these terms: arginine vasopressin, septic, shock, and sepsis. Citations, including controlled trials, observational studies, review articles, guidelines, and consensus statements, were reviewed. Study Selection and Data Extraction: Relevant clinical data focusing on specific controversial questions regarding the utility of vasopressin in patients with septic shock were narratively summarized. Data Synthesis: Current literature does not strongly support the use of vasopressin as a first-line initial therapy for septic shock. Additionally, there are conflicting data for weight-based dosing of vasopressin in overweight patients. Evidence for vasopressin renal protection and interaction with corticosteroids is minimal. However, vasopressin has the ability to reduce catecholamine requirements in septic shock patients and may provide a mortality benefit in specific subgroups. Discontinuation of vasopressin last, not second to last, in resolving septic shock may reduce hypotension development. Relevance to Patient Care and Clinical Practice: This review addresses specific clinical controversies that drive vasopressin use in septic shock patients in real-world practice. Conclusion: Vasopressin should remain second-line adjunct to norepinephrine to augment mean arterial pressures. Dosing should be initiated at 0.03 U/min, and higher doses offer minimal benefit. There are conflicting data on the impact of weight on vasopressin response. Studies have failed to show renal benefit with vasopressin use or an interaction with corticosteroid therapy.
Subject(s)
Arginine Vasopressin/therapeutic use , Hypotension/drug therapy , Norepinephrine/therapeutic use , Shock, Septic/drug therapy , Vasoconstrictor Agents/therapeutic use , Arginine Vasopressin/administration & dosage , Arginine Vasopressin/adverse effects , Arterial Pressure/drug effects , Body Weight , Humans , Norepinephrine/administration & dosage , Norepinephrine/adverse effects , Practice Guidelines as Topic , Vasoconstrictor Agents/administration & dosage , Vasoconstrictor Agents/adverse effectsABSTRACT
Memory deficits with aging are related to the neurodegeneration in the brain, including a reduction in arginine vasopressin (AVP) in the brain of patients with Alzheimer's disease (AD). AVP(4-8), different from its precursor AVP, plays memory enhancement roles in the CNS without peripheral side-effects. However, it is not clear whether AVP(4-8) can improve cognitive behaviors and synaptic plasticity in the APP/PS1 mouse model of AD. Here, we investigated for the first time the neuroprotective effects of AVP(4-8) on memory behaviors and in vivo long-term potentiation (LTP) in APP/PS1-AD mice. The results showed that: (1) APP/PS1-AD mice had lower spontaneous alternation in the Y-maze than wild-type (WT) mice, and this was significantly reversed by AVP(4-8); (2) the prolonged escape latency of APP/PS1-AD mice in the Morris water maze was significantly decreased by AVP(4-8), and the decreased swimming time in target quadrant recovered significantly after AVP(4-8) treatment; (3) in vivo hippocampal LTP induced by high-frequency stimulation had a significant deficit in the AD mice, and this was partly rescued by AVP(4-8); (4) AVP(4-8) significantly up-regulated the expression levels of postsynaptic density 95 (PSD95) and nerve growth factor (NGF) in the hippocampus of AD mice. These results reveal the beneficial effects of AVP(4-8) in APP/PS1-AD mice, showing that the intranasal administration of AVP(4-8) effectively improved the working memory and long-term spatial memory of APP/PS1-AD mice, which may be associated with the elevation of PSD95 and NGF levels in the brain and the maintenance of hippocampal synaptic plasticity.
Subject(s)
Alzheimer Disease/drug therapy , Arginine Vasopressin/analogs & derivatives , Hippocampus/drug effects , Long-Term Potentiation/drug effects , Maze Learning/drug effects , Memory Disorders/drug therapy , Neuroprotective Agents/pharmacology , Peptide Fragments/pharmacology , Animals , Arginine Vasopressin/administration & dosage , Arginine Vasopressin/pharmacology , Disease Models, Animal , Male , Mice , Mice, Transgenic , Neuroprotective Agents/administration & dosage , Peptide Fragments/administration & dosageABSTRACT
Evidence to date suggests that ß-arrestins act beyond their role as adapter proteins. Arginine vasopressin (AVP) may be a factor in inflammation and fibrosis in the pathogenesis of heart failure. In the present study we investigated the effect of AVP on inflammatory cytokine IL-6 production in murine hearts and the impact of ß-arrestin 2-dependent signaling on AVP-induced IL-6 production. We found that administration of AVP (0.5 U/kg, iv) markedly increased the levels of IL-6 mRNA in rat hearts with the maximum level occurred at 6 h. In ß-arrestin 2 KO mouse hearts, deletion of ß-arrestin 2 decreased AVP-induced IL-6 mRNA expression. We then performed in vitro experiments in adult rat cardiac fibroblasts (ARCFs). We found that AVP (10-9-10-6 M) dose-dependently increased the expression of IL-6 mRNA and protein, activation of NF-κB signaling and ERK1/2 phosphorylation, whereas knockdown of ß-arrestin 2 blocked AVP-induced IL-6 increase, NF-κB activation and ERK1/2 phosphorylation. Pharmacological blockade of ERK1/2 using PD98059 diminished AVP-induced NF-κB activation and IL-6 production. The selective V1A receptor antagonist SR49059 effectively blocked AVP-induced NF-κB phosphorylation and activation as well as IL-6 expression in ARCFs. In AVP-treated mice, pre-injection of SR49059 (2 mg/kg, iv) abolished AVP-induced NF-κB activation and IL-6 production in hearts. The above results suggest that AVP induces IL-6 induction in murine hearts via the V1A receptor-mediated ß-arrestin2/ERK1/2/NF-κB pathway, thus reveal a novel mechanism of myocardial inflammation in heart failure involving the V1A/ß-arrestin 2/ERK1/2/NF-κB signaling pathway.
Subject(s)
Arginine Vasopressin/pharmacology , Heart/physiopathology , Interleukin-6/metabolism , beta-Arrestin 2/genetics , Animals , Arginine Vasopressin/administration & dosage , Dose-Response Relationship, Drug , Fibroblasts/metabolism , Gene Knockdown Techniques , Heart Failure/physiopathology , Male , Mice , Mice, Knockout , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , NF-kappa B/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Vasopressin/metabolismABSTRACT
Importance: 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. Objective: 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. Design, Setting, and Participants: 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. Interventions: 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. Main Outcomes: 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. Results: 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). Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov identifier: NCT01611935.
Subject(s)
Arginine Vasopressin/administration & dosage , Blood Component Transfusion/statistics & numerical data , Hemostatics/administration & dosage , Shock, Hemorrhagic/therapy , Wounds and Injuries/therapy , Adolescent , Adult , Aged , Clinical Protocols , Double-Blind Method , Female , Humans , Male , Middle Aged , Shock, Hemorrhagic/etiology , Trauma Centers , Young AdultABSTRACT
BACKGROUND: Chronic ethanol (EtOH) exposure induces neurobehavioral maladaptations in the brain though the precise changes have not been fully explored. The central nucleus of the amygdala (CEA) regulates anxiety-like behavior induced by withdrawal from chronic intermittent EtOH (CIE) exposure, and the arginine vasopressin (AVP) system within the CEA regulates many anxiety-like behaviors. Thus, adaptations occur in the CEA AVP system due to chronic EtOH exposure, which lead to anxiety-like behaviors in rats. METHODS: Chronic exposure to a low-dose EtOH (4.5% wt/vol) induces anxiety-like behavior in rats. Wistar or Sprague Dawley rats were exposed to a modified CIE or CIE, while intra-CEA microinjections of AVP or a V1b receptor antagonist were used to elicit or block withdrawal-induced anxiety. Additionally, AVP microinjections into the CEA were given 24 hours following 15 days of continuous high-dose EtOH (7% wt/vol), a time period when rats no longer express anxiety. Chemogenetics was also used to activate the basolateral amygdala (BLA) or deactivate the dorsal periaqueductal gray=(dm/dlPAG) therefore PAG=periaqueductal gray to elicit or block withdrawal-induced anxiety. RESULTS: AVP microinjected into the CEA in lieu of exposure to the first 2 cycles of CIE was sufficient to induce anxiety-like behavior in these commonly used rat strains. The V1b receptor antagonist, but not an oxytocin receptor agonist, into the CEA during the first 2 withdrawal cycles suppressed anxiety. However, activation of the BLA in lieu of exposure to the first 2 cycles of CIE was insufficient to induce anxiety-like behavior. AVP microinjection into the CEA 24 hours into withdrawal reelicited anxiety-like behavior, and deactivation of the dm/dlPAG reduced this effect of CEA AVP. CONCLUSIONS: Taken together, this study demonstrates a role of CEA AVP and a CEA-dm/dlPAG circuit in the development of anxiety induced by CIE. Such information is valuable for identifying novel therapeutic targets for alcohol- and anxiety-associated disorders.
Subject(s)
Amygdala/drug effects , Anxiety/psychology , Arginine Vasopressin/pharmacology , Central Nervous System Depressants , Ethanol , Interpersonal Relations , Substance Withdrawal Syndrome/psychology , Animals , Anxiety/etiology , Anxiety/physiopathology , Arginine Vasopressin/administration & dosage , Behavior, Animal , Male , Microinjections , Periaqueductal Gray/drug effects , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Vasopressin/drug effects , Substance Withdrawal Syndrome/complications , Substance Withdrawal Syndrome/physiopathologyABSTRACT
Despite the high prevalence of aggression across a wide range of disorders, there is a severe lack of pharmacological treatments. Recent rodent studies have shown both centrally and peripherally administered oxytocin is effective in reducing territorial aggression, an adaptive form of aggression not reflective of pathological hyper-aggression. The current study tested i.p. administered oxytocin and vasopressin in a model of non-territorial hyper-aggression and examined the involvement of oxytocin receptors (OXTR) and vasopressin V1a receptors (V1aR). Male Swiss mice (Nâ¯=â¯160) were either socially isolated or group housed for 6 weeks prior to the commencement of testing; wherein two unfamiliar weight and condition matched mice were placed into a neutral context for 10â¯min. Socially isolated mice exhibited heightened aggression that was powerfully and dose-dependently inhibited by oxytocin and vasopressin and that was accompanied by dose-dependent increases in close social contact (huddling) and grooming. These anti-aggressive effects of oxytocin were blocked by pre-treatment with a higher dose of selective V1aR antagonist SR49059 (20â¯mg/kg i.p.), but not a lower dose of SR49059 (5â¯mg/kg i.p.) or selective OXTR antagonist L-368,899 (10â¯mg/kg i.p.). This is consistent with a growing number of studies linking a range of effects of exogenous oxytocin to actions at the V1a receptor. Interestingly, the highest dose of the OXTR agonist TGOT (10â¯mg/kg) also reduced isolation-induced aggression. These results suggest that while activation of the V1a receptor appears critical for the anti-aggressive effects of oxytocin, activation of the oxytocin receptor cannot be excluded. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity.'
Subject(s)
Aggression/physiology , Oxytocin/physiology , Social Isolation , Vasopressins/physiology , Aggression/drug effects , Animals , Arginine Vasopressin/administration & dosage , Arginine Vasopressin/physiology , Male , Mice , Oxytocin/administration & dosage , Receptors, Oxytocin/physiology , Receptors, Vasopressin/physiology , Vasopressins/administration & dosageABSTRACT
The neuropeptides oxytocin (OT) and arginine vasopressin (AVP) influence social functions in many mammals. In humans and rhesus macaques, OT delivered intranasally can promote prosocial behavior in certain contexts. Yet the precise neural mechanisms mediating these behavioral effects remain unclear. Here we show that treating a group of male macaque monkeys intranasally with aerosolized OT relaxes their spontaneous social interactions with other monkeys. OT reduces differences in social behavior between dominant and subordinate monkeys, thereby flattening the status hierarchy. OT also increases behavioral synchrony within a pair. Intranasal delivery of aerosolized AVP reproduces the effects of OT with greater efficacy. Remarkably, all behavioral effects are replicated when OT or AVP is injected focally into the anterior cingulate gyrus (ACCg), a brain area linked to empathy and other-regarding behavior. ACCg lacks OT receptors but is rich in AVP receptors, suggesting exogenous OT may shape social behavior, in part, via nonspecific binding. Notably, OT and AVP alter behaviors of both the treated monkey and his untreated partner, consistent with enhanced feedback through reciprocal social interactions. These findings bear important implications for use of OT in both basic research and as a therapy for social impairments in neurodevelopmental disorders.
Subject(s)
Arginine Vasopressin/metabolism , Gyrus Cinguli/physiology , Oxytocin/metabolism , Administration, Intranasal , Animals , Arginine Vasopressin/administration & dosage , Empathy , Female , Interpersonal Relations , Macaca mulatta , Male , Oxytocin/administration & dosage , Social DominanceABSTRACT
In nearly every vertebrate species examined thus far arginine vasopressin (AVP) and its homologues modulate behavior; thus, providing rich systems for comparative research. In rodents, AVP is best known for its modulation of social behavior; however, to date, research on AVPs effects on behavior have been limited to laboratory models and a few experiments using large outdoor enclosures. To extend our understanding of AVPs role in modulating social behavior and communication in an ecologically relevant context, we examined the effects of AVP on behavior of free-living Richardson's ground squirrels (Urocitellus richardsonii). To test the hypothesis that AVP influences social behavior and communication, we implanted osmotic minipumps into Richardson's ground squirrels and centrally administered AVP or saline as a control. Three different behavioral experiments quantifying behavior before and after AVP or saline administration were performed: a general behavior survey, a predator model presentation, and a social challenge test. AVP administration increased male vocalization rate when approached by a conspecific, but not when presented with a predator model. In males, social aggression decreased, but antipredator vigilance increased with AVP administration. Finally, AVP-treated females had increased "anxiety-like" behaviors during the social challenge test. Our data reveal that AVP has sex-specific effects on vocalizations and antipredator vigilance, as well as other social behaviors. Further, our data illustrate the importance of social context to AVPs modulation of behavior. (PsycINFO Database Record
Subject(s)
Arginine Vasopressin/metabolism , Sciuridae/metabolism , Social Behavior , Vocalization, Animal/physiology , Animals , Anxiety/metabolism , Arginine Vasopressin/administration & dosage , Catheters, Indwelling , Feces/chemistry , Female , Glucocorticoids/analysis , Male , Random Allocation , Sex Characteristics , Vocalization, Animal/drug effectsABSTRACT
RATIONALE: The amygdala plays a paramount role in the modulation of anxiety and numerous studies have shown that arginine vasopressin (AVP) elicits anxiogenic effects following either its systemic or septal administration. OBJECTIVES: The aim of this paper was to study the involvement of vasopressinergic neurotransmission in the amygdaloid modulation of unconditioned anxiety and to ascertain whether or not AVP receptor subtypes may have a differential role in this modulation. METHODS: Anxiety behavior was evaluated both in Shock-Probe Burying Test and Light-Dark Box following the bilateral microinfusion of AVP alone or AVP together with either AVP 1a or AVP 1b receptor antagonists into the central amygdala (CeA). RESULTS: AVP microinfusion elicited at low (1 ng/side) but not at high doses (10 ng/side) anxiogenic-like responses in the Shock-Probe Burying Test but not in the Light-Dark Box. SSR149415, an AVP 1b antagonist unlike Manning compound, an AVP 1a antagonist, fully prevented AVP effects in the Shock-Probe Burying Test when it was administered simultaneously with AVP. In addition, oxytocin receptor blockade also failed to affect AVP effects. No effects of any AVP antagonist by itself were observed in both anxiety paradigms. CONCLUSIONS: Our results indicate that AVP 1b receptor contribute to the amygdaloid modulation of anxiety at least in the context of the Shock-Probe Burying Test since no effects were noticed in the Light-Dark Box. It remains to the future to ascertain whether AVP receptor subtypes have indeed differential actions either in the modulation of global or specific features of unconditioned anxiety.
Subject(s)
Amygdala/drug effects , Amygdala/metabolism , Anxiety/metabolism , Arginine Vasopressin/administration & dosage , Receptors, Vasopressin/metabolism , Animals , Antidiuretic Hormone Receptor Antagonists/administration & dosage , Anxiety/chemically induced , Anxiety/drug therapy , Hormone Antagonists/administration & dosage , Male , Microinjections , Rats , Rats, Wistar , Receptors, Vasopressin/agonistsABSTRACT
The memory impairment is a core deficit in the first-episode schizophrenia patients. Arginine vasopressin (AVP) in the brain can improve learning and memory. We performed multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial to study the cognitive functioning in Han Chinese first-episode schizophrenic patients in a 12-week treatment regime with the intranasal administration of AVP (128 cases) or placebo (131 cases) in addition to the conventional treatment. The methods of positive and negative syndrome scale (PANSS), Wechsler memory scale-4th edition (WMS-IV) and event-related potential (ERP) were used to study the effects of AVP on the cognitive function. The results showed that (1) AVP concentration decreased in cerebrospinal fluid (CSF) of the right-handed Han Chinese first-episode schizophrenic patients comparing with that of the health volunteers (7.1±1.5pg/ml vs 13.3±1.9pg/ml, p<0.01), and did not change in plasma; (2) AVP significantly improved PANSS scores including total scores, positive symptoms, negative symptoms and general psychopathology comparing with those of the placebo group; (3) AVP elevated WMS-IV scores including the long-term memory (accumulation), short-term memory (recognition, comprehension), immediate memory (number recitation) and memory quotient 4, 8 and 12 weeks after treatment; and (4) AVP did not influence the latency and wave amplitude of target stimulus of P300 of right-handed Han Chinese first-episode schizophrenic patients. The data suggested that AVP might improve cognitive process, such as memorizing and extraction of the information although there were many changes of cognitive functions in the right-handed Han Chinese first-episode schizophrenic patients.
Subject(s)
Antipsychotic Agents/therapeutic use , Arginine Vasopressin/therapeutic use , Memory Disorders/drug therapy , Schizophrenia/drug therapy , Administration, Intranasal , Adult , Antipsychotic Agents/administration & dosage , Arginine Vasopressin/administration & dosage , Asian People , Cognition/drug effects , Double-Blind Method , Female , Humans , Male , Memory/drug effects , Middle Aged , Placebo Effect , Time Factors , Wechsler Memory ScaleABSTRACT
BACKGROUND: Administration of arginine vasopressin (AVP) is associated with reducing jugular venous (SjvO2) and regional cerebral (rScO2) oxygen saturation under propofol-remifentanil (P/R) anaesthesia. We determined whether background anaesthetics modulate the effect of AVP on cerebral oxygenation and haemodynamics. METHODS: We randomly allocated 60 adult patients scheduled for shoulder surgery in the beach chair position (BCP) into 4 groups, to receive either an intravenous bolus of saline (groups PR-S and SN-S) or 0.05 U/kg AVP (groups PR-AVP and SN-AVP) under P/R or sevoflurane-nitrous oxide (S/N) anaesthesia (n = 15 each). Haemodynamic variables, SjvO2 and rScO2 were measured. RESULTS: AVP significantly increased mean arterial blood pressure (MAP) and decreased rScO2 in either anaesthetic group. AVP also decreased SjvO2 in the P/R groups but not in the S/N groups. The AVP-treated groups showed higher MAP and cerebral desaturation (>20% rScO2 decrease from baseline), along with lower HR and rScO2 in the BCP than those in the saline-treated groups. In contrast, AVP did not affect SjvO2 values or the incidence of SjvO 2 < 50%. Baseline SjvO2 was lower and the magnitude of its reduction in the BCP was greater in the PR-AVP group than in the SN-AVP group, and the lowest SjvO2 values were 37 ± 6 and 57 ± 8%, respectively (P < 0.001). CONCLUSIONS: The choice of anaesthetic regimen did not affect cerebral oxygenation or haemodynamics of AVP in the BCP. However, the negative effect of AVP on cerebral oxygenation should be considered, especially under P/R anaesthesia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01687894 , registered on September 18, 2012.
Subject(s)
Arginine Vasopressin/administration & dosage , Brain/metabolism , Oxygen/metabolism , Patient Positioning , Vasoconstrictor Agents/administration & dosage , Aged , Anesthetics/administration & dosage , Blood Pressure/drug effects , Cerebrovascular Circulation , Female , Heart Rate/drug effects , Humans , Male , Methyl Ethers/administration & dosage , Middle Aged , Nitrous Oxide/administration & dosage , Oximetry , Piperidines/administration & dosage , Propofol/administration & dosage , Prospective Studies , Remifentanil , Sevoflurane , Shoulder Joint/surgery , Single-Blind Method , Spectroscopy, Near-InfraredABSTRACT
Background: Adrenocorticotropic hormone (ACTH) secretion is controlled by unobservable hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) pulses. Clamping exogenous CRH or AVP input could allow indirect quantification of the impact of the endogenous heterotypic hormone. Methods: We conducted a randomized, double-blind, placebo-controlled, crossover study in 28 healthy adults (16 men). Volunteers underwent a sex-steroid clamp and a cortisol clamp. ACTH was measured over 10 hours by 10-minute sampling during each of four randomized intravenous (IV) secretagogue clamps (i.e., continuous IV CRH, AVP, both peptides, or saline). Desensitization was tested by bolus injection of the noninfused peptide. Results: Mean ± standard error of the mean 10-hour ACTH concentrations (ng/L) in the sex-combined analysis were: saline, 32 ± 4.6; AVP, 29 ± 4.6; CRH, 67 ± 6.2; and CRH-AVP, 67 ± 8.8 (any CRH vs AVP or saline, P < 0.0001). CRH and AVP increased approximate entropy (relative randomness) of ACTH release (P < 0.0001). Bolus AVP injection after CRH infusion yielded a 2.5-hour ACTH concentration of 46 ± 4.3, exceeding that seen after bolus CRH or saline injection (26 ± 3.3 and 24 ± 3.6, respectively; P = 0.002 and 0.001). Sex hormone clamps did not influence ACTH levels. Conclusions: A CRH, but not AVP, clamp yields sustained pulsatile ACTH secretion with high ACTH secretory-burst mass and randomness. After 10-hour CRH infusion, bolus AVP but not CRH, evoked marked ACTH release, likely caused by heterotypic sensitization of corticotropes by CRH. Similar interactions might underlie chronic stress states.