Doses Of Arginine Vasopressin Research Articles

Assessment of the hypothalamic-pituitary-adrenocortical axis function using a vasopressin stimulation test in neonatal foals.

Bacterial sepsis is the leading cause of death in foals and is associated with hypothalamic-pituitary-adrenocortical axis (HPAA) dysfunction. HPAA function can be evaluated by an arginine-vasopressin (AVP) stimulation test. Administration of AVP will stimulate a dose-dependent rise in systemic adrenocorticotropin-releasing hormone (ACTH) and cortisol in neonatal foals. There will be no response seen in corticotropin-releasing hormone (CRH) and baseline AVP will be within reference interval. Twelve neonatal foals, <72 hours old. HPAA function was assessed in foals utilizing 3 doses of AVP (2.5, 5, and 7.5 IU), administered between 24 and 48 hours of age in this randomized cross-over study. Cortisol, ACTH, CRH and AVP were measured at 0 (baseline), 15, 30, 60 and 90 minutes after AVP administration with immunoassays. The fold increase in cortisol and ACTH was calculated at 15 and 30 minutes compared to baseline. All doses of AVP resulted in a significant increase in cortisol concentration over time, and a dose-dependent increase in ACTH concentration over time. ACTH and cortisol were significantly increased at 15 and 30 minutes, respectively after all 3 doses of AVP compared to baseline (P < .01). There was no change in endogenous CRH after stimulation with AVP. Administration of AVP is safe and results in a significant rise in ACTH and cortisol in neonatal foals. A stimulation test with AVP (5 IU) can be considered for HPAA assessment in septic foals.

Kidney injury molecule-1 and podocalyxin dysregulation in an arginine vasopressin induced rodent model of preeclampsia

ObjectiveTo assess renal injury in an arginine vasopressin (AVP) rodent model of preeclampsia. Study designUrinary expression of kidney injury molecule-1 (KIM-1), urinary protein and creatinine was determined in rodents (n = 24; pregnant AVP, pregnant saline, non-pregnant AVP and non-pregnant saline), which received a continuous dose of either AVP or saline via subcutaneous mini osmotic pumps for 18 days, using a Multiplex kidney toxicity immunoassay. Renal morphology was assessed using haematoxylin and eosin staining and transmission electron microscopy. The immunolocalization of KIM-1 and podocalyxin was qualitatively evaluated using immunohistochemistry. ResultsUrinary KIM-1 and urinary protein levels were significantly increased in treated vs. untreated rats on gestational days 8 (p < 0.05), 14 (p < 0.001) and 18 (p < 0.001). The pregnant rats displayed a lower trend of creatinine compared to the non-pregnant groups, albeit non-significantly. KIM-1 was immunolocalized in the proximal convoluted tubules in AVP treated vs. untreated groups. In contrast, podocalyxin was weakly immunostained within glomeruli of pregnant AVP treated vs. pregnant untreated rats. Histological evaluation revealed reduced Bowman’s space, with some tubular and blood vessel necrosis in the pregnant treated group. Ultrastructural observations included effacement and fusion of podocyte foot processes, glomerular basement membrane abnormalities, podocyte nuclear crenations, mitochondrial oedema and cristae degeneration with cytoplasmic lysis within treated tissue. ConclusionOur findings demonstrate region-specific kidney injury particularly glomerular impairment and endothelial injury in AVP-treated rats. The findings highlight the utility of this model in studying the mechanisms driving renal damage in a rodent model of preeclampsia.

PS-B04-11: THE EFFECTS OF PLANT-DERIVED COMPOUNDS AND PLANT EXTRACTS ON BLOOD PRESSURE IN AN AVP INDUCED RAT MODEL OF PRE-ECLAMPSIA

Objective: In resource-limited settings, such as South Africa, hypertensive disorders of pregnancy such as preeclampsia (PE), is the most common direct cause of maternal deaths. Current management of PE includes the use of pharmaceutical drugs, which are frequently associated with major side-effects and not cost effective. Globally, angiotensin-converting enzyme inhibitors (ACEi) are widely used antihypertensive drugs. As a result, patients are reliant on traditional medicine obtained from medicinal plants to manage hypertension related issues. Hence, this study aimed to determine the anti-hypertensive effects of the plant derived bioactive compounds (hesperidin and nicotinamide) and medicinal plant extract (Dombeya rotundifolia ) in a Sprague Dawley rat model induced with arginine vasopressin (AVP). Methods: Female Sprague Dawley rats (n = 30; pregnant AVP saline (PAVPS), pregnant AVP hesperidin (PAVPH), pregnant AVP nicotinamide (PAVPN), pregnant AVP Dombeya rotundifolia (PAVPP), and positive control; pregnant AVP captopril (PAVPC) received a continuous dose of AVP (200 ng/h) via subcutaneous mini osmotic pumps for 18 days. Treatment groups were orally dosed with either 200 mg/kg/BW of the bioactive compounds; the plant extract; or 40 mg/kg/BW of captopril over a 2-week period. Blood pressure was recorded throughout gestation and fetal and placental weights were taken following sacrifice. Results: Treatment groups (PAVPH, PAVPN and PAVPP) significantly (p &lt; 0.05) reduced diastolic, systolic, and mean arterial blood pressure in AVP treated rats when compared to the control group (PAVPS). Furthermore, urine output differed significantly in the AVP-treated vs the treatment groups (p &lt; 0.05). Moreover, placental, and individual pup weight were significantly different in the PAVPS vs PS and treatment groups (p &lt; 0.05). Conclusion: This study showed that Hesperidin, Nicotinamide and Dombeya rotundifolia have the potential to cause a blood pressure lowering effect. Thus, these bioactive compounds and extract may be considered as potential molecules in the development of new naturally occurring pharmaceutical products, as a means to reduce maternal and neonatal mortality and morbidity.

Melatonin alleviates arginine vasopressin-induced cardiomyocyte apoptosis via increasing Mst1-Nrf2 pathway activity to reduce oxidative stress

Heart failure patients have elevated arginine vasopressin (AVP) levels, which are involved in inducing peripheral vasoconstriction and cardiac hypertrophy. This hypertrophy, along with cardiomyocyte apoptosis, results from oxidative stress. Therefore, the antioxidant drug, melatonin (Mel), is commonly used to treat cardiac hypertrophy and apoptosis; however, whether it could alleviate AVP-induced myocardialinjury remains to be addressed. In this study, high AVP doses were found to induce H9c2 cardiomyoblast apoptosis, demonstrated by increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, pro-apoptotic B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) up-regulation, and anti-apoptotic Bcl-2 downregulation. This AVP-induced apoptotic increase, along with lowered cell viability, was also associated with higher reactive oxygen species (ROS) levels and lowered mitochondrial membrane potentials (MMP), which were all reversed upon Mel administration. Further investigations found that apoptosis, ROS, and MMP outcomes under high AVP were associated with Mst1-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway suppression, yielding mitochondrial dysfunction, and Mel reversed them via promoting Mst1 phosphorylation, which then activated Nrf2 to increase anti-oxidative enzyme production. These findings were supported by siRNA gene suppression, where knocking down either Nrf2 or Mst1 abrogated the anti-apoptotic effects of Mel in cardiomyoblasts. Therefore, Mel could reduce cardiomyoblast apoptosis under high AVP levels, via Mst1-Nrf2 pathway re-activation, to enhance anti-oxidative responses.

Developmental exposure to intranasal vasopressin impacts adult prairie vole spatial memory

Spatial memory is critical for many tasks necessary for survival (i.e., locating mates and food resources). The two mammalian nonapeptides arginine vasopressin (AVP) and oxytocin (OT) are mechanistically important in modulating memory ability, albeit in contrasting ways. In general, AVP facilitates memory consolidation and retrieval while OT is an amnesic. Although AVP and OT are known to have these memory effects, past work has focused on their impact in social memory with little research on their effects on spatial memory. In this experiment, we tested the impact of AVP and OT on spatial memory as determined by performance in the Morris water maze (MWM). We administered doses of AVP, OT, or saline (a control) intranasally to male prairie voles (Microtus ochrogaster), a species whose spatial memory is hypothesized to impact their mating tactics. We also investigated if acute doses (given immediately prior to the memory trial in the MWM) and chronic doses (given daily during adolescence) had differing impacts on spatial cognition. We found that chronic intranasal administration of AVP during post-wean development improved spatial memory performance. In contrast, both chronic and acute administration of OT and acute administration of AVP had no impact on spatial memory. These results together suggest that 1) chronic exposure to AVP has organizational effects on spatial memory in the prairie vole, and 2) acute administration of nonapeptides does not impact the retrieval of spatial memories.

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.

Arginine-vasopressin infusion in a child with cranial diabetes insipidus during hyperhydration therapy with chemotherapy: a therapeutic challenge.

SummaryAn 11-year-old girl presented with acute lower limb weakness, dehydration, hypernatraemia and secondary rhabdomyolysis on a background of an 8-month history of polyuria. Radiological investigations revealed a suprasellar tumour which was diagnosed on biopsy as a non-metastatic germinoma. Further endocrinological investigations confirmed panhypopituitarism and she commenced desmopressin, hydrocortisone and thyroxine. Her chemotherapeutic regime consisted of etoposide, carboplatin and ifosfamide, the latter of which required 4 litres of hyperhydration therapy daily. During the first course of ifosfamide, titration of oral desmopressin was trialled but this resulted in erratic sodium control leading to disorientation. Based on limited literature, we then trialled an arginine-vasopressin (AVP) infusion. A sliding scale was developed to adjust the AVP dose, with an aim to achieve a urine output of 3–4 mL/kg/h. During the second course of ifosamide, AVP infusion was commenced at the outset and tighter control of urine output and sodium levels was achieved. In conclusion, we found that an AVP infusion during hyperhydration therapy was required to achieve eunatraemia in a patient with cranial diabetes insipidus. Developing an AVP sliding scale requires individual variation; further reports/case series are required to underpin practice.Learning pointsCertain chemotherapeutic regimens require large fluid volumes of hyperhydration therapy which can result in significant complications secondary to rapid serum sodium shifts in patients with diabetes insipidus.The use of a continuous AVP infusion and titrating with a sliding scale is more effective than oral desmopressin in regulating plasma sodium and fluid balance during hyperhydration therapy.No adverse effects were found in our patient using a continuous AVP infusion.Adjustment of the AVP infusion rate depends on urine output, fluid balance, plasma sodium levels and sensitivity/response of the child to titrated AVP doses.

What's New in Shock, February 2021?

What's New in Shock, February 2021?

Abrupt Discontinuation Versus Down-Titration of Vasopressin in Patients Recovering from Septic Shock

To compare patient outcomes based on management of arginine vasopressin (AVP) during the recovery phase of septic shock (abrupt vs. tapering discontinuation). 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. 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, P = 0.60). After controlling for baseline discrepancies, down-titration was not an independent predictor of time to ICU discharge (HR = 0.99, 95% CI: 0.85-1.15, P = 0.91). There was no difference in ICU mortality (21.8% vs. 18.0%, P = 0.13) or hospital mortality (28.9% vs. 31.1%, P = 0.44). Although incidence of hypotension was similar (39.7% vs. 41.7%, P = 0.53), patients in the down-titration group more frequently required an escalation of AVP dose (5.7% vs. 11.1%, P < 0.001). 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], P < 0.001). 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.

Effects of Arginine Vasopressin and Oxytocin on Neurite Outgrowth and Cellular Signaling in SH‐SY5Y Human Neuroblastoma Cell Line

IntroductionIn the central nervous system, arginine vasopressin (AVP) and oxytocin (OT) stimulate neural networks that regulate social behaviors, including social attachment, aggression, and complex social cognition. AVP and OT are neuropeptides that are expressed in the social behavioral network and bind to G‐protein coupled receptors, stimulating cellular signaling patterns that ultimately affect social behaviors at the organismal level. Consensus mammalian AVP and OT sequences are highly conserved. In addition to sequence homology between AVP and OT, there is ~85% structural homology between the OT receptor (OTR) and vasopressin 1a receptor (V1aR) resulting in significant cross‐reactivity between the ligands and receptors. Perturbations in OT and/or OT receptor expression results in social behavioral deficits, and is associated with a number of psychopathologies including autism spectrum disorder, schizophrenia, anxiety, and depression.MethodsThe human neuroblastoma derived SH‐SY5Y cell line demonstrates morphological characteristics of neurons including neurites and formation of functional synapses, endogenously expresses OTR, and is often used as an in vitro model for human neurons. Functional assays were performed using Fluo8‐AM to measure ligand‐induced Ca2+ mobilization and FLIPR Membrane Potential (FMP) assays were performed to assess ligand‐induced hyperpolarization. To assess effects on neurite outgrowth, cells were treated with logarithmic doses of AVP and OT for 24 hours, fixed and stained with phalloidin and DAPI.ResultsIn SH‐SY5Y cells, OT was more potent than AVP at both ligand‐induced Ca2+ mobilization and membrane hyperpolarization, which is consistent with OT being more potent and efficacious at the human OTR. Specificity of the signaling at the OTR were confirmed using the vasopressin 1a receptor antagonist SR49059 and the oxytocin receptor antagonist L‐371,257. These data are consistent with previous reports that vasopressin 1a receptors are absent in SH‐SY5Y cells. Additionally, OT demonstrated a dose‐dependent increase in neurite outgrowth, which is inhibited by L‐371,257.ConclusionsTogether, these data demonstrate that OTR mediated signaling pathways lead to neurite outgrowth in SH‐SY5Y cells. Additional studies are needed to assess the specific molecular mechanisms that contribute to neurite outgrowth, and whether functional synapses are formed. Integrative studies of behavior, genetics and ligand‐receptor interaction are crucial for translating signaling activation at the cellular level to effects of AVP and OT ligands on social behavior. Knowledge of how OT alters neuronal structure and function has the potential to both identify mechanisms that produce social dysfunction and to inform the development of therapeutic agents.

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.

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.

Dose-Dependent and Lasting Influences of Intranasal Vasopressin on Face Processing in Men.

Arginine vasopressin (AVP) and related peptides have diverse effects on social behaviors in vertebrates, sometimes promoting affiliative interactions and sometimes aggressive or antisocial responses. The type of influence, in at least some species, depends on social contexts, including the sex of the individuals in the interaction and/or on the levels of peptide within brain circuits that control the behaviors. To determine if AVP promotes different responses to same- and other-sex faces in men, and if those effects are dose dependent, we measured the effects of two doses of AVP on subjective ratings of male and female faces. We also tested if any influences persist beyond the time of drug delivery. When AVP was administered intranasally on an initial test day, 20 IU was associated with decreased social assessments relative to placebo and 40 IU, and some of the effects persisted beyond the initial drug delivery and appeared to generalize to novel faces on subsequent test days. In single men, those influences were most pronounced, but not exclusive, for male faces, whereas in coupled men they were primarily associated with responses to female faces. Similar influences were not observed if AVP was delivered after placebo on a second test day. In a preliminary analysis, the differences in social assessments observed between men who received 20 and 40 IU, which we suggest primarily reflect lowered social assessments induced by the lower dose, appeared most pronounced in subjects who carry what has been identified as a risk allele for the V1a receptor gene. Together, these results suggest that AVP’s effects on face processing, and possibly other social responses, differ according to dose, depend on relationship status, and may be more prolonged than previously recognized.

Sex-specific effect of intranasal vasopressin, but not oxytocin, on emotional recognition and perception in schizophrenia patients

BackgroundImpairments in social behavior and cognition, such as the ability to identify others’ emotional state, are important features in schizophrenia. Arginine vasopressin (AVP) and oxytocin (OXT) and are nonapeptides that influence social cognition and behavior. Previous studies have shown that the administration of intranasal AVP or OXT may affect the ability to recognize facial emotions. The primary objective of this study was to investigate the effects of a single dose of AVP or OXT on social cognition in patients with schizophrenia. The secondary objective of the study was to test for sex-specific effects of intranasal AVP and OXT administration on social cognition.MethodsIn this double-blind, placebo-control, cross-over study, 34 patients diagnosed with schizophrenia or schizo-affective disorder, received a dose of AVP, OXT or placebo in three separate meetings. Forty-five minutes after administration, subjects performed facial emotion recognition tasks.ResultsThere were no significant main effects of hormone administration on the ability to recognize facial emotions between treatment conditions. However, AVP administration resulted in sex-specific differences in emotion recognition. Specifically, in men, AVP administration reduced the ability to recognize angry faces. In women, AVP administration reduced the ability to recognize sad faces and improved the ability to recognize fearful faces.ConclusionsThese findings indicate that intranasal AVP may affect the recognition of facial emotions differently in men and women. Thus, AVP may increase the differences between men and women on social cognition.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Role of vasopressin in current anesthetic practice.

Arginine vasopressin (AVP), also known as antidiuretic hormone, is a peptide endogenously secreted by the posterior pituitary in response to hyperosmolar plasma or systemic hypoperfusion states. When administered intravenously, it causes an intense peripheral vasoconstriction through stimulation of V1 receptors on the vascular smooth muscle. Patients in refractory shock associated with severe sepsis, cardiogenic or vasodilatory shock, or cardiopulmonary bypass have inappropriately low plasma levels of AVP (‘relative vasopressin deficiency’) and supersensitivity to exogenously-administered AVP. Low doses of AVP and its synthetic analog terlipressin can restore vasomotor tone in conditions that are resistant to catecholamines, with preservation of renal blood flow and urine output. They are also useful in the treatment of refractory arterial hypotension in patients chronically treated with renin-angiotensin system inhibitors, cardiac arrest, or bleeding esophageal varices. In the perioperative setting, they represent attractive adjunct vasopressors in advanced shock states that are unresponsive to conventional therapeutic strategies.

Arginine-vasopressin therapy in hypotensive neonates and infants after cardiac surgery: response is unrelated to baseline ventricular function.

We hypothesised that infants with ventricular dysfunction after cardiac surgery have impaired haemodynamic response to arginine-vasopressin therapy. We retrospectively reviewed the medical records of neonates and infants treated with arginine-vasopressin within 48 hours of corrective or palliative cardiac surgery who underwent echocardiographic assessment of ventricular function before initiation of therapy. Patients were classified as "responders" if their systolic blood pressure increased by ⩾10% without increase in catecholamine score or if it was maintained with decreased catecholamine score. Response was assessed 1 hour after maximum upward titration of arginine-vasopressin. A total of 36 children (15 neonates) were reviewed (17 male). The median (interquartile) age was 10.4 weeks (1.1-26.9), and the median weight was 4.3 kg (3.2-5.8). Diagnoses included single ventricle (eight), arch abnormalities (five), atrioventricular septal defect (four), double-outlet right ventricle (three), tetralogy of Fallot (three), and others (13). In all, 12 patients (33%) had ventricular dysfunction. Only 15 (42%) responded favourably according to our definition 1 hour after the "target" arginine-vasopressin dose was achieved. Ventricular dysfunction was not associated with poor response. The overall mortality was 25%, but mortality in patients with ventricular dysfunction was 42%. Favourable response was associated with shorter ICU stay (9.5 days versus 19.5 days, p=0.01). We conclude that arginine-vasopressin fails to increase blood pressure in ~50% of hypotensive children after cardiac surgery. The response rate does not increase with duration of therapy. Ventricular function does not predict haemodynamic response. The mortality in this group is very high. Prospective comparison of vasopressin with other vasoactive agents and/or inotropes is warranted.

DIVERSITY OF VASCULAR REACTIVITY AND THE TREATMENT RESPONSE IN DIABETIC, HYPERTENSIVE, HYPERLIPIDEMIC, AND HEALTHY RATS SUBJECTED TO HEMORRHAGIC SHOCK.

The current diagnosis and treatment guidelines for severe trauma and shock are all for healthy population. Few studies focused on the pathophysiological features and treatments in metabolic diseases after severe trauma and shock. Vascular reactivity is significantly decreased after severe trauma and shock. Improving the vascular reactivity with arginine vasopressin (AVP) and phorbol-12 myristate-13-acetate (PMA) is beneficial to trauma and shock. Whether the cardiovascular function and treatment responses have the own features in hypertensive, diabetic, and hyperlipidemic patients after traumatic hemorrhagic shock is not known. Using hypertensive, diabetic, and hyperlipidemic and healthy rats, we compared the change patterns in cardiovascular function including vascular reactivity, tissue perfusion, and the hemodynamics after hemorrhagic shock and their responses to AVP, PMA, and common antishock agents including dopamine and norepinephrine. A same degree of hemorrhagic shock (40% hemorrhage or mean arterial pressure maintained at 40 mm Hg for 2 h) resulted in a more obvious decrease in vascular reactivity, hemodynamics, tissue perfusion, and mitochondrial function of liver and kidney in hypertensive, diabetic, and hyperlipidemic rats, and a more rapidly natural death than in healthy rats. The effectiveness of AVP and PMA in these diseased rats was lower than in healthy rats. The effective dosage of common antishock agents including norepinephrine, dopamine, and AVP in healthy rats was wider than that in these diseased rats. Among the antishock agents used in the current study, AVP had the best effect in improving animal survival and vascular reactivity both in healthy and in diseased rats. These findings suggest that hypertensive, diabetic, and hyperlipidemic rats have a worse vascular reactivity and organ function than the healthy rats after traumatic hemorrhagic shock, which result in the worse treatment responses and effects to vasoactive agents. Lower dose of AVP can be recommended as the first-line antishock agents for these diseased rats.

Arginine Vasopressin Injected into the Dorsal Motor Nucleus of the Vagus Inhibits Gastric Motility in Rats.

Background. Until now, the effect of arginine vasopressin (AVP) in the DMV on gastric motility and the possible modulating pathway between the DMV and the gastrointestinal system remain poorly understood. Objectives. We aimed to explore the role of AVP in the DMV in regulating gastric motility and the possible central and peripheral pathways. Material and Methods. Firstly, we microinjected different doses of AVP into the DMV and investigated its effects on gastric motility in rats. Then, the possible central and peripheral pathways that regulate gastric motility were also discussed by microinjecting SR49059 (a specific AVP receptor antagonist) into the DMV and intravenous injection of hexamethonium (a specific neuronal nicotinic cholinergic receptor antagonist) before AVP microinjection. Results. Following microinjection of AVP (180 pmol and 18 pmol) into the DMV, the gastric motility (including total amplitude, total duration, and motility index of gastric contraction) was significantly inhibited (P < 0.05). Moreover, the inhibitory effect of AVP (180 pmol) on gastric motility could be blocked completely by both SR49059 (320 pmol) and hexamethonium (8 μmol). Conclusions. It is concluded that AVP inhibits the gastric motility by acting on the specific AVP receptor in the DMV, with the potential involvement of the parasympathetic preganglionic cholinergic fibers.

Spinal vasopressin alleviates formalin-induced nociception by enhancing GABAA receptor function in mice

Arginine vasopressin (AVP) plays a regulatory role in nociception. Intrathecal administration of AVP displays an antinociceptive effect. However, little is understood about the mechanism underlying spinal AVP analgesia. Here, we have found that spinal AVP dose dependently reduced the second, but not first, phase of formalin-induced spontaneous nociception in mice. The AVP analgesia was completely blocked by intrathecal injected SR 49059, a vasopressin-1A (V1A) receptor antagonist. However, spinal AVP failed to exert its antinociceptive effect on the second phase formalin-induced spontaneous nociception in V1A receptor knock-out (V1A-/-) mice. The AVP analgesia was also reversed by bicuculline, a GABAA receptor antagonist. Moreover, AVP potentiated GABA-activated currents in dorsal root ganglion neurons from wild-type littermates, but not from V1A-/- mice. Our results may reveal a novel spinal mechanism of AVP analgesia by enhancing the GABAA receptor function in the spinal cord through V1A receptors.

Beneficial and side effects of arginine vasopressin and terlipressin for septic shock

Arginine vasopressin (AVP) and its analog, terlipressin (TP), were all demonstrated beneficial for septic shock. What advantages and disadvantages that AVP and TP have for septic shock as well as the mechanism, however, are not completely known. With cecal ligation and puncture-induced septic shock rats and lipopolysaccharide-induced septic shock rabbits, we systematically compared the beneficial and side effects of AVP and TP, in septic shock and the sex difference, and investigated their relationship to Rho kinase and calcium sensitivity. The results indicated that low dose of TP (2.6 μg/kg/h) in combination with norepinephrine (NE) improving vascular reactivity and animal survival were superior to a small dose of AVP (0.03 U/kg/h) in septic shock rats and rabbits. This improving effect of AVP and TP on vascular reactivity was closely related to the activation of Rho-kinase and Rho-kinase–mediating vascular calcium sensitization. A small dose of TP did not result in hyponatremia, did not increase blood bilirubin and decrease platelet count, whereas AVP did. Animal survival and vascular reactivity in female rats after TP or AVP administration were slightly better than male rats, while there were no significant differences. It was suggested that a small dose of TP has better beneficial effect and less side effects on septic shock than AVP. AVP and TP improving vascular reactivity is closely related to Rho-kinase activation and calcium sensitivity improvement. TP or plus NE may be more appropriate for early emergency care for severe septic shock than AVP.