Arginine Vasopressin Infusion Research Articles

Vasopressin in Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials

To summarize the results of randomized controlled trials on the use of vasopressin as a vasopressor agent in cardiac surgery. Meta-analysis. Six-hundred-twenty-five adult patients undergoing elective or emergency cardiac surgery. Arginine vasopressin infusion (n = 313) or control/standard therapy (n = 312). The rates of perioperative complications and postoperative mortality were used as primary and secondary endpoints, respectively. Fixed and/or random effects models were used to compare pooled odds ratios. Arginine vasopressin reduced the pooled odds ratio (OR) of perioperative complications (OR, 0.33; 95% confidence interval [CI], 0.2-0.54; p < 0.0001). A sensitivity analysis excluding the largest trial showed an unchanged reduction in perioperative complications (OR, 0.35; 95% CI, 0.18-0.69; p = 0.002). When analyzing each perioperative complication separately, vasopressin reduced the pooled OR of vasodilatory shock (OR, 0.4; 95% CI, 0.16-0.97; p = 0.04) and new-onset atrial fibrillation (OR, 0.42; 95% CI, 0.21-0.82; p = 0.01). The pooled OR of postoperative death was not different between patients treated with arginine vasopressin and those receiving standard therapy or placebo (OR, 0.83; 95% CI, 0.45-1.53; p = 0.55). The funnel plot for the primary endpoint suggested a relevant publication bias. All included trials suffered from a high risk of bias. Our meta-analysis suggests that arginine vasopressin may reduce the rate of perioperative complications in patients undergoing elective or emergency cardiac surgery. No difference in postoperative mortality was observed. An adequately powered multicenter trial is required for reliable estimation of the effects of arginine vasopressin on perioperative complication rates and mortality in cardiac surgical patients.

Arginine Vasopressin Infusion In C57BL/6J Mice Induces Changes In The Placenta Transcriptome That Parallel Changes Observed In Placenta From Human Preeclampsia

Preeclampsia (PE), a cardiovascular disorder of late pregnancy characterized by new onset hypertension and proteinuria, remains a devastating disease affecting approximately 10% of all pregnancies in the United States. Multiple independent studies demonstrate a correlation between PE and elevated maternal plasma copeptin, the C‐terminal fragment of arginine vasopressin (AVP), which supports the concept that AVP secretion is elevated during PE. Previously we demonstrated the sufficiency of chronic low‐dose AVP infusion to initiate major phenotypes of PE in pregnant C57BL/6J mice, including hypertension, renal glomerular endotheliosis, intrauterine growth restriction, and altered placental morphology. Thus, we generally hypothesize that elevated AVP secretion is mechanistically involved in the pathogenesis of PE. Here, we tested the hypothesis that chronic infusion of AVP during gestation in mice would cause changes in the placental transcriptome which parallel changes documented in human PE. Placentas were collected on gestational day 12.5 from mice that received chronic saline or AVP (24 ng/hr) infusion through pregnancy and RNA‐sequencing was performed. Differential expression analyses revealed 87 transcripts, corresponding to 82 unique genes as well as 3 non‐coding RNAs, that were differentially expressed between AVP‐ and saline‐treated placentas (FDR &lt; 0.1). Among the differentially expressed genes identified, six genes (Trpm2, Itih4, Ncmap, Sema3f, Scnn1g, Nfat5) had been previously associated with human PE. Ingenuity Pathway Analysis (IPA) identified that the disease and functional annotations significantly altered in AVP‐treated placentas included hypertension, preeclampsia, as well as cell death. As expected, IPA also identified likely canonical upstream mediators including AVP, desmopressin, and calcium signaling. Notably, Gene Set Enrichment Analysis (GSEA) and IPA did not uncover any enrichment for hypoxia‐associated signaling, suggesting that despite the PE‐like morphological and genetic signatures induced by AVP, AVP does not induce these phenotypes via placental hypoxia. Parallel in silico re‐analyses of a large published dataset from NCBI‐GEO (GSE75010) describing the transcriptomes of control and PE human placentas with various clinical covariates demonstrated that some subtypes of human PE similarly do not exhibit placental hypoxia. Collectively, these data highlight molecular phenotypes of PE induced within the placenta of mice by AVP, and highlight the potential utility of the AVP infusion approach to model specific subtypes of human PE.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

EARLY OBSERVATIONS FROM CONCURRENT USE OF CALCIUM CHLORIDE AND VASOPRESSIN INFUSIONS IN PEDIATRIC HEART FAILURE

Acute heart failure (AHF) can cause low cardiac output and poor end-organ perfusion. Inotropic agents along with vasodilators can improve organ perfusion. Arginine vasopressin (AVP) and calcium chloride (CaCl) infusions are increasingly being used in low cardiac output states in pediatric AHF. We

Impact of vasopressin receptors on regulation of immune response in preeclampsia

Preeclampsia is a common disorder of pregnancy resulting in increased blood pressure and end organ effects. The pathogenesis of preeclampsia is multi-factorial. Arginine vasopressin (AVP) is increased in preeclampsia, and the chronic infusion of AVP throughout gestation has previously been shown to be sufficient to produce a phenotype of preeclampsia in C57BL/6J mice representative of some of the cardiovascular and renal events seen in humans. Alterations in T-helper cell populations and their effector cytokines are also known to occur in preeclampsia. Therefore, we proposed that the increased secretion of AVP may be responsible for the immune changes that occur in preeclampsia. We also hypothesized that known pharmacological AVP antagonist, vaptans, may be able to reverse the effects of AVP infusion.

Elevated vasopressin in pregnant mice induces T-helper subset alterations consistent with human preeclampsia.

The pathogenesis of preeclampsia (PreE), a hypertensive disorder of pregnancy, involves imbalanced T helper (TH) cell populations and resultant changes in pro- and anti-inflammatory cytokine release. Elevated copeptin (an inert biomarker of arginine vasopressin (AVP)), secretion precedes the development of symptoms in PreE in humans, and infusion of AVP proximal to and throughout gestation is sufficient to initiate cardiovascular and renal phenotypes of PreE in wild-type C57BL/6J mice. We hypothesize that AVP infusion in wild-type mice is sufficient to induce the immune changes observed in human PreE. AVP infusion throughout gestation in mice resulted in increased pro-inflammatory interferon γ (IFNg) (TH1) in the maternal plasma. The TH17-associated cytokine interleukin (IL)-17 was elevated in the maternal plasma, amniotic fluid, and placenta following AVP infusion. Conversely, the TH2-associated anti-inflammatory cytokine IL-4 was decreased in the maternal and fetal kidneys from AVP-infused dams, while IL-10 was decreased in the maternal kidney and all fetal tissues. Collectively, these results demonstrate the sufficiency of AVP to induce the immune changes typical of PreE. We investigated if T cells can respond directly to AVP by evaluating the expression of AVP receptors (AVPRs) on mouse and human CD4+ T cells. Mouse and human T cells expressed AVPR1a, AVPR1b, and AVPR2. The expression of AVPR1a was decreased in CD4+ T cells obtained from PreE-affected women. In total, our data are consistent with a potential initiating role for AVP in the immune dysfunction typical of PreE and identifies putative signaling mechanism(s) for future investigation.

Abstract P256: Vasopressin Infusion During Pregnancy in Mice Induces Early Histological Placental Phenotypes of Preeclampsia

Human preeclampsia (PE) is associated with elevated secretion of arginine vasopressin (AVP), and chronic infusion of AVP into pregnant mice is sufficient to model PE by causing hypertension, renal glomerular endotheliosis, proteinuria, fetal placental hypoxia, and growth restriction. Early stages of PE are associated with defective trophoblast invasion of maternal spiral arteries, leading to decreased artery diameter and placental oxygenation. AVP infusion (24 ng/hr, sc) into pregnant mice caused placental hypoxia (chromatin-bound HIF1α on gestational day (GD)17.5; saline n=5, 0.31±0.01; AVP n=5, 0.34±0.01 AU, p&lt;0.05) and reduced placental growth factor mRNA (n=18, 1.0 (0.7-1.3) vs n=21, 0.3 (0.2-0.4) fold (1 se), p&lt;0.05). Therefore, we performed histological analyses of placentas collected from mice at GD12.5 infused with saline or AVP, with the hypothesis that AVP leads to early placental PE phenotypes. Similar to effects on GD17.5, this preliminary cohort demonstrated increased urine protein content (n=7, 27±3 vs n=13, 44±3, g/L p&lt;0.05) and mid-gestational systolic blood pressure (-7.6±3.1 vs +3.5±2.2, mmHg p&lt;0.05), similar fetal (75±7 vs 78±4 mg, p=0.75) and placental (83±10 vs 81±4 mg, p=0.80) masses, and similar changes in heart rate (+37±16 vs +39±12 bpm, p=0.93). GD12.5 placentas were then stained with haemotoxylin and eosin or immunostained for cytokeratin-8 to examine morphological changes induced by AVP. AVP infusion had no significant effects on labyrinth (saline n=3, 647±25 vs AVP n=7, 602±35 um, p=0.45), spongiotrophoblast (342±19 vs 363±24 um, p=0.61), or decidua (622±47 vs 520±47 um, p=0.24) layer thicknesses. AVP caused a reduction in average maximum spiral artery diameter (171±28 vs 121±8 um, p&lt;0.05) and a trend toward reduced total spiral artery number (8.4±2.9 vs 4.9±0.7, p=0.13), but no difference in the maximum invasion depth of CK8-positive trophoblasts (310±50 vs 286±37 um, p=0.72). We conclude that AVP infusion is sufficient to induce cardinal mid-gestational features of PE in pregnant mice, including reduced spiral artery diameter. Such morphological changes may be associated with the placental hypoxia and reduced placental growth factor expression in model.

Abstract P262: Vasopressin Receptors Regulate Immune Responses in Preeclampsia

The pathogenesis of preeclampsia (PE) involves imbalanced T helper (T H ) cell populations and resultant changes in pro- and anti-inflammatory cytokine release. Elevated secretion of arginine vasopressin (AVP) precedes the development of symptoms in PE in humans, and chronic infusion of AVP (24 ng/hr s.c.) throughout gestation is sufficient to initiate cardiovascular, renal, and immune phenotypes of PE in wild-type C57BL/6J mice. We hypothesize that increased AVP signaling may mediate the immune changes observed in PE. AVP infusion throughout gestation in mice resulted in increased pro-inflammatory IFNγ (T H 1) in the maternal plasma (N=7, p&lt;0.05) and IL-17 (T H 17) in the placenta (N≥10, p&lt;0.001). The T H 2-associated anti-inflammatory cytokines IL-4 and IL-10 were decreased in maternal kidney (IL-4: N=8, p&lt;0.05; IL-10: N=5, p&lt;0.01) and fetal kidney (IL-4: N=5, p&lt;0.05; IL-10: N=5, p&lt;0.05) of AVP-infused dams. To elucidate the receptor dependency of these effects, AVP-infused dams were simultaneously treated with chronic infusion of AVP V 1A and/or V 2 receptor antagonists (22 ng/hr s.c). Combined blockade of V 1a +V 2 receptors by conivaptan, as well as specifically blocking V 2 by tolvaptan, corrected AVP induced reductions in IL-4 in maternal (conivaptan: N=5, p&lt;0.05; tolvaptan: N=5, p&lt;0.0.0001) and fetal kidneys (conivaptan: N=5, p&lt;0.0001; tolvaptan: N=5, p&lt;0.05). These data implicate V 2 as the receptor involved in kidney IL-4 deficiency in PE, whereby blockade of V 2 restores IL-4, preventing inflammation. Combined blockade of V 1A +V 2 receptors by conivaptan corrected the placental loss of IL-4 (N=5, p&lt;0.05), whereas blockade of either receptor alone was insufficient, suggesting loss of placental IL-4 via AVP is mediated by both V 1a and V 2 receptors. In contrast, increased placental IL-17 was only corrected by selective blockade of V 1A by relcovaptan (N=5, p&lt;0.05), suggesting a novel role for V1a receptor in pro-inflammatory placental IL-17 production in PE. Collectively these results demonstrate the sufficiency of AVP to induce the immune changes typical of PE, and support a dominant role for V 1A in the induction of pro-inflammatory IL-17 (T H 17) release versus a dominant role for V 2 receptors in the suppression of anti-inflammatory IL-4 (T H 2) release.

Abstract P261: Vasopressin System Components are Dysregulated in Human Preeclamptic Placenta

Preeclampsia (PE) is a cardiovascular disorder of late pregnancy characterized by pregnancy-specific onset of hypertension and proteinuria. Although initiating events leading to PE development remain unclear, emerging studies suggest arginine vasopressin (AVP) signaling may contribute to PE pathogenesis, as elevated circulating copeptin (a stable biomarker of AVP secretion) levels precede the onset of human PE, and chronic infusion of AVP into wildtype mice phenocopies PE. Here, we tested the hypothesis that AVP signaling is dysregulated in PE placenta by performing in-silico reanalysis of a publically available gene expression dataset derived from placentas of human PE and normal pregnancies (GSE75010). Significant increases in expression [log 2 values] of AVP (Con: 6.96 ± 0.02, PE: 7.03 ± 0.17, p=0.005) and its receptors AVPR1a (Con: 5.73 ± 0.02, PE: 5.80 ± 0.02, p=0.03) and OXTR (Con: 6.58 ± 0.02, PE: 6.65 ± 0.02, p=0.003) were observed in PE placentas (n=80) compared to normal placentas (n=77). Preeclamptic placentas also displayed an enrichment in a hypoxic gene signature, as shown by gene set enrichment analyses (NES: 1.75, FDR q&lt;0.001, FWER p &lt;0.001), suggesting that these placentas exhibited increased hypoxia-related signaling. Interestingly, AVPR1a expression as well as OXTR is positively and significantly correlated with the expression of two hypoxia-inducible genes HK2 and DDIT4 ( AVPR1a v HK2 : r 2 =0.04, p=0.02, AVPR1a v DDIT4 : r 2 =0.06, p=0.003, OXTR v HK2 : r 2 =0.05, p=0.007, OXTR v DDIT4 : r 2 =0.04, p=0.008). To further elucidate the role hypoxia may play in promoting AVP signaling, HTR8/SVNeo cells (immortalized human first trimester trophoblasts) were treated with the hypoxia mimetic dimethyloxallyl glycine (DMOG). DMOG incubation did not significantly alter the expression of AVP and AVPR1a . Unexpectedly, a marked reduction in OXTR expression was observed upon DMOG treatment. In summary, these data suggest that 1) components of the AVP signaling pathway are aberrantly expressed in human PE placentas, 2) PE placentas exhibit a gene expression signature consistent with increased canonical hypoxia signaling, and 3) hypoxia may not be the cause of elevated placental AVP , AVPR1a , and OXTR expression in human PE.

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.

Transient Diabetes Insipidus After Discontinuation of Vasopressin in Neurological Intensive Care Unit Patients: Case Series and Literature Review

Arginine vasopressin (AVP) is a common second-line or third-line vasopressor used in critically ill neurosurgical patients. Neurosurgical indications include hyperdynamic therapy for vasospasm, maintenance of cerebral perfusion pressure in patients with intracranial hypertension, and prevention of hypotension in patients with sepsis. A series of 6 neurosurgical patients receiving AVP infusions developed severe but transient diabetes insipidus (tDI) after cessation of AVP. To our knowledge, no previous reports of this phenomenon in neurosurgical patients have been published. We reviewed the clinical histories, intensive care unit treatment, medication administration records, and laboratory values of these patients, and we found recurrent elevated serum sodium and urine output and decreased urine specific gravity after discontinuation of AVP. Resolution of tDI occurred upon resumption of AVP or administration of desmopressin. Elevated serum sodium levels were often severe, resulting in worsened clinical outcomes. When AVP was resumed, tDI typically recurred if AVP was again tapered and discontinued. Routine administration of desmopressin was useful in controlling sodium levels until the tDI resolved. Recognition of this phenomenon has caused us to change our clinical management of neurosurgical patients receiving AVP. We hypothesize that tDI is caused by downregulation of the V2 receptor mass in the renal distal convoluted tubule and collecting duct cells. When AVP is discontinued, patients develop nephrogenic tDI secondary to decreased V2 receptor binding, which explains why desmopressin is effective in correcting tDI. Future research includes a large prospective study to determine risk factors for tDI, its incidence, and its pathophysiology.

Abstract P178: Vasopressin Induces Discrete Symptoms of Preeclampsia Through Receptor- and Gestational Age-specific Mechanisms

Preeclampsia (PE) is a common late-gestational disorder characterized by de novo pregnancy specific hypertension, proteinuria, and renal glomerular endotheliosis (RGE). Arginine vasopressin (AVP) secretion (as measured by copeptin) is elevated as early as 6 weeks gestation in pregnancies which later develop PE, and chronic low-dose AVP infusion is sufficient to phenocopy PE in pregnant mice. However, the identity and timeframe of involvement of specific AVP receptors initiating discrete symptoms of PE in this model remain unclear. Wildtype C57BL/6J mice were instrumented with subcutaneous osmotic minipumps to infuse AVP (24 ng/hr) and/or inhibitors during gestation. To clarify the involvement of AVP V 1A and V 2 receptors, one cohort of saline- or AVP-infused pregnant mice was simultaneously infused with the combined V 1A +V 2 antagonist, conivaptan (22 ng/hr). Conivaptan co-treatment ameliorated the hypertension phenotype (SBP on gestational day (GD)15: saline 108.3±2.1, n=24; AVP 120.5±2.1, n=17; conivaptan 112.8±4.1, n=8; AVP+conivaptan 109.8±3.5 mmHg, n=11) but did not prevent proteinuria (on GD17: saline 46.4±6.4, n=15; AVP 79.3±8.5, n=15; conivaptan 64.6±6.7, n=7; AVP+conivaptan 72.9±12.3 mg/mL, n=11) or RGE. To clarify the important timeframes of involvement of AVP for discrete symptoms, subsets of mice were infused with AVP throughout gestation or to only GD10. Continuous infusion of AVP was required to maintain the hypertensive phenotype, as infusion to only GD10 initially elevated blood pressure (SBP at GD10: saline 103.7±1.3, n=26; AVP to GD10 111.5±1.6 mmHg, n=19) but failed to sustain hypertension for the remainder of gestation (SBP at GD15: 112.2±1.3 mmHg, n=19). In contrast, infusion of AVP only to GD10 caused a sustained proteinuria (at GD17: 88.2±9.2 mg/mL, n=19). Infusion of AVP only to GD3 had no effect on any examined endpoint. These data support a specific role for AVP V 1A /V 2 receptors throughout gestation for the hypertension but not proteinuria or RGE phenotypes of PE. Our results therefore indirectly support an early-gestational role for other receptors (perhaps V 1B , cullin-5, or the oxytocin receptor) in the proteinuria and RGE phenotypes of this disorder.

Vasopressin: the missing link for preeclampsia?

Preeclampsia is a devastating cardiovascular disorder of late pregnancy, affecting 5-7% of all pregnancies and claiming the lives of 76,000 mothers and 500,000 children each year. Various lines of evidence support a "tissue rejection" type reaction toward the placenta as the primary initiating event in the development of preeclampsia, followed by a complex interplay among immune, vascular, renal, and angiogenic mechanisms that have been implicated in the pathogenesis of preeclampsia beginning around the end of the first trimester. Critically, it remains unclear what mechanism links the initiating event and these pathogenic mechanisms. We and others have now demonstrated an early and sustained increase in maternal plasma concentrations of copeptin, a protein by-product of arginine vasopressin (AVP) synthesis and release, during preeclampsia. Furthermore, chronic infusion of AVP during pregnancy is sufficient to phenocopy essentially all maternal and fetal symptoms of preeclampsia in mice. As various groups have demonstrated interactions between AVP and immune, renal, and vascular systems in the nonpregnant state, elevations of this hormone are therefore positioned both in time (early pregnancy) and function to contribute to preeclampsia. We therefore posit that AVP represents a missing mechanistic link between initiating events and established midpregnancy dysfunctions that cause preeclampsia.

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Objectives The objective of this study is to determine if chronic infusion of arginine vasopressin (AVP) during mouse pregnancy recapitulates the human phenotypes of preeclampsia. We hypothesize a causative role of elevated AVP in the pathogenesis of preeclampsia. Methods Wildtype C57Bl/6J females were chronically infused with AVP (24 ng/h, s.c., or saline vehicle) before syngeneic mating. Systolic blood pressure during pregnancy was measured by tail-cuff plethysmography. Dams were placed in metabolic cages to collect 24 h urine samples at gestational day (GD) 17; and then sacrificed for necropsy at GD 18. Results In comparison to saline infused females, AVP infused females exhibited a pregnancy specific, significant increase in systolic blood pressure at GD 16 (110 ± 3 vs 120 ± 3 mmHg, p Conclusions Chronic AVP infusion throughout pregnancy represents a novel, pregnancy specific, clinically relevant model of human preeclampsia that phenocopies all the cardinal physiologic, vascular, obstetric and immunologic phenotypes of human preeclampsia in mice. Disclosures M. Santillan: holds 2 provisional patents on the use of the vasopressin pathway for the prediction, prevention, and treatment of preeclampsia. D. Santillan: None. S. Scroggins: None. J. Sandgren: None. N. Pearson: None. K. Gibson-Corley: None. J. Grobe: holds 2 provisional patents on the use of the vasopressin pathway for the prediction, prevention, and treatment of preeclampsia.

Vasopressin in preeclampsia: a novel very early human pregnancy biomarker and clinically relevant mouse model.

Preeclampsia, a cardiovascular disorder of late pregnancy, is characterized as a low-renin hypertensive state relative to normotensive pregnancy. Because other nonpregnant low-renin hypertensive disorders often exhibit and are occasionally dependent on elevated arginine vasopressin (AVP) secretion, we hypothesized a possible use for plasma AVP measurements in the prediction of preeclampsia. Copeptin is an inert prosegment of AVP that is secreted in a 1:1 molar ratio and exhibits a substantially longer biological half-life compared with AVP, rendering it a clinically useful biomarker of AVP secretion. Copeptin was measured throughout pregnancy in maternal plasma from preeclamptic and control women. Maternal plasma copeptin was significantly higher throughout preeclamptic pregnancies versus control pregnancies. While controlling for clinically significant confounders (age, body mass index, chronic essential hypertension, twin gestation, diabetes mellitus, and history of preeclampsia) using multivariate regression, the association of higher copeptin concentration and the development of preeclampsia remained significant. Receiver operating characteristic analyses reveal that as early as the sixth week of gestation, elevated maternal plasma copeptin concentration is a highly significant predictor of preeclampsia throughout pregnancy. Finally, chronic infusion of AVP during pregnancy (24 ng per hour) is sufficient to phenocopy preeclampsia in C57BL/6J mice, causing pregnancy-specific hypertension, renal glomerular endotheliosis, proteinuria, and intrauterine growth restriction. These data implicate AVP release as a novel predictive biomarker for preeclampsia very early in pregnancy, identify chronic AVP infusion as a novel and clinically relevant model of preeclampsia in mice, and are consistent with a potential causative role for AVP in preeclampsia in humans.

Abstract 286: Immune Dysfunction in a Vasopressin-Induced Mouse Model of Preeclampsia

Preeclampsia is a disease of pregnancy and the postpartum period, affecting 5-7% of all U.S. pregnancies. We recently determined that elevated secretion of arginine vasopressin (AVP) in humans is detected as early as the 6th week of pregnancy in the women that subsequently develop preeclampsia. Further, we have determined that in C57BL/6 mice, chronic AVP infusion serves as a clinically-relevant and pregnancy-specific model of preeclampsia. Although the pathogenesis of preeclampsia is still poorly understood, an inflammatory immune response is clearly involved. AVP secretion is stimulated by proinflammatory cytokines and AVP in turn can act upon receptors present on lymphocytes. We hypothesize that hypersecretion of AVP results in maternal-fetal immune alterations in preeclamptics. Immune responses were evaluated in wild-type C57BL/6 female mice chronically infused with AVP (24 ng/hr or saline s.c.) throughout pregnancy. We observed an increase in the frequency of IL-12 (saline N=7: 1.1±0.2, vs AVP N=9: 2.2±0.4, P&lt;0.05), IL-17 (saline N=7: 1.2±0.17, vs AVP N=9: 2.6±0.4, P&lt;0.05) and TNFa (saline N=8: 0.9±0.1, vs AVP N=9: 1.6±0.1, P&lt;0.005) expressing lymphocytes isolated from AVP mice. Additionally, the frequency of IFNg expressing lymphocytes was increased in AVP mice, approaching statistical significance (saline N=8: 2.2±0.9, vs AVP N=9: 3.0±0.4, P=0.059). The frequency of IL-6, IL-10, and LAP expressing splenic lymphocytes were similar between saline vs. AVP mice. Interestingly, maternal plasma revealed a significant reduction in IL-17 (saline N=4: 1.0e+7±3.8e+6, vs AVP N=5: 3.1e=5±1.3e+5 ng/g, P&lt;0.05) in AVP mice. Neither IL-4 nor IFNg were detectable in maternal plasma of either group. Additionally, IL-17 trended higher in the amnionic fluid and lower in the placenta of AVP mice. IL-4 production trended lower in both the placenta and amnionic fluid of AVP-infused mice, while IFNg was similar between groups. These data support our hypothesis that AVP hypersecretion results in the maternal-fetal immune alterations associated with the development of preeclampsia. Ongoing experiments are aimed at identifying the lymphocytes and cytokines involved as well as local vs. systemic immune dysfunction associated with AVP-induced preeclampsia.

Effects and mechanism analysis of combined infusion by levosimendan and vasopressin on acute lung injury in rats septic shock.

This research is aimed to discover the influence and underling mechanism of combined infusion of arginine vasopressin with levosimendan on acute lung injury in rat septic shock with norepinephrine supplemented. The traditional fecal peritonitis-induced septic shock model was undergone in rats for study. It is observed that the combined infusion supplemented with norepinephrine brought about a lower mean pulmonary artery pressure; lower high-mobility group box 1 levels, pulmonary levels of interleukin-6, and arterial total nitrate/nitrite; lower apoptotic cells scores and total histological scores; but higher pulmonary gas exchange when compared with the separate infusion group and norepinephrine group. This therapy shows potential clinical beneficial assistance in sepsis-induced acute lung injury. The results suggest the mechanism of such effect is through abating pulmonary artery pressure, and more importantly suppressing inflammatory responses in lung when compared with norepinephrine infusion group and the separate infusion of levosimendan or vasopressin alone.

The Selective Vasopressin Type 1a Receptor Agonist Selepressin (FE 202158) Blocks Vascular Leak in Ovine Severe Sepsis*

To determine if the selective vasopressin type 1a receptor agonist selepressin (FE 202158) is as effective as the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist vasopressor hormone arginine vasopressin when used as a titrated first-line vasopressor therapy in an ovine model of Pseudomonas aeruginosa pneumonia-induced severe sepsis. Prospective, randomized, controlled laboratory experiment. University animal research facility. Forty-five chronically instrumented sheep. Sheep were anesthetized, insufflated with cooled cotton smoke via tracheostomy, and P. aeruginosa were instilled into their airways. They were then placed on assisted ventilation, awakened, and resuscitated with lactated Ringer's solution titrated to maintain hematocrit ± 3% from baseline levels. If, despite fluid management, mean arterial pressure fell by more than 10 mm Hg from baseline level, an additional continuous IV infusion of arginine vasopressin or selepressin was titrated to raise and maintain mean arterial pressure within no less than 10 mm Hg from baseline level. Effects of combination treatment of selepressin with the selective vasopressin V2 receptor agonist desmopressin were similarly investigated. In septic sheep, MAP fell by ~30 mm Hg, systemic vascular resistance index decreased by ~50%, and ~7 L of fluid were retained over 24 hours; this fluid accumulation was partially reduced by arginine vasopressin and almost completely blocked by selepressin; and combined infusion of selepressin and desmopressin increased fluid accumulation to levels similar to arginine vasopressin treatment. Resuscitation with the selective vasopressin type 1a receptor agonist selepressin blocked vascular leak more effectively than the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist arginine vasopressin because of its lack of agonist activity at the vasopressin V2 receptor.

The Effect of Vasopressin on Ciliary Blood Flow and Aqueous Flow

Previous experiments have shown that arginine-vasopressin (AVP) reduces intraocular pressure (IOP) dose-dependently. The present study investigated the relationships between IOP, ciliary blood flow (CilBF), and aqueous flow (AqF) responses to AVP in anesthetized rabbits. CilBF was measured by laser Doppler flowmetry and AqF by fluorophotometry. Mean arterial pressure (MAP) and IOP were monitored continuously and simultaneously. Perfusion pressure (PP) was varied mechanically. Four experimental protocols were performed: the dose-response (n = 11) and the pressure-flow relationship (n = 8) for CilBF and the effects on CilBF, and AqF at low (0.08 ng/kg/min; n = 14) and high AVP infusion rates (1.33 ng/kg/min; n = 12). AVP decreased CilBF and IOP dose-dependently. At the low AVP infusion rate, AqF was reduced by 21.48% ± 2.52% without changing CilBF significantly. The high AVP infusion rate caused a 24.49% ± 3.53% decrease of AqF and a significant reduction in CilBF (35.60% ± 3.58%). IOP was reduced by 9.56% ± 2.35% at low and by 41.02% ± 3.19% at high AVP infusion rates. Based on the Goldmann equation, the decrease of AqF at the low AVP infusion rate accounted for 77.1% of the IOP reduction, whereas at the high AVP infusion rate, decreased AqF accounted for 28.4% of the IOP decline. The results indicate that AVP can modulate IOP by different dose-dependent physiological mechanisms. The shifts of the CilBF-AqF relationship suggest that the reduction of AqF by the low AVP infusion rate is mainly provoked by inhibiting secretory processes in the ciliary epithelium. In contrast, at the high AVP infusion rate, the AqF reduction is caused by either reduced CilBF or more likely by a combined effect of reduced CilBF and secretory inhibition.

Vasopressin infusion into the lateral septum of adult male rats rescues progesterone-induced impairment in social recognition

It is well established that social recognition memory is mediated, in part, by arginine vasopressin (AVP). AVP cells within the bed nucleus of the stria terminalis (BST) and medial amygdala (MeA) send AVP-ergic projections to the lateral septum (LS). We have demonstrated that progesterone treatment decreases AVP immunoreactivity within the BST, the MeA and the LS, and that progesterone treatment impairs social recognition. These data suggested that progesterone may impair social recognition memory by decreasing AVP. In the present experiment, we hypothesized that infusions of AVP into the LS would rescue the progesterone-induced impairment in social recognition within adult male rats. One week after adult male rats underwent cannula surgery, they were given systemic injections of either a physiological dose of progesterone or oil control for 3days. Four hours after the last injection, we tested social recognition memory using the social discrimination paradigm, a two-trial test that is based on the natural propensity for rats to be highly motivated to investigate novel conspecifics. Immediately after the first exposure to a juvenile, each animal received bilateral infusions of either AVP or artificial cerebrospinal fluid into the LS. Our results show that, as expected, control animals exhibited normal social discrimination. In corroboration with our previous results, animals given progesterone have impaired social discrimination. Interestingly, animals treated with progesterone and AVP exhibited normal social discrimination, suggesting that AVP treatment rescued the impairment in social recognition caused by progesterone. These data also further support a role for progesterone in modulating vasopressin-dependent behavior within the male brain.

Renal Vasodilatory Action of Arginine Vasopressin in Extremely Low Birth Weight Infants

In extremely low birth weight (ELBW) infants, systemic hypotension is associated with poor neurological outcomes as a result of cerebral hypoperfusion. Treatment with arginine vasopressin (AVP) has been shown to increase blood pressure (BP) and urine output in ELBW infants suffering from refractory hypotension. The purpose of this study was to clarify whether low doses of AVP increased renal blood flow (RBF) in ELBW infants. We retrospectively analyzed data from the medical charts describing nine AVP infusions at 0.3-0.8 mU/kg/min in four ELBW infants. The median gestational age was 23 (22.5-23.5, interquartile range) weeks, and the median birth weight was 466 (414-563) g. Changes in the heart rate, BP, urine output, and RBF velocity patterns in response to the AVP infusions were compared using statistical analyses. The AVP infusion caused significant increases in systolic BP from 44 (41.0-47.0) to 50 (42.5-55.5) mmHg, diastolic BP from 17 (15.0-26.5) to 31 (28.5-33.0) mmHg, mean BP from 26 (24.5-30.5) to 36 (34.5-40.5) mmHg, and urine output from 1.4 (0.2-2.5) to 2.8 (1.0-8.6) mL/kg/hr. We also observed significant decreases in the resistance index from 1.0 (0.96-1.0) to 0.8 (0.71-0.91) and peak systolic flow velocity in the renal artery from 40 (27.2-50.6) to 28 (16.0-28.9) cm/s after AVP infusions. AVP infusions at 0.3-0.8 mU/kg/min in ELBW infants appeared to significantly increase the RBF by inducing renal vascular dilation and increasing the BP. Increasing the RBF most likely induces an increase in the glomerular filtration rate, resulting in the diuretic effect of AVP.