Arginine Vasopressin Infusion Research Articles

Serum Sodium Concentration During Arginine Vasopressin Infusion in Critically Ill Children.

Intravenous arginine vasopressin is increasingly used for the treatment of critically ill children. It bears the risk of hyponatraemia with potential severe long-term sequelae, but data on hyponatraemia as a side effect of continuous vasopressin infusion for paediatric intensive care patients is scarce. In this retrospective analysis performed at a tertiary care paediatric intensive care unit with 2000 annual admissions, patients were included if they were treated with intravenous vasopressin between 2016 and 2022. Baseline sodium concentrations, lowest sodium concentrations during arginine vasopressin treatment, and time to lowest sodium concentration (nadir) were derived. In total, 170 patients with a median age of 4 months [interquartile range, IQR, 0-33] were included, 92.4% underwent surgery, and 28.8% died. Median arginine vasopressin dose rate was 0.027 IU/kg/h [0.019-0.036] and arginine vasopressin was started 3.2 [0-26] h after intensive care admission. Median arginine vasopressin application duration was 13.6 h [6.2-32.6]. Baseline sodium was 141 mmol/L [138-145], and lowest median sodium during arginine vasopressin infusion was 137 mmol/L [132-141] (nadir at 8.4 h [1.0-28.1] after arginine vasopressin start). Hyponatraemia (<135 mmol/L) occurred in 38.2% of patients during AVP treatment, and physicians administered a median of 10.2 mmol/kg/d [6.2-16.4] sodium during arginine vasopressin therapy. Under arginine vasopressin infusion, hyponatraemia was common, although high daily doses of sodium were administered to keep the serum values in physiologic ranges. This emphasises the need for close electrolyte monitoring and sodium substitution in children and adolescents under arginine vasopressin treatment to avoid hyponatraemia and related sequelae.

Cellular Immunotherapy in Mice Prevents Maternal Hypertension and Restores Anti-Inflammatory Cytokine Balance in Maternal and Fetal Tissues.

Preeclampsia is the leading cause of maternal-fetal morbidity worldwide. The concept that persistent feto-placental intolerance is important in the pathogenesis of preeclampsia (PreE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion during pregnancy induces cardiovascular, renal, and T helper (TH) cell alterations in mice consistent with human PreE. In addition to their conventional immuno-stimulatory role, dendritic cells (DCs) also play a vital role in immune tolerance. In contrast to conventional DCs, regulatory DCs (DCregs) express low levels of co-stimulatory markers, produce anti-inflammatory cytokines, induce T regulatory (Treg) cells, and promote tolerance. In mice, DCregs prevent pro-inflammatory responses and induce antigen-specific tolerance. Given these known functions of DCregs, we hypothesize that DCregs will prevent the development of AVP-induced PreE in mice. C57BL/6J females were infused with AVP (24 ng/h) or saline throughout gestation via an osmotic minipump. Bone-marrow-derived DCregs were injected into AVP-infused dams at the time of the pump implantation or on gestational day (GD) 7. The blood pressure of the mice was taken throughout their pregnancy. The maternal urine proteins and TH-associated cytokines in maternal and fetal tissues were measured on GD 18. The treatment with DCregs effectively prevented the elevation of maternal blood pressure, proteinuria, and fetal growth restriction that were observed in AVP-infused dams. Furthermore, we noted a reduction in the pro-inflammatory TH-associated cytokines IFNγ and IL-17, while anti-inflammatory cytokines IL-4, IL-10, and TGFβ showed an increase following DCreg treatment. These outcomes provide strong evidence supporting the potential of DCregs as a valuable therapeutic approach in addressing PreE.

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

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

Central diabetes insipidus with anti-rabphilin-3A antibody positivity causing hypovolemic shock after resection of tumorous lesions in the pelvic cavity.

A 36-year-old female was pointed out to have liver enzyme elevation by routine health checkup. Subsequent contrast-enhanced CT scan identified gigantic uterine fibroids and retroperitoneal tumor. She was referred to the gynecologist at JA Toride Medical Center and planned to undergo a uterus enucleation and biopsy of the retroperitoneal tumor. The surgery was conducted without any troubles. After the surgery, the patient presented polyuria with urine volume 10-20 L a day and developed hypovolemic shock. Laboratory test revealed hypotonic urine and hypernatremia. Arginine vasopressin (AVP) loading test suggested shortage of endogenous vasopressin. Since the subcutaneous administration of AVP was not sufficient to control the urine volume, continuous intravenous infusion of AVP was initiated. After achieving hemodynamic stability, the treatment was switched to oral desmopressin. MRI finding indicated attenuation of high signal in posterior pituitary in T1 weighted image while neither enlargement of pituitary nor thickening of pituitary stalk was indicated by enhanced MRI. Hypertonic salt solution test indicated no responsive elevation of AVP, confirming the diagnosis of central diabetes insipidus (CDI). Her anterior pituitary function was preserved. Only anti-rabphilin-3A antibody was found positive in the serum of the patient, while other secondary causes for CDI were denied serologically and radiologically. Hence, lymphocytic infundibuloneurohypophysitis (LINH) was suspected as the final diagnosis. Hormonal replacement therapy by nasal desmopressin was continued and the patient managed to control her urine volume. In cases of CDI considered idiopathic with conventional examinations, anti-rabphilin-3A antibody may be a clue for determining the cause as LINH.

Abstract P095: Arginine Vasopressin Infusion Is Sufficient To Cause Pregnancy-specific Cardiac Hypertrophy

Preeclampsia is a prevalent gestational disorder characterized by hypertension, proteinuria, and renal damage. Mothers with a history of preeclampsia (PE) are at increased risk of future cardiovascular disease (CVD). Yet, the mechanism by which preeclampsia predisposes patients to future CVD is unknown. Previously published data demonstrated that arginine vasopressin (AVP) infusion in mice recapitulates clinical features of PE including pregnancy-specific hypertension. We hypothesized that chronic AVP infusion in pregnant mice would cause cardiac hypertrophy. C57Bl6/J mice were implanted with an osmotic minipump to deliver 24ng/hr of AVP throughout gestation until necropsy on gestational day 18. Blood pressures were monitored by tail cuff plethysmography and showed no increase in mean arterial pressure (MAP) in nonpregnant mice. However in pregnant mice, an increase of 18.8 ± 7.4 mmHg (82.1 vs 100.8, p=0.05) in MAP was observed in AVP-infused mice compared to saline-infused pregnant mice. Similarly, there was pregnancy-specific 13.4 ± 0.9 mg (93.6 vs 106.9, p=0.0001) increase in the heart weight of AVP-infused mice. Plasma levels of NT-ProBNP were measured by ELISA and showed a significant 163.6 ± 61.00 pg/ml (426.0 vs 589.6, p=0.01) increase in pregnant AVP-infused mice. Human 3rd trimester maternal plasma samples were obtained from the Iowa Maternal Fetal Tissue Bank (IRB# 200910784) for a case control study. In plasma samples from preeclamptic patients there was a significant 264.6 ± 79.72 pg/ml (185.1 vs 449.8, p=0.001) and a 27.9 ± 11.5 pg/ml (64.6, n=32 vs 92.5, n=66, p=0.02) increase in NT-ProBNP and MR-proANP respectively compared to normal pregnancy plasma. H9C2 rat cardiomyocytes treated with pooled plasma from preeclamptic patients showed a 6.6 and 1.8 fold increase in rat ANP and BNP expression respectively. These data suggest that AVP infusion in mice specifically during pregnancy is sufficient to cause cardiac hypertrophy beyond typical hypertrophy seen in a normal pregnancy and that unknown circulating factors in preeclamptics may contribute to the development of hypertrophy. Importantly, these data support using AVP-infusion as a novel mouse model of pregnancy-specific cardiac hypertrophy to study postpartum cardiomyopathies.

Synthetic Oxytocin and Vasopressin Act Within the Central Amygdala to Exacerbate Aggression in Female Wistar Rats.

Exacerbated aggression is a high-impact, but poorly understood core symptom of several psychiatric disorders, which can also affect women. Animal models have successfully been employed to unravel the neurobiology of aggression. However, despite increasing evidence for sex-specificity, little is known about aggression in females. Here, we studied the role of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the central amygdala (CeA) on aggressive behavior displayed by virgin female Wistar rats using immunohistochemistry, receptor autoradiography, and neuropharmacology. Our data show that CeA GABAergic neurons are activated after an aggressive encounter in the female intruder test. Additionally, neuronal activity (pERK) negatively correlated with the display of aggression in low-aggressive group-housed females. Binding of OXT receptors, but not AVP-V1a receptors, was increased in the CeA of high-aggressive isolated and trained (IST) females. Finally, local infusion of either synthetic OXT or AVP enhanced aggression in IST females, whereas blockade of either of these receptors did not affect aggressive behavior. Altogether, our data support a moderate role of the CeA in female aggression. Regarding neuropeptide signaling, our findings suggest that synthetic, but not endogenous OXT and AVP modulate aggressive behavior in female Wistar rats.

Contrasting central and systemic effects of arginine-vasopressin on urinary marking behavior as a social signal in male mice

Arginine-vasopressin (AVP) is a neurohypophyseal peptide that plays a critical role in the regulation of social behavior in mammals. Neuronal AVP regulates male-specific social signaling processes, such as exocrine urinary scent deposition and marking behavior in mice. In the periphery, AVP is transported to the portal bloodstream and acts as an antidiuretic hormone. These AVP dynamics imply that the central role of AVP in the stimulation of urinary marking is dissociated with the peripheral role of AVP in the retention of osmotic conditions. Using male BALB/c mice as subjects, peripheral injection of AVP decreased urinary marking and urination. In contrast, a central infusion of AVP facilitated urinary marking with no effect on urination, while an antagonist of the AVP 1a receptor inhibited marking. Centrally AVP-injected mice also exhibited typical behaviors, such as hiccough/sneeze-like reactions and flash scratching, particularly when confronted with a stimulus mouse through a wire mesh screen. Significant expression of these typical reactions in these mice resulted in the disruption of marking deposition. Further analysis of AVP synthesis illustrated that AVP levels increased in the midbrain but not in the circulation immediately after the test, particularly when confronted with a stimulus mouse. The central AVP regulates urinary marking and other typical behaviors in a dose- and situation-dependent manner. The sequential process implies that centrally synthesized AVP may be secreted into the circulation following immediate neuronal processes, and then peripheral AVP acts as an antidiuretic hormone on urinary marking behavior.

Betamethasone reverses AVP-induced dysfunction in trophoblast cells

Previously published data demonstrate that arginine vasopressin (AVP) secretion is elevated throughout gestation in pregnancies affected by preeclampsia. Additionally, chronic infusion of AVP in mice mimics human preeclampsia with pregnancy-specific hypertension, glomerular endotheliosis, proteinuria, and inflammation. In this AVP-infusion mouse model, betamethasone (BMTZ) has been shown to reverse the preeclampsia phenotype. Corticosteroids have previously been used to ameliorate human HELLP syndrome. Steroids have pleotropic therapeutic effects. The mechanism of BMTZ in reversing preeclampsia is unknown. The objective of this study is to determine if BMTZ improves AVP-induced placental dysfunction. Cell migration of HTR8/SVneo cells was analyzed via closure of a 500um gap over 48 hours (Ibidi). Cells were treated with saline, AVP + vasopressin receptor antagonists, and AVP + BMTZ. The area of migration was imaged and calculated (Olympus Cell Sens) and percent change from baseline area was calculated. MMP-9, a marker of inflammation, was measured in cultured media using a commercially available ELISA (Invitrogen). Statistical significance was determined by ANOVA (α=0.05). At 48 hours, AVP demonstrated lower cell migration in comparison to saline (23.8 vs. 32.3 percent change). This dysfunction was reversed with the addition BMTZ (53.8 vs. 32.3 percent change, p< 0.001). Administration of AVP + AVP antagonists (Conivaptan [29.4], Relcovaptan [32.5], Tolvaptan [35.4]) did not significantly affect migration (p >0.05). MMP-9 concentration was significantly lowered in the cell culture supernatant of cells treated with AVP+BMTZ vs. AVP alone (0.242 vs. 0.286 ng/mL, p=0.04). Treating HTR8/Svneo trophoblastic cells in vitro with AVP results in abnormal migration and cytokine expression. BMTZ reverses this AVP-induced dysfunction. In part, this effect may be due to a reversal of MMP-9 associated inflammation. Our results suggest that further investigation is warranted in the use of betamethasone as a novel therapeutic strategy for preeclampsia.

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.

Signaling of Phoenixin via GPR173 and the Paradox of Increased Vasopressin Secretion in Preeclampsia

Preterm birth affects over 15 million pregnancies annually worldwide, and is associated with severe health risks for both mother and child. The leading cause of clinically indicated, non-spontaneous preterm delivery is preeclampsia, which can lead to maternal and fetal morbidity and mortality if not appropriately and promptly managed. At this time, the only “cure” for preeclampsia is delivery of the fetus and associated products of conception, which presents the clinical challenge of weighing the risks versus benefits of delivery if the pregnancy is preterm. The etiology of preeclampsia is multifactorial and incompletely understood. However, several carefully conducted studies have implicated the paradoxical secretion of the posterior pituitary hormone, arginine vasopressin (AVP) as a potential causative factor. Women with preeclampsia exhibit elevated plasma levels of AVP even in the face of the ongoing hypertension and hyponatremia, and infusion of AVP into pregnant rodents recapitulated multiple features of preeclampsia. The reason for the inappropriately elevated AVP in preeclampsia is unknown. Using a bioinformatic algorithm, our group identified a novel peptide that is conserved across multiple species, and named it phoenixin (PNX) (PMID 22963497). Our published data demonstrate a reproductive role of the peptide, and indicate that hypothalamic and pituitary PNX expression is modulated by sex hormones (PMID 27440717). Likewise, we recently have demonstrated that cerebroventrcular administration of PNX elevated plasma AVP levels in rats (PMID 29364701). Using the RNAscope approach we have now demonstrated that the receptor for PNX, identified by our group as GPR173 (PMID 27440717), is expressed by AVP neurons. Importantly expression of GPR173 increased across pregnancy in the rat hypothalamus coincident with increased AVP production and release (PMID 27330717). These data strongly suggest that PNX, acting through GPR173, could act as a molecular link between sex hormones and AVP secretion. In addition, we now demonstrate that central injection of PNX increases blood pressure, likely through PNX-induced elevation in AVP secretion. We hypothesize that the paradox of increased AVP secretion in the hyponatremic and hypervolemic state of preeclampsia is due to exaggerated PNX signaling in hypothalamus via GPR173 on AVP neurons and possibly on GPR173 expressing neurons in autonomic centers in hindbrain.

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.

A case of catecholamine-resistant septic shock with polyuria after discontinuation of arginine vasopressin infusion

A case of catecholamine-resistant septic shock with polyuria after discontinuation of arginine vasopressin infusion

Organ blood flow in response to infusion of arginine vasopressin in premature fetal sheep.

Arginine vasopressin (AVP) infusion has been shown to be a useful strategy for the management of systemic perfusion failure in premature infants. Our objective was to determine the characteristics of the blood flow redistribution induced by AVP infusion in premature fetal sheep. Nine sheep fetuses at 99 to 113days of gestation were continuously infused with AVP. Measurement of blood flow to individual fetal organs was performed using a colored microsphere technique, with measurements performed at 30min before and 90min after the initiation of AVP infusions. The AVP infusion significantly increased blood flow to the medulla oblongata (P < 0.05), and significantly decreased flow to the adrenal glands (from 492.0 ± 239.6 to 364.9 ± 143.3mL/min/100g, P < 0.05) and heart (from 592.6 ± 184.5 to 435.6 ± 137.4mL/min/100g, P < 0.05). The infusion significantly increased the vascular resistance in adrenal glands, kidneys, ileum, colon, heart, and cerebellum. In the brain, except for the cerebellum, no significant increase in resistance was identified. There was no significant response to AVP infusion in cerebral blood flow in mid-gestation fetal sheep. Our observations suggest that, under AVP stimulation, the blood flow to the adrenal glands and myocardium might be decreased due to an increase in vascular resistance.

Concurrent Use of Calcium Chloride and Arginine Vasopressin Infusions in Pediatric Patients with Acute Cardiocirculatory 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 retrospectively reviewed 77 patients (0-18years) with AHF admitted between January 2014 and May 2017 who received concurrent AVP and CaCl infusions. Surrogates of cardiac output and organ perfusion included hemodynamic vital signs, laboratory parameters, and urine output (UO). Organ dysfunction and vasopressor inotropic scores were also calculated. Median (IQR) age was 0.88 years (0, 3.75), and median weight was 6.62kg (3.5, 13.7). Congenital heart disease was present in 70% (46/77) patients. Univentricular physiology was present in 25% (25/77) patients. None of the patients were in the immediate postoperative period. Median durations of AVP and CaCl were 2 days (1, 3) and 3 days (2, 6), respectively. Using Wilcoxon-signed rank test and Bonferroni correction, post hoc comparison showed that at 8h post infusion, all systolic blood pressure (SBP) and diastolic blood pressure (DBP) results, and UO were greater than those 1h prior to infusion. Median SBP increased from 79mmHg (71, 92) 1 h prior to 97mmHg (84, 107) 8h post. Median DBP increased from 44 mm Hg (35, 52) 1 h prior to 54 mm Hg (44, 62) 8h post. Heart rate showed a decrease between measurements 1 h prior to infusion and 8h post, with median scores 146 (127, 162) and 136 (114, 150) beats per minute, respectively. Within first 8h, median UO continuously increased from 6mL/h. (0, 25) at 1h post infusion to 20mL/h. (2, 62) at 8h post infusion. Median pediatric logarithmic organ dysfunction scores on days 4 through 7 post infusion were lower compared to day 1; median vasopressor inotropic scores on day 2 through 7 post infusion were lower compared to day 1. Serum lactate level, arterial pH, and base excess all showed favorable trend. Concurrent use of AVP and CaCl infusions may improve surrogates of cardiac output, and intensive care outcomes, and prevent organ dysfunction in children with AHF.

105: Regulatory dendritic cell treatment prevents the development of vasopressin-induced preeclampsia in mice

The concept that poor fetal tolerance is important in the pathogenesis of preeclampsia (PE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion throughout pregnancy phenocopies human PE in mice mirroring the tonically elevated AVP secretion throughout human PE pregnancy. These findings identify AVP as a potential contributor to poor fetal tolerance and the development of PE. In addition to their conventional immuno-stimulatory role, dendritic cells (DCs) also play a vital role in immune tolerance. In contrast to conventional DCs, regulatory DCs (DCreg) promote tolerance via regulatory T cell induction, cell-to-cell interactions, and anti-inflammatory cytokine production. The objective of this study is to determine if DCreg treatment will prevent PE in an AVP-induced mouse model of PE. C57BL/6 dams were infused with AVP (24 ng/hour) or saline throughout gestation via osmotic minipump. To generate DCreg, bone marrow derived cells from C57BL/6 mice were cultured with human TGFβ1 and murine GM- CSF and IL-10. At the time of pump implantation (gestational day, GD -3) or early post-placentation on GD 7, AVP dams received a single intravenous injection of DCreg. Blood pressure was taken throughout pregnancy and total urine protein was measured on GD 18. Maternal tissues were collected on GD 18. Cytokine concentrations were determined via ELISA and normalized to total protein. Treatment of AVP-infused dams with DCreg before mating (GD -3) or on GD 7 prevented PE development. DCreg prevented hypertension (AVP: 120 ±1.8, n=27 vs GD -3: 108 ±3.3, n=7 vs GD 7: 110 ±4.4, n=5 p<0.05) and elevations in proteinuria (AVP: 37.4 ±2.3, n=24 vs GD -3: 25.6 ±2.9, n=7 vs GD 7: 24.1 ±3.1, n=5 p<0.05) (Figure 1). Elevations in pro- inflammatory plasma IFNγ were reversed with treatment (AVP: 27.7 ±12.0, n=6 vs GD -3: 0.0±0.0, n=4 vs GD 7: 0.0±0.0, n=6 pg/g, p<0.05) (Figure 2A). DCreg also reversed suppression of anti-inflammatory TGFβ in the plasma (AVP: 1.3 ± 0.91, n=9 vs GD -3: 3.2 ±0.50, n=4 vs GD 7: 2.9 ±0.25, n=6 ug/g, p<0.05) (Figure 2B). These data support the hypothesis that DCreg treatment prevents AVP-induced PE. It further provides evidence for the potential use of personalized, cellular therapy in the prevention of cardiovascular, renal, and immune alterations induced by preeclampsia.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Betamethasone: a novel therapeutic intervention for preeclampsia

The early pathogenesis of preeclampsia (PE) involves a systemic inflammatory immune response. Recent data demonstrate that increased circulating arginine vasopressin (AVP) in humans is predictive of PE and that infusion of AVP in mouse dams phenocopies the pregnancy-specific cardiovascular and immune alterations observed in human PE. Specifically, AVP suppresses anti-inflammatory cytokines and cells. Betamethasone (BMTZ), commonly given to women at risk for preterm birth, is both an AVP and immune response modulator. We hypothesize that early treatment with BMTZ will prevent the development of AVP-induced PE.

Regulatory dendritic cell treatment prevents the development of vasopressin-induced preeclampsia

The concept that persistent feto-placental intolerance is important in the pathogenesis of preeclampsia (PE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion during pregnancy induces cardiovascular, renal, and immune alterations in mice consistent with human PE. These findings identify AVP as a potential contributor to poor fetal tolerance and the development of PE. In addition to their conventional immuno-stimulatory role, dendritic cells (DCs) also play a vital role in immune tolerance. In contrast to conventional DCs, regulatory DCs (DCregs) express low levels of co-stimulatory markers, produce anti-inflammatory cytokines, induce T regulatory cells, and promote tolerance. In mice, DCregs are able to prevent pro-inflammatory responses and induce antigen-specific tolerance. Given these known functions of DCregs, we hypothesize that DCregs will prevent the development of AVP-induced PE.

Central Diabetes Insipidus and Chemotherapy: Use of a Continuous Arginine Vasopressin Infusion for Fluid and Sodium Balance

Central diabetes insipidus can occur in the setting of primary or metastatic tumors that disrupt the hypothalamic-pituitary axis. Usual treatment consists of water intake to replace ongoing fluid losses and desmopressin administration aimed at decreasing the urine output to enable maintenance of eunatremia without polyuria. Marked derangement in plasma sodium concentration can occur when high-volume intravenous fluid administration is required during chemotherapy to prevent nephrotoxicity, particularly if obligate fluid intake exceeds the total daily fluid intake necessary to maintain eunatremia. We developed a protocol for a rapidly titratable low-dose continuous intravenous arginine vasopressin infusion to maintain eunatremia in patients with central diabetes insipidus during periods of obligate fluid intake. We successfully maintained eunatremia in 2 patients with central nervous system lymphoma who underwent several cycles of obligate intravenous fluid administration with 5% dextrose in 0.45% sodium chloride for chemotherapy. Obligate fluid administration can result in dangerous and severe fluctuations in plasma sodium concentration in patients with central diabetes insipidus receiving conventional desmopressin therapy. The use of a rapidly titratable low-dose continuous vasopressin infusion successfully maintained eunatremia in this setting. This protocol can be replicated to prevent the wide and potentially dangerous fluctuations in plasma sodium concentration that can occur in patients with central diabetes insipidus who require high-volume intravenous fluid administration. This protocol has not been assessed among patients with impaired renal function and, thus, may not be generalizable to this population. (AACE Clinical Case Rep. 2018;4:e487-e492).

Arginine vasopressin infusion is sufficient to model clinical features of preeclampsia in mice.

Copeptin, a marker of arginine vasopressin (AVP) secretion, is elevated throughout human pregnancies complicated by preeclampsia (PE), and AVP infusion throughout gestation is sufficient to induce the major phenotypes of PE in mice. Thus, we hypothesized a role for AVP in the pathogenesis of PE. AVP infusion into pregnant C57BL/6J mice resulted in hypertension, renal glomerular endotheliosis, intrauterine growth restriction, decreased placental growth factor (PGF), altered placental morphology, placental oxidative stress, and placental gene expression consistent with human PE. Interestingly, these changes occurred despite a lack of placental hypoxia or elevations in placental fms-like tyrosine kinase-1 (FLT1). Coinfusion of AVP receptor antagonists and time-restricted infusion of AVP uncovered a mid-gestational role for the AVPR1A receptor in the observed renal pathologies, versus mid- and late-gestational roles for the AVPR2 receptor in the blood pressure and fetal phenotypes. These findings demonstrate that AVP is sufficient to initiate phenotypes of PE in the absence of placental hypoxia, and indicate that AVP may mechanistically (independently, and possibly synergistically with hypoxia) contribute to the development of clinical signs of PE in specific subtypes of human PE. Additionally, they identify divergent and gestational time-specific signaling mechanisms that mediate the development of PE phenotypes in response to AVP.

Abstract 014: Betamethasone: A Novel Therapeutic Intervention for Preeclampsia

The early pathogenesis of preeclampsia (PE) involves a systemic inflammatory immune response. Recent data demonstrate that increased circulating arginine vasopressin (AVP) in humans is predictive of PE and that infusion of AVP in mouse dams phenocopies the pregnancy-specific cardiovascular and immune alterations observed in human PE. Specifically, AVP suppresses anti-inflammatory cytokines and cells. Betamethasone (BMTZ), commonly given to women at risk for preterm birth, is both an AVP and immune response modulator. We hypothesize that early treatment with BMTZ will prevent the development of AVP-induced PE. C57BL/6J dams were infused with AVP (24 ng/hour) or saline throughout gestation via osmotic minipump. AVP dams received a single subcutaneous injection of BMTZ (100ug) early post-placentation (gestational day (GD) 7). Blood pressure was measured throughout pregnancy. Total protein was measured on 24 hour urine collected on GD 17. Maternal and fetal tissues were collected on GD 18. Cytokine concentrations were determined via commercially available ELISAs and normalized to total protein. BMTZ reversed the hypertension (ANOVA n=11, p=0.007) and proteinuria (ANOVA n=11, p=0.025) induced by AVP. BMTZ reversed the AVP-induced decreases in the maternal and fetal anti-inflammatory responses. In maternal kidney, both anti-inflammatory IL-4 (AVP: 0.034, n=10 vs BTMZ: 0.092, n=5 ug/g, p&lt;0.05) and TGFb (AVP: 4.3, n=10 vs BTMZ: 9.2, n=5 ug/g, p&lt;0.05) were increased in BMTZ-treated dams. Decreases in fetal kidney IL-4 (AVP: 0.013, n=5 vs BTMZ: 0.043, n=5 ug/g, p&lt;0.05), IL-10 (AVP: 1.2, n=5 vs BTMZ: 2.1, n=5 ug/g, p=0.05), and TGFb (AVP: 1.8, n=5 vs BMTZ: 2.9, n=5 ug/g, p&lt;0.05) were reversed with BMTZ treatment. Lastly, placental concentrations of IL-4 (AVP: 0.002, n=5 vs BTMZ: 0.005, n=5 ug/g, p&lt;0.05) and TGFb (AVP: 0.090, n=5 vs BTMZ: 1.4, n=5 ug/g, p&lt;0.05) were also improved following BMTZ in AVP-infused dams. Supportive of our hypothesis, early BMTZ treatment prevented hypertension and reduced proteinuria in AVP-infused dams. BMTZ also reversed AVP-induced inhibition of anti-inflammatory responses, creating a more tolerogenic milieu. These data support the concept for the potential use of BMTZ in early gestation as a novel preventative agent for PE.