Plasma Arginine Vasopressin Levels Research Articles

Further analysis of behavioral and endocrine consequences of chronic exposure of male Wistar rats to subtoxic doses of endocrine disruptor chlorobenzenes

Many chemicals utilized by humans are present as environmental pollutants and may influence homeostasis from neurological, immunological, endocrinological and/or behavioral aspects. Such agents, acting alone or in ambient mixtures, may be biologically active even at extremely low doses, and it may be postulated that stable, bioaccumulative, reactive endorine disruptors may affect central and/or peripheral secretion of arginine–vasopressin (AVP) and oxytocin (OXT) and thereby related physiological and behavioral functions, potentially leading to disorders in exposed subjects. The primary aim of this study was to demonstrate effects of chronic exposure to a low dose of an orally administered chlorobenzene mixture on anxiety-related and aggressive behavior mediated largely by AVP and OXT. Chlorobenzenes were applied to model ambient mixtures of endocrine disruptors. Adult, male Wistar rats were exposed daily to 0.1μg/kg of 1,2,4-trichlorobenzene and hexachlorobenzene via a stomach tube for 30, 60 or 90days, after which anxiety-related and aggressive behavioral elements were examined in open-field, elevated plus maze and resident–intruder tests. The plasma levels of AVP, OXT and adrenocorticotrophic hormone at the endpoints were measured by radioimmunoassay or immunochemiluminescence assay. The levels of basal and serotonin- or norepinephrine-stimulated AVP and OXT secretion in pituicyte cultures prepared from the posterior lobe of the pituitaries were also measured. The hormone levels proved to be increased to extents depending on the duration of exposure to the chlorobenzenes. Several anxiety-related and aggressive behavioral elements were also enhanced following chlorobenzene exposure, while certain explorative and locomotive elements of the animals were decreased. As both physiological and behavioral elements were modulated by chronic, subtoxic doses of chlorobenzenes, it is concluded that doses of such environmental pollutants low enough to fall outside the range of legal regulation may pose potential risks of anxiogenic and/or aggressive consequences in exposed subjects, including humans.

Copeptin in the Differential Diagnosis of the Polydipsia-Polyuria Syndrome—Revisiting the Direct and Indirect Water Deprivation Tests

The water deprivation test (WDT) with direct or indirect measurement of plasma arginine vasopressin (AVP) is the method of choice for the differential diagnosis of the polydipsia-polyuria syndrome. In theory, direct measurement of AVP is highly attractive but is hampered by technical difficulties. The aim of the study was to evaluate the utility of copeptin, a surrogate of AVP secretion, in the diagnostic work-up of the polyuria-polydipsia syndrome and to compare its performance with the current diagnostic standard. In two tertiary referral centers, 20 healthy subjects and 50 patients with polydipsia-polyuria syndrome underwent WDT with measurements of both plasma AVP and copeptin levels. The reference diagnosis was based on clinical information and treatment response. Twenty-two patients (44%) were diagnosed with primary polydipsia, 17 (34%) with partial central diabetes insipidus (DI), nine (18%) with complete central DI, and two (4%) with nephrogenic DI. The indirect WDT led to a correct diagnosis in 35 of 50 patients (70%). The direct WDT with AVP or copeptin measurement correctly diagnosed 23 patients (46%) or 36 patients (72%), respectively. Baseline copeptin values greater than 20 pmol/liter identified patients with nephrogenic DI, and concentrations below 2.6 pmol/liter indicated complete central DI. The ratio between Δ copeptin (0800 to 1600 h) and serum sodium concentration at 1600 h yielded optimal diagnostic accuracy, allowing us to also discern partial central DI from primary polydipsia (sensitivity 86%, and specificity 100%). Copeptin holds promise as a diagnostic tool in the polyuria-polydipsia syndrome, improving significantly the diagnostic accuracy of the direct WDT.

Reverse Remodeling With Left Ventricular Assist Devices

Over the last 2 decades, numerous advancements in medical therapies have improved patient outcomes in heart failure (HF). However, a significant number of patients still progress to end-stage HF, in which treatment options are largely limited to cardiac transplantation. As patient demands for transplant continue to exceed the supply of available organs, mechanical assist devices—specifically, the left ventricular assist device (LVAD)—were initially introduced as a bridge to cardiac transplantation. LVADs have 2 important beneficial effects. First, LVADs are placed in parallel to the native left ventricle (LV), causing pressure and volume unloading of the LV. Second, LVADs restore cardiac output and subsequent perfusion to the organs. As a result of these 2 effects, it became evident that some patients had actual improvement in LV function after LVAD placement. The term reverse remodeling was used to describe the improvement in myocardial function that was observed in patients with a seemingly end-stage disease. With reverse remodeling, a new hope for the treatment of HF was born—using LVADs as a bridge to recovery; however, to date, this promise has largely been unrealized. This probably is reflective of the fact that the sequela of mechanical ventricular unloading are quite complex and appear to involve the engagement of competing biological pathways including regression of cardiomyocyte hypertrophy as well as progressive cell atrophy. Although the promise of ventricular recovery still persists, its actualization will await a more comprehensive dissection of these competing biological processes. This review will discuss the beneficial clinical effects of LVAD support as well as review what is known about the cellular and molecular response to mechanical unloading and mechanisms of reverse remodeling. Key research findings have been summarized in the Table. View this table: Table. Summary of Research of LVAD Support on Clinical Effects and the Cellular and Molecular Changes That May Contribute to Reverse …

Early Development of Hyponatremia Implicates Short- and Long-Term Outcomes in ST-Elevation Acute Myocardial Infarction

Clinical importance of hyponatremia in ST-elevation acute myocardial infarction (STEMI) in the era of primary intervention has not been fully understood. The aim of this study was to investigate the impact of hyponatremia on outcomes in patients with STEMI and secondarily to investigate the contribution of arginine vasopressin (AVP) to hyponatremia in STEMI. Hyponatremia was defined as a sodium concentration <136 mmol/L at 72h after hospitalization. First, the short-term (in-hospital mortality or congestive heart failure (CHF)) and long-term prognosis (cardiac death, re-admission for CHF) in STEMI patients was conducted. Second, the relationship between serum sodium level and plasma AVP was investigated. In hyponatremic patients the incidence of in-hospital heart failure was significantly greater (P=0.0018), long-term cardiac death was a higher trend (17.2% vs. 6.3%, P=0.19) and re-admission due to CHF was significantly more frequent (20.7% vs. 4.5%, P=0.0024). Plasma AVP level was higher in the hyponatremia group (4.5 vs. 2.7 pg/ml, P=0.003), and it had a negative correlation with serum sodium level (r=-0.28, P=0.02). Hyponatremia was frequently found in the early phase of STEMI, and associated with heart failure in both short- and long-term outcomes. Non-osmotic secretion of AVP could be involved in hyponatremia in STEMI patients.

Angiotensin II-stimulated secretion of arginine vasopressin is inhibited by atrial natriuretic peptide in humans

We investigated the effect of the intravenous infusion of atrial natriuretic peptide (ANP) on the response of plasma arginine vasopressin (AVP) levels to intravenous infusion of angiotensin II (ANG II) in healthy individuals. Intravenous infusion of ANP (10 ng·kg(-1)·min(-1)) slightly but significantly decreased plasma AVP levels, while intravenous infusion of ANG II (10 ng·kg(-1)·min(-1)) resulted in slightly increased plasma AVP levels. ANG II infused significant elevations in arterial blood pressure and central venous pressure (CVP). Because the elevation in blood pressure could have potentially inhibited AVP secretion via baroreceptor reflexes, the effect of ANG II on blood pressure was attenuated by the simultaneous infusion of nitroprusside. ANG II alone produced a remarkable increase in plasma AVP levels when infused with nitroprusside, whereas the simultaneous ANP intravenous infusion (10 ng·kg(-1)·min(-1)) abolished the increase in plasma AVP levels induced by ANG II when blood pressure elevation was attenuated by nitroprusside. Thus, ANG II increased AVP secretion and ANP inhibited not only basal AVP secretion but also ANG II-stimulated AVP secretion in humans. These findings support the hypothesis that circulating ANP modulates AVP secretion, in part, by antagonizing the action of circulating ANG II.

Arginine vasopressin plasma levels could indicate childern undergoing cardiopulmonary bypass that might benefit from exogenous arginine vasopressin*

Arginine vasopressin plasma levels could indicate childern undergoing cardiopulmonary bypass that might benefit from exogenous arginine vasopressin*

Osmoregulation of vasopressin secretion is altered in the postacute phase of septic shock*

To determine whether septic shock patients have an abnormal reponse to increasing osmolarity. Prospective interventional study. Intensive care unit at Raymond Poincaré and Etampes Hospitals. Normonatremic patients at > 72 hrs from septic shock onset. Osmotic challenge consisting of infusing 500 mL of hypertonic saline solution (with cumulative amount of sodium not exceeding 24 g) over 120 mins. Plasma arginine vasopressin levels were measured 15 mins before the test and then four times every 30 mins. A slope of the relation between arginine vasopressin and plasma sodium levels of < 0.5 pg/mEq defined nonresponders. Among the 33 included patients, 17 (52%) were nonresponders. During osmotic challenge, variations throughout the test in plasma sodium levels, blood pressure, and central venous pressure were comparable between the two groups. Arginine vasopressin increased from 4.8 pg/mL [3.3-6.4 pg/mL] to 14.4 pg/mL [11.2-23.3 pg/mL] in responders but only from 2.8 pg/mL [2.3-4.0 pg/mL] to 4.0 pg/mL [3.1-5.3 pg/mL] in nonresponders (p < .0001). Responders had a higher plasma arginine vasopressin levels at baseline and a more severe hematosis alteration. Nonresponders had more frequently bacteremia and liver dysfunction, been referred from the ward and undergone surgery. Critical illness severity, hemodynamic alteration, hydroelectrolytic disturbances, treatment, and outcome did not differ between the two groups. Osmoregulation is dramatically altered in half of patients with prolonged septic shock.

Water Prescription in Autosomal Dominant Polycystic Kidney Disease

In animal models of polycystic kidney disease, the ingestion of large amounts of water promotes diuresis by suppressing plasma levels of arginine vasopressin (AVP) and renal levels of cAMP, slowing cyst progression. Whether simple water ingestion is a potential therapeutic strategy for individuals with autosomal dominant polycystic kidney disease (ADPKD) is unknown. In this study, a simple method to quantify the amount of water to achieve a specific mean urine osmolality target in patients with ADPKD was developed and tested. In eight ADPKD patients eating typical diets, osmolality and volume were measured in 24-hour urine collections. The amount of additional ingested water required daily to achieve a mean urine osmolality of 285 ± 45 mosm/kg was determined. Participants were instructed to distribute the prescribed water over waking hours for each of 5 days. Blood chemistries, 24-hour urine collections, BP, and weight were measured before and after the period of supplemental water intake. Five patients achieved the 285 mosm/kg urine target without difficulty. Mean urine osmolality decreased and mean urine volume increased; serum sodium, weight, and BP were unchanged. Daily osmolar excretion remained constant, indicating a stable ad lib dietary intake of solutes and protein over the 2-week study period. The amount of additional water needed to achieve a urine osmolality target can be approximated from the urine osmolar excretion in ADPKD patients eating typical diets, providing a quantitative method to prescribe supplemental water for such individuals.

Central NOS inhibition differentially affects vasopressin gene expression in hypothalamic nuclei in septic rats

Our aim was to investigate the effect of central NOS inhibition on hypothalamic arginine vasopressin (AVP) gene expression, hormone release and on the cardiovascular response during experimental sepsis. Male Wistar rats were intracerebroventricularly injected with the non-selective NO synthase (NOS) inhibitor (L-NAME) or aminoguanidine, a selective inhibitor of the inducible isoform (iNOS). After 30min, sepsis was induced by cecal ligation and puncture (CLP) causing an increase in heart rate (HR), as well as a reduction in median arterial pressure (MAP) and AVP expression ratio (AVPR), mainly in the supraoptic nucleus. AVP plasma levels (AVPp) increased in the early but not in the late phase of sepsis. L-NAME pretreatment increased MAP but did not change HR. It also resulted in an increase in AVPp at all time points, except 24h, when it returned to basal levels. AVPR, however remained reduced in both nuclei. Aminoguanidine pretreatment resulted in increased MAP in the early phase and higher AVPR in the supraoptic, but not in the paraventricular nucleus, while AVPp remained elevated at all time points. We suggest that increased central NO production, mainly inducible NOS-derived, reduces AVP gene expression differentially in supraoptic and paraventricular nuclei, and that this may contribute to low AVP plasma levels and hypotension in the late phase of sepsis.

Nephrogenic syndrome of inappropriate antidiuresis

The nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare, recently recognized disorder in water balance affecting not only infants but also adults. A new molecular mechanism responsible for NSIAD has recently been identified: a gain of function of the arginine vasopressin (AVP) receptor type 2 (V2R), causing the constitutive activation of the receptor. Clinical presentation and laboratory findings of NSIAD resemble those of the syndrome of inappropriate secretion of antidiuretic hormone and consist of hyponatraemia, seizures and the lack of urinary dilution; however, the AVP levels in plasma are undetectable or very low. An elucidation of the pathophysiology of this syndrome will provide more insight into the action of AVP. An effective treatment of NSIAD is available. It consists of fluid restriction and administration of oral urea. Reported experience with furosemide treatment in NSIAD is still lacking.

Diagnostic and Predictive Values of Thirst, Angiotensin II, and Vasopressin During Trauma Resuscitation

Background. Thirst perception involves neurochemical signals attributed to acute elevation of arginine vasopressin (AVP) and angiotensin II (AT2) levels, and may accompany acute hemorrhage. Objective. To determine whether thirst or plasma AVP or AT2 levels predict hemorrhagic shock, injury severity, or outcome in trauma patients at initial presentation. Methods. This was a prospective case series of adult subjects presenting as trauma activations to an urban level I trauma center. Subjects were included if they were alert and nonintoxicated. During resuscitation, subjects were queried for thirst perception using binary and continuous data formats employing a 100-mm nonhatched visual analog scale. Blood for AT2 and AVP assessment was obtained during initial laboratory collection. Other data were abstracted retrospectively from our trauma registry. Crude and stratified analyses (blunt and penetrating trauma) assessed the correlation of thirst, AVP, and AT2 to the initial shock index, base deficit, blood transfusion requirement, admission, and Injury Severity Score (ISS). Our institutional review board (IRB) granted a waiver of informed consent. Results. Of 105 subjects, the average age was 35 years (95% confidence interval [CI] 32 to 38), with 31% penetrating trauma. For AVP, there was no difference in thirst perception between subjects with normal (59 mm, 95% CI 47 to 71) versus elevated (63 mm, 95% CI 56 to 70) plasma levels. For AT2, results were likewise insignificant for normal (63 mm, 95% CI 56 to 70) versus elevated (58 mm, 95% CI 46 to 70) plasma levels. Thirst, AT2 level, and AVP level demonstrated no correlation to shock index, base deficit, transfusion requirement, hospital admission, or ISS. Conclusion. The results of this study imply that thirst severity and AVP and AT2 plasma levels are not reliable predictors of impending hemorrhagic shock, injury severity, or outcome. The presence or absence of severe thirst should not be employed as a primary marker for dismissing or suspecting incipient shock.

Nitric Oxide and Vasopressin Expression during Sepsis

We investigated the role of centrally produced NO on hypothalamic arginine vasopressin (AVP) expression and release and on cardiovascular response during experimental sepsis. Male Wistar rats were i.c.v injected with the non‐selective NO synthase (NOS) inhibitor L‐NAME, or aminoguanidine (AG), a selective inhibitor of the inducible isoform (iNOS). After 30min sepsis was induced by cecal ligation and puncture (CLP) causing increases in NO plasma levels and heart rate (HR) and a reduction in arterial pressure (MAP) and AVP expression ratio (AVPR) in the supraoptic (SON) and paraventricular (PVN) nuclei. AVP plasma levels (AVPp) increased, but only in the early phase. L‐NAME pretreatment, reduced NO production and increased MAP and did not change HR. AVPp further increased in the early phase but decreased in the late phase while AVPR decreased in both phases. AG i.c.v injected did not change substantially the increase of NO plasma levels but increased MAP in the initial phase of sepsis. AVPR increased only in the SON, and AVPp remained all time elevated. These results show that increased central NO production differentially inhibits AVPR in SON and PVN, contributing to basal AVPp and hypotension in the late phase of sepsis.Financial support: FAPESP

Hypothalamic osmoregulation is maintained across the wake-sleep cycle in the rat

In different species, rapid eye movement sleep (REMS) is characterized by a thermoregulatory impairment. It has been postulated that this impairment depends on a general insufficiency in the hypothalamic integration of autonomic function. This study aims to test this hypothesis by assessing the hypothalamic regulation of body fluid osmolality during the different wake-sleep states in the rat. Arginine-vasopressin (AVP) plasma levels were determined following intracerebroventricular (ICV) infusions of artificial cerebrospinal fluid (aCSF), either isotonic or made hypertonic by the addition of NaCl at three different concentrations (125, 250 and 500 mM). Animals were implanted with a cannula within a lateral cerebral ventricle for ICV infusions and with electrodes for the recording of the electroencephalogram. ICV infusions were made in different animals during Wake, REMS or non-REM sleep (NREMS). The results show that ICV infusion of hypertonic aCSF during REMS induced an increase in AVP plasma levels that was not different from that observed during either Wake or NREMS. These results suggest that the thermoregulatory impairment that characterizes REMS does not depend on a general impairment in the hypothalamic control of body homeostasis.

Early change of plasma and cerebrospinal fluid arginine vasopressin in traumatic subarachnoid hemorrhage

Objective To investigate the changes and effects of arginine vasopressin (AVP) in patients with acute traumatic subarachnoid hemorrhage (tSAH). Methods The plasma and cerebrospinal fluid (CSF) level of AVP, and intracranial pressure (ICP) were measured in a total of 21 patients within 24 hours after tSAH. The neurological status of the patients was evaluated by Glasgow Coma Scale (GCS). Correlation between AVP and ICP, GCS was analyzed respectively. Meanwhile, 18 healthy volunteers were recruited as control group. Results Compared with control group, the levels (pg/ml) of AVP in plasma and CSF (x±s) in tSAH group were significantly increased within 24 hours (38.72±24.71 vs 4.54±1.38 and 34.61±21.43 vs 4.13±1.26, P <0.01), and was remarkably higher in GCS≤8 group than GCS>8 group (50.96±36.81 vs 25.26±12.87 and 44.68±31.72 vs 23.53±10.94, P 0.05). The CSF AVP level was correlated with ICP ( r = 0.46, P<0.05), but no statistically significant correlation was found between plasma AVP, CSF AVP and initial GCS ( r = −0.29, P>0.05 and r= −0.32, P>0.05, respectively). The ICP (mm Hg) in tSAH patients was elevated and higher in GCS=8 group than in GCS≤8 gro up (25.9±9.7 vs 17 .6±5.2, P<0. 05). Conclusion Our research suggests that AVP is correlated with the severity of tSAH, and may be involved in the pathophysiological process of brain damage in the early stage after tSAH. It seems that compared with the plasma AVP concentration, CSF AVP is more related to the severity of tSAH.

Effect of melatonin supplementation on plasma vasopressin response to different conditions in rats with hyperthyroidism induced by l-thyroxine

The present study was performed to determine how basal, isotonic, hypertonic and hypovolemic conditions affect fluid–electrolyte balance and plasma arginine vasopressin (AVP) levels in rats with experimental hyperthyroidism supplemented with melatonin. The rats were divided into four groups of twenty-four subjects each kept under the following treatments during one month: (1) Controls; (2) treated with l-thyroxine; (3) treated with l-thyroxine and sham melatonin and (4) treated with l-thyroxine and melatonin. After this each group was further subdivided into subgroups that were subject to normal, isotonic, hypertonic and hypovolemic conditions. The plasma AVP, total triiodothyronine (TT 3), total thyroxine (TT 4) and melatonin levels were measured in plasma by means of a Phoenix Pharmaceutical RIA test kit. Hematocrit and osmolality levels were also determined. There were significant increases of total T3 and T4 levels in the l-thyroxine treated groups, p < 0.001. The AVP levels were also increased in groups 2 and 3, but not so in the rats treated with melatonin ( p < 0.001), which also showed increased plasma melatonin levels ( p < 0.001). These results indicate that treatment with l-thyroxine increases stimulated and non-stimulated AVP release that are inhibited by melatonin supplementation. It was also shown that AVP response to hypertonic and hypovolemic conditions was not affected by l-thyroxine treatment and/or l-thyroxine + melatonin treatment.

The association of the plasma vasopressin level during attacks with a prognosis of Meniere's disease

An elevation of the plasma arginine vasopressin (AVP) level has frequently been observed in Meniere's disease patients. However, little is known regarding the mechanism behind this elevation. The plasma AVP levels in acute phase were determined in 21 Meniere's disease patients and 16 patients with other types of vertigo. The plasma AVP levels of Meniere's disease patients in the acute phase were significantly higher than in those of other vertigo patients (p < 0.01). In Meniere's disease patients with abnormally high levels of AVP (more than 3.5 pg/ml) in the acute phase, 36% of patients were resistant to conservative treatments for frequent vertigo attacks for the follow-up period of at least 2years. A significant correlation was observed between the plasma AVP in the acute phase and the highest hearing threshold level at a frequency of 1kHz for the follow-up period of at least 1 year (r=0.45, p < 0.05). These results suggest that the elevation in plasma AVP level in the acute phase is associated with the prognosis of Meniere's disease.SumarioLa elevación del nivel plasmático de vasopresina arginina (AVP) ha sido frecuentemente observado en los pacientes con enfermedad de Meniere. Sin embargo, se sabe poco de los mecanismos detrás de esta elevación. Se determinaron los niveles plasmáticos de AVP durante la fase aguda en 21 paciente con enfermedad de Meniere y en 16 pacientes con otro tipo de vértigo. Los niveles plasmáticos de AVP en los pacientes en la fase aguda de la enfermedad de Meniere fueron significativamente más elevados que aquellos con otro tipo de vértigo (p < 0.01). De los pacientes con enfermedad de Meniere y niveles anormalmente elevados de AVP (más de 5.5 pg/ml) durante la fase aguda, 36% de ellos fueron resistentes al tratamiento conservador para los ataques frecuentes de vértigo en un periodo de seguimiento de hasta 2 años. Se observó una correlación significativa entre el nivel plasmático de AVP en la fase aguda y el umbral más elevado en la frecuencia de 1kHz durante el periodo de seguimiento de un año (r = 0.45, p < 0.05). Estos resultados sugieren que la elevación plasmática de AVP en la fase aguda está asociada con el pronóstico de la enfermedad de Meniere.

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

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

Autosomal recessive familial neurohypophyseal diabetes insipidus: onset in early infancy

Familial neurohypophyseal diabetes insipidus (FNDI), usually an autosomal dominant disorder, is caused by mutations in the arginine vasopressin (AVP)-neurophysin II preprohormone leading to aberrant preprohormone processing and gradual destruction of AVP-secreting cells. Patients typically present between 1 and 6 years of age with polyuria and polydipsia. Clinical, biochemical, and genetic studies of three new cases of autosomal recessive FNDI presenting in early infancy. Three Palestinian cousins presented with failure to thrive, vomiting, irritability, and fever. The parents were asymptomatic. Patients developed hypernatremia (154-163 mmol/l) and serum hyperosmolality (>320 mOsm/kg), while urine osmolality remained between 73 and 229 mOsm/kg. Plasma AVP levels were low, and the posterior pituitary bright spot was absent on magnetic resonance imaging (MRI). All patients responded to desmopressin. Patients were homozygous and parents were heterozygous for microsatellite markers flanking the AVP gene. All patients were homozygous for the P26L (proline to leucine) substitution affecting mature AVP. A founder effect with the single original kindred carrying the P26L mutation was confirmed by microsatellite analysis, but patients in that family presented only at 2 years of age. In microsatellite analysis, the new kindred patients were not homozygous and did not share a single allele at the aquaporin 2 and vasopressin receptor-2 genes locuses. This is the first description of autosomal recessive FNDI presenting in the neonatal period. The unusual early clinical and radiological (MRI) presentation argues against gradual destruction of AVP-secreting neurons as the pathophysiological mechanism. Factors beside allelism of AVP-related genes must influence the age of FNDI presentation given the founder effect demonstrated for the P26L mutation.

Exaggerated response of a vasopressin-enhanced green fluorescent protein transgene to nociceptive stimulation in the rat.

Nociceptive stimulation elicits neuroendocrine responses such as arginine vasopressin (AVP) release as well as activation of the hypothalamo-pituitary-adrenal axis. We have generated novel transgenic rats expressing an AVP-enhanced green fluorescent protein (eGFP) fusion gene, and we examined the effects of nociceptive stimulation on transgene expression in the hypothalamus after subcutaneous injection of saline or formalin into the bilateral hindpaws in these rats. We have assessed (1) AVP levels in plasma and the changes of eGFP mRNA and AVP heteronuclear RNA (hnRNA) in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) using in situ hybridization histochemistry, (2) gene expression changes in distinct magnocellular and parvocellular divisions of the PVN, (3) eGFP fluorescence in the SON, the PVN, the median eminence (ME), and the posterior pituitary gland (PP). Plasma AVP levels were significantly increased 15 min after formalin injection. In the same time period, the AVP hnRNA levels in the PVN were increased, especially in the parvocellular division of the PVN in formalin-injected rats. In the same region, eGFP mRNA levels after formalin injection were also significantly increased to a much greater extent than those of AVP hnRNA. The eGFP fluorescence in the SON, the PVN, the ME, and the PP was markedly increased in formalin-injected rats and especially increased in the parvocellular divisions of the PVN. Together, our results demonstrate robust and rapid changes in the expression of the AVP-eGFP transgene in the rat hypothalamus after acute nociceptive stimulation.

Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial

To compare the effects of two arginine vasopressin (AVP) dose regimens on the hemodynamic response, catecholamine requirements, AVP plasma concentrations, organ function and adverse events in advanced vasodilatory shock. In this prospective, controlled, open-label trial, patients with vasodilatory shock due to sepsis, systemic inflammatory response syndrome or after cardiac surgery requiring norepinephrine >0.6 microg/kg/min were randomized to receive a supplementary AVP infusion either at 0.033 IU/min (n = 25) or 0.067 IU/min (n = 25). The hemodynamic response, catecholamine doses, laboratory and organ function variables as well as adverse events (decrease in cardiac index or platelet count, increase in liver enzymes or bilirubin) were recorded before, 1, 12, 24 and 48 h after randomization. A linear mixed effects model was used for statistical analysis in order to account for drop-outs during the observation period. Heart rate and norepinephrine requirements decreased while MAP increased in both groups. Patients receiving AVP at 0.067 IU/min required less norepinephrine (P = 0.006) than those infused with AVP at 0.033 IU/min. Arterial lactate and base deficit decreased while arterial pH increased in both groups. During the observation period, AVP plasma levels increased in both groups (both P < 0.001), but were higher in the 0.067 IU/min group (P < 0.001) and in patients on concomitant hydrocortisone. The rate of adverse events and intensive care unit mortality was comparable between groups (0.033 IU/min, 52%; 0.067 IU/min, 52%; P = 1). A supplementary AVP infusion of 0.067 IU/min restores cardiovascular function in patients with advanced vasodilatory shock more effectively than AVP at 0.033 IU/min.