AVP Levels Research Articles

Growing up in the family or growing up alone influences behavior and hormones, but not arginine vasopressin receptor 1a expression in male African striped mice

In many species males display alternative reproductive tactics (ARTs). While males of different tactics differ behaviorally in the field, it is often not known whether these behavioral differences would also occur under standardized laboratory conditions, nor how ARTs are regulated by the brain. In the present study we kept male African striped mice (Rhabdomys pumilio) in captivity either in family groups or solitary, to mimic ARTs observed in the field. This allowed us to study these males behaviorally under standardized conditions, to replicate physiological findings from the field, and to study the expression of the arginine vasopressin 1a receptor (AVPR1a) in their brains. Changes in either peptide release or receptor expression (or both) might regulate ARTs with differential timelines, with peptide secretion being faster than receptor expression. As observed in the field, family living males had higher corticosterone but lower testosterone levels than singly housed males. Surprisingly, singly housed males were less aggressive while at the same time having higher testosterone levels. We found no differences in AVPR1a expression. In a previous study it was shown that singly housed males have higher levels of AVP stored in their brain, which potentially could be secreted when the social situation changes, for example to establish social bonds. Our study on AVPR1a suggests the hypothesis that, given that the receptor distribution and expression of singly housed males do not differ from that of family-living males, the brains of singly-housed males have a similar capacity to be responsive to AVP when given the chance to interact socially.

Neuroendocrine responses to social isolation and paternal deprivation at different postnatal ages in mandarin voles

Neonatal isolation and paternal deprivation have long lasting effects on the behavior and neuroendocrine system at adulthood. Whether these effects at adulthood are induced by neonatal changes in relevant neuroendocrine parameters lead by these early-life social experiences is not well understood. Whether monogamous rodents exhibit a stress hypo-responsive period (SHRP) also remains unclear. Using the monogamous mandarin vole, we found that 30 min of isolation did not affect levels of corticosterone (CORT) and adrenocorticotropin (ACTH) at postnatal days 8, 10, and 12 displaying a SHRP, but increased these at postnatal days 4, 14, 16, and 18. Isolation increased vasopressin (AVP)-ir neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) from postnatal days 4 to 12, and up-regulated oxytocin (OT)-ir neurons in the PVN at postnatal days 4 and 8 and SON at postnatal day 4. Paternally deprived pups showed increase in ACTH and CORT after 30 min of social isolation from postnatal days 8 to 14, increase in AVP-ir neurons in the PVN from postnatal days 10 to 14, reduction in OT-ir neurons in the PVN from postnatal days 10 to 14 and in the SON at postnatal days 12 and 14. These results indicate that monogamous mandarin voles display a short SHRP which can be disrupted by paternal deprivation. Central AVP and OT levels may also be altered by paternal deprivation and social isolation. We propose that changes in these neuroendocrine parameters induced by early-life social experiences such as those tested here persist and result.

Alcohol-Induced Changes in Methylation Status of Individual CpG Sites, and Serum Levels of Vasopressin and Atrial Natriuretic Peptide in Alcohol-Dependent Patients during Detoxification Treatment

Disturbances of volume-regulating peptides like vasopressin (AVP) and atrial natriuretic peptide (ANP) have been described in early abstinent alcohol-dependent patients. In a longitudinal approach, we investigated whether changes in AVP and ANP serum levels correlated to cytosine-phosphatidyl-guanine (CpG) methylation of the respective gene promoters on days 1, 7 and 14 of alcohol withdrawal. We analyzed the blood samples of 99 patients suffering from alcohol dependence alongside age- and BMI-matched controls. Concerning AVP promoter methylation, we observed an interaction between time of measurement and CpG loci with CpG 2 showing a significant increase in methylation from day 1 to 14. Serum levels of AVP were significantly decreased in the patient group. Compared to healthy controls, promoter-related DNA methylation of the ANP promoter was significantly reduced on days 7 and 14. Moreover, we detected a significant interaction between CpG position and group. In both cases the difference was mainly observed at CpG 1. The present study shows significant changes in the methylation status of individual CpG sites of AVP and ANP. Observing respective alterations of AVP serum protein levels in alcohol-dependent patients during detoxification treatment, we consider methylation as a possible mode of regulation for these proteins during alcohol detoxification.

Thirst Perception and Osmoregulation of Vasopressin Secretion Are Altered During Recovery From Septic Shock

ObjectiveVasopressin (AVP) secretion during an osmotic challenge is frequently altered in the immediate post-acute phase of septic shock. We sought to determine if this response is still altered in patients recovering from septic shock.DesignProspective interventional studySettingIntensive care unit (ICU) at Raymond Poincaré and Etampes Hospitals.PatientsNormonatremic patients at least 5 days post discontinuation of catecholamines given for a septic shock.InterventionOsmotic challenge involved infusing 500 mL of hypertonic saline solution (with cumulative amount of sodium not exceeding 24 g) over 120 minutes.Measurements and main resultsPlasma AVP levels were measured 15 minutes before the infusion and then every 30 minutes for two hours. Non-responders were defined as those with a slope of the relation between AVP and plasma sodium levels less than < 0.5 ng/mEq. Among the 30 included patients, 18 (60%) were non-responders. Blood pressure and plasma sodium and brain natriuretic peptide levels were similar in both responders and non-responders during the course of the test. Critical illness severity, hemodynamic alteration, electrolyte disturbances, treatment and outcome did not differ between the two groups. Responders had more severe gas exchange abnormality. Thirst perception was significantly diminished in non-responders. The osmotic challenge was repeated in 4 non-responders several months after discharge and the abnormal response persisted.ConclusionMore than half of patients recovering from septic shock have an alteration of osmoregulation characterised by a dramatic decrease in vasopressin secretion and thirst perception during osmotic challenge. The mechanisms of this alteration but also of the relationship between haematosis and normal response remain to be elucidated.

Oxytocin and vasopressin support distinct configurations of social synchrony

Social synchrony – the coordination of behavior between interacting partners during social contact – is learned within the parent-infant bond and appears in a unique form in mothers and fathers. In this study, we examined hormonal effects of OT and AVP on maternal and paternal behavioral patterns and detail the processes of parent-infant social synchrony as they combine with hormonal activity. Participants included 119 mothers and fathers (not couples) and their 4–6 month-old infants. Baseline OT and AVP were collected from parents and a 10-minute face-to-face interaction with the infant was filmed. Interactions were micro-coded for parent-child contact, social signals, and social- versus-object focused play. Proportions and lag-sequential patterns of social behaviors were computed. Mothers provided more affectionate contact, while fathers provided more stimulatory contact. Parents with high OT levels displayed significantly more affectionate contact compared to parents with low OT and constructed the interaction towards readiness for social engagement by increasing social salience in response to infant social gaze. In contrast, parents with high AVP engaged in stimulatory contact and tended to increase object-salience when infants showed bids for social engagement. OT levels were independently predicted by the amount of affectionate contact and the durations of gaze synchrony, whereas AVP levels were predicted by stimulatory contact, joint attention to objects, and the parent increasing object salience following infant social gaze. Results further specify how synchronous bio-behavioral processes with mother and father support the human infant's entry into the family unit and prepare the child for joining the larger social world.This article is part of a Special Issue entitled Oxytocin and Social Behav.

Cocaine withdrawal influences paternal behavior and associated central expression of vasopressin, oxytocin and tyrosine hydroxylase in mandarin voles

Although the disruptive effects of cocaine on the maternal care are well known, little is known about paternal care in the context of cocaine abuse. Vasopressin (AVP), oxytocin (OT) and dopamine (DA) have been found to regulate paternal behavior and are also involved in cocaine abuse. Mandarin voles (Microtus mandarinus) are socially monogamous and display high levels of paternal care. Here, we investigated whether paternal behavior and associated central levels of AVP, OT and DA were altered following 24h of withdrawal from 4day administration of 20mg/kg/day cocaine. Our data shows that vole fathers did not experience altered levels of locomotion during an open field test. However, compared to controls, cocaine attenuated licking/grooming and contact behavior and shortened the latency to crouching, contact and pup retrieval. Last, fewer AVP and OT immunoreactive neurons in the paraventricular nucleus and more tyrosine hydroxylase immunoreactive neurons in the ventral tegmental area were observed in cocaine-treated fathers. These results indicate that cocaine withdrawal disturbs the expression of partial paternal behavior by altering central levels of AVP, OT and DA.

Congestive heart failure in rats is associated with increased collecting duct vasopressin sensitivity and vasopressin type 2 receptor reexternalization

A number of studies have shown that rats with congestive heart failure (CHF) have increased protein levels of the vasopressin (AVP)-regulated water channel aquaporin-2 (AQP2) even during conditions with unchanged circulating levels of AVP, suggesting an increase in the sensitivity of the AVP type 2 (V2) receptor in experimental CHF. The present study was aimed at investigating AVP signaling in rats with moderate CHF (left ventricular end diastolic pressure >10 mmHg; normal plasma AVP levels) induced by ligation of the left anterior descending coronary artery. Sham-operated rats were used as controls. Western blotting analyses revealed an increased abundance of AQP2 in renal cortex (+33 ± 9% of sham; P < 0.05) and in inner medulla (IM) (+54 ± 15% of sham; P < 0.05) in CHF rats compared with sham-operated controls. Dose-response studies on isolated collecting ducts (CDs) showed an increased accumulation of cAMP in response to AVP in CHF rats compared with controls. V2 receptor surface-binding studies in isolated IMCDs showed a marked and comparable AVP-induced V2 receptor internalization in response to AVP in both CHF and control rats. As expected V2 receptor surface binding remained low after AVP challenge in control rats. In contrast to this, V2 receptor surface binding returned to pre-AVP levels within 30 min in the CHF rats, indicating an obtained recycling ability of the V2 receptor in CHF. Together the results indicate the presence of an increased AVP sensitivity in the CDs from CHF rats, associated with an acquired recycling ability of the V2 receptor.

Renal Damage after Myocardial Infarction is Prevented by Linagliptin, a Dipeptidyl Peptidase Inhibitor, for Cardio-renal Protection

with heart failure (HF). Forty-six ambulatory patients with HF were enrolled in this study. We analyzed the associations between cardiovascular events during 6 months follow-up and baseline clinical characteristics. We divided study patients into two groups; patients with loop diuretics therapy (n527) and those without (n519). Event-free rate of patients with loop diuretics was significantly lower than those without (70.4% vs. 94.7%, p ! 0.05). Multivariate regression analysis revealed that creatine clearance (CCr) was independently associated with poor prognosis. (HR: 0.895, 95%CI: 0.818-0.980, p 5 0.017). In patients with loop diuretics, cortical collecting duct flow rate (CCDFR) was significantly increased (1.7 6 0.5% vs. 2.0 6 0.5%, p!0.05) and the free water retention had a stronger correlation with plasma AVP level (r 5 0.402, p ! 0.05 vs. NS) compared with those in patients without loop diuretics. We also revealed that CCDFR was the significant associated factor with adverse events. (HR: 5.366, 95%CI: 1.090-26.418, p 5 0.039). In conclusion, renal dysfunction is a strong associated factor with poor prognosis. Loop diuretics increase CCDFR and develop the sensitivity to AVP. Those renal functional changes induced may play an important role in diuretic resistance.

Abstract 261: Relationship of Arginine Vasopressin and Blood Pressure in Patients with Orthostatic Intolerance and Nausea

Children with chronic unexplained nausea have a high incidence of cardiovascular instability (~ 75%) manifesting as orthostatic intolerance (OI), with exaggerated suppression of baroreflexes upon standing. Because vasopressin (AVP) causes nausea and may be triggered by a fall in blood pressure (BP), we aimed to determine the relationship between AVP and tilt-induced changes in BP in children with OI. Forty-eight patients (mean age [range] of 15.2 [10-18] years) (36 females, 12 males) underwent tilt table testing for symptoms of OI and nausea. Subjects were maintained supine for 15 min before 45 min upright tilt (from 0 to 70 degrees). Plasma AVP was measured in blood sampled immediately before and 15 min into upright tilt. Of the 48 tilt tests: 9 were normal and 39 abnormal. Abnormal tests were classified as: postural orthostatic tachycardia syndrome (POTS, heart rate &gt;120 bpm or increase by 30 bpm during first 10 min of tilt; n = 15), neutrally mediated hypotension (NMH, decrease in systolic BP [SBP] &gt;25 mmHg during first 10 min of tilt; n = 2), and neurocardiogenic syncope (NCS, hypotension followed by syncope; n = 22). Mean supine SBP of normal subjects was 129 ± 9 mmHg and diastolic BP [DBP] was 64 ± 3 mm Hg (mean ± SEM). There were no differences in supine BPs among groups. Supine AVP levels were 4 ± 2 and 2 ± 1 in abnormal vs normal subjects (p = NS) There was a positive correlation between SBP and AVP in the supine position before tilt (0.34, p = 0.02). AVP increased by 44 ± 13 pg/mL vs. 1 ± 1 pg/mL for subjects with abnormal vs. normal tilt tests (p = 0.002), by 43 ± 17 pg/mL for NCS alone vs. normal (p = 0.02), and by 37 ± 20 pg/mL for POTS vs. normal (p = NS). There was a negative correlation between AVP and both SBP and DBP during tilt (-0.3, p = 0.035 and -0.4, p = 0.005, respectively). Hypotension and syncope upon tilt are associated with acute increases in AVP in subjects with OI and nausea. The increase in AVP may serve as a compensatory mechanism in the face of impaired autonomic reflexes. It is not known whether the increase in AVP contributes to the nausea observed during tilt, but better understanding of this relationship may allow for more effective treatment options for the management of nausea in these subjects.

Oxytocin in the Central Amygdaloid Nucleus Modulates the Neuroendocrine Responses Induced by Hypertonic Volume Expansion in the Rat

The present study investigated the involvement of the oxytocinergic neurones that project into the central amygdala (CeA) in the control of electrolyte excretion and hormone secretion in unanaesthetised rats subjected to acute hypertonic blood volume expansion (BVE; 0.3 M NaCl, 2 ml/100 g of body weight over 1 min). Oxytocin and vasopressin mRNA expression in the paraventricular (Pa) and supraoptic nucleus (SON) of the hypothalamus were also determined using the real time-polymerase chain reaction and in situ hybridisation. Male Wistar rats with unilaterally implanted stainless steel cannulas in the CeA were used. Oxytocin (1 μg/0.2 μl), vasotocin, an oxytocin antagonist (1 μg/0.2 μl) or vehicle was injected into the CeA 20 min before the BVE. In rats treated with vehicle in the CeA, hypertonic BVE increased urinary volume, sodium excretion, plasma oxytocin (OT), vasopressin (AVP) and atrial natriuretic peptide (ANP) levels and also increased the expression of OT and AVP mRNA in the Pa and SON. In rats pre-treated with OT in the CeA, previously to the hypertonic BVE, there were further significant increases in plasma AVP, OT and ANP levels, urinary sodium and urine output, as well as in gene expression (AVP and OT mRNA) in the Pa and SON compared to BVE alone. Vasotocin reduced sodium, urine output and ANP levels, although no changes were observed in plasma AVP and OT levels or in the expression of the AVP and OT genes in both hypothalamic nuclei. The results of the present study suggest that oxytocin in the CeA exerts a facilitatory role in the maintenance of hydroelectrolyte balance in response to changes in extracellular volume and osmolality.

Cleaved caspase-3 expression in hypothalamic magnocellular neurons may affect vasopressin secretion during experimental polymicrobial sepsis

We investigated whether the vasopressin (AVP) secretion deficiency observed during cecal ligation and puncture (CLP)-induced sepsis may be caused by apoptosis in hypothalamic magnocellular neurons. Plasma cytokines (TNF-α, IL-1β and IL-6) and nitrate levels were increased during sepsis and plasma AVP levels were higher in the early phase returning to basal levels in the late phase. Concomitantly, expression of the apoptosis effector, cleaved caspase 3, was increased in magnocellular neurons, inferring that this increase in hypothalamic neurons may be caused by cytokines and elevated nitrate levels. This in turn could compromise AVP secretion in the late phase of sepsis.

Neonatal tactile stimulation alleviates the negative effects of neonatal isolation on novel object recognition, sociability and neuroendocrine levels in male adult mandarin voles (Microtus mandarinus)

Neonatal isolation results in long-lasting negative alterations to the brain and behavior. Some of these changes include effects on non-spatial learning and memory, sociability and neuroendocrine levels. Theoretically, neonatal tactile stimulation should reverse the impacts of neonatal isolation; however, this remains unknown for changes relating to learning, memory, sociability and hormones in social animals. Using socially monogamous mandarin voles (Microtus mandarinus), the long-lasting effects of these early manipulations on anxiety-like behavior, novel object recognition, sociability, and neuroendocrine levels were investigated. Compared with neonatal-isolated males, males subjected to the same manipulation but accompanied with tactile stimulation had heavier body weights across PND4-18 and displayed significantly less anxiety-like behavior in an open field test. In addition, tactile stimulation increased the preference index for novel object recognition reduced by neonatal isolation. Compared with control males, neonatal-isolated males engaged in less body contact with unfamiliar same-sex individuals and this effect was reversed by neonatal tactile stimulation. Tactile stimulation enhanced aggressive behavior in neonatal-isolated males and increased the levels of AVP and OT in the paraventricular nucleus (PVN) which were decreased by neonatal isolation. This early manipulation also reduced serum CORT levels that were significantly up-regulated by neonatal isolation in both neonatal and adult offspring. These results indicate that adequate tactile stimulation in early life plays an important role in the prevention of behavioral disturbances induced by neonatal isolation, possibly through the alteration of central OT, AVP and the serum corticosterone levels.

Late‐onset familial neurohypophyseal diabetes insipidus due to a novel mutation in the AVP gene

Familial neurohypophyseal diabetes insipidus (FNDI) is mainly an autosomal dominant inherited disorder presenting with severe polydipsia and polyuria in early childhood. In this study, we aimed to determine the molecular genetics and clinical characteristics of a large Swedish-Norwegian family presenting with very late-onset autosomal dominant FNDI. Six probands with a history of developing polyuria and polydipsia during adolescence were studied. Information on family demography was collected by personal interview with family members. The genetic cause of FNDI was identified by DNA sequencing analysis of the coding regions of the AVP gene. The clinical characteristics were determined by the measurement of basal urine production and osmolality as well as by measurements of concurrent levels of plasma AVP, plasma osmolality, and urine osmolality during fluid deprivation and bolus injection of DDAVP. The integrity of the neurohypophysis was evaluated by magnetic resonance imaging. The mean age of encountering the first clinical symptoms in the family was 14·8 years (range 3-30 years) (n = 17). All six affected subjects investigated were heterozygous for a novel mutation in the AVP gene (g.1848C>T) predicting a p.Pro84Leu substitution in the AVP precursor protein. We found partial deficiency in evoked AVP secretion during fluid deprivation in one subject and complete deficiency in another. The pituitary bright spot was absent in all six affected subjects studied. A novel mutation in the AVP gene predicted to cause a neurophysin II dimerization defect is causing surprisingly late onset of FNDI in a large, six generation, Swedish-Norwegian family. The mutation is associated with both complete and partial deficiency in evoked AVP secretion during fluid deprivation in patients who have suffered from FNDI for decades.

Abstract 213: Neuron-specific (Pro)renin Receptor Deletion Attenuates Neurogenic Hypertension and is Associated With Improvement of Autonomic Function

Although (pro)renin receptor (PRR) is highly expressed in the brain, the physiological importance of brain PRR remains to be determined. We previously showed that PRR mRNA levels were up-regulated in the brain regions involved in blood pressure (BP) regulation including the subfornical organs (SFO), paraventricular nuclei (PVN), and rostral ventrolateral medulla (RVLM) in the DOCA-salt-induced hypertensive mice. To elucidate whether the increase of PRR expression contributes to the development of hypertension, we developed a neuron-specific PRR knockout mouse (Nefh-PRR) model by crossing PRR-floxed mice with mice that express Cre-recombinase with neurofilament-H (Nefh-Cre) promoter. Immunostaining showed that PRR expression was significantly reduced in cardiac regulatory brain regions including SFO (0.35± 0.15), PVN (0.34 ± 0.09), and RVLM (0.41 ± 0.1), where the Cre-recombinase was expressed, in Nefh-PRR compared to Nefh-cre mice (1 ± 0.1, 1 ± 0.19 and 1 ± 0.06). Nefh-PRR mice and Nefh-cre mice with wild type PRR gene (WT, n=8/group) were implanted with telemetric probes. BP (mmHg) and heart rate (HR, bpm) were recorded for baseline and following DOCA-salt treatment (50mg DOCA, 0.9%NaCl drinking solution, 21 days). Nefh-PRR mice exhibited normal baseline BP and HR. Following DOCA-salt treatment, BP was significantly lower in Nefh-PRR mice (108 ± 3) compared to WT mice (132 ± 6, P&lt;0.05). The cardiac sympathetic tone (HR response to propranolol, ΔHR: -128±46vs. -180±45) and the vasomotor sympathetic tone (BP response to chlorisondamine, ΔBP: -46 ±17vs.-68± 12) were lower in Nefh-PRR than WT mice after DOCA-salt treatment. Moreover, HR response to methylatropine (ΔHR: 98±38 vs. 43±19) was greater in Nefh-PRR. In addition, DOCA-salt treatment increased plasma vasopressin (AVP) levels (33.6 ± 5.3 vs.3.0 ± 0.3pg/ml) in WT mice. PRR deletion significantly attenuated the increase in plasma AVP levels (19.0 ± 2.0pg/ml) induced by DOCA-salt. The data suggest PRR deletion prevents the development of DOCA-salt hypertension and is associated with reduction of plasma AVP levels and improvement of autonomic function. We conclude that brain PRR may be a novel therapeutic target for the treatment of hypertension.

Chronic Administration of Oral Vasopressin Type 2 Receptor Antagonist Tolvaptan Exerts Both Myocardial and Renal Protective Effects in Rats With Hypertensive Heart Failure

Although recent clinical trials have demonstrated the efficacy of the oral vasopressin (AVP) type 2 receptor (V2R) antagonist tolvaptan, its long-term effects on the myocardium and kidney in heart failure (HF) are not clear. We examined the chronic effects of tolvaptan administration on both the myocardium and kidney in a rat hypertensive HF model. Not only circulating AVP level but also myocardial AVP and V1a receptor (V1aR) expressions, renal V1aR, and V2R expressions were significantly upregulated during the transition to HF. The animals were chronically treated with low-dose or high-dose (HD) tolvaptan or vehicle from the left ventricular (LV) hypertrophic stage. Chronic tolvaptan treatment persistently increased urine volume but did not affect blood pressure. In the HD group, the animal survival significantly improved (log-rank test, P<0.01). At the HF stage, the progression of LV dysfunction was prevented and lung congestion was suppressed. Activation of atrial natriuretic peptide, endothelin-1, AVP, and V1aR mRNA levels were significantly suppressed in the LV myocardium. Meanwhile, renal histopathologic damage was ameliorated and renal function was improved in the HD group at the HF stage. Concomitantly, not only activation of aquaporin-2 but also those of V2R, V1aR, renin, and endothelin-1 in the kidney were significantly suppressed (all P<0.05). These results indicate that chronic tolvaptan treatment has beneficial effects by preventing not only the progression of LV dysfunction but also that of renal injury in hypertensive rats with HF. The underlying mechanism may be related to the suppression of myocardial and renal neurohumoral activation.

Defective renal water handling in transgenic mice over-expressing human CD39/NTPDase1

Ectonucleoside triphosphate diphosphohydrolase-1 hydrolyzes extracellular ATP and ADP to AMP. Previously, we showed that CD39 is expressed at several sites within the kidney and thus may impact the availability of type 2 purinergic receptor (P2-R) ligands. Because P2-Rs appear to regulate urinary concentrating ability, we have evaluated renal water handling in transgenic mice (TG) globally overexpressing hCD39. Under basal conditions, TG mice exhibited significantly impaired urinary concentration and decreased protein abundance of AQP2 in the kidney compared with wild-type (WT) mice. Urinary excretion of total nitrates/nitrites was significantly higher in TG mice, but the excretion of AVP or PGE(2) was equivalent to control WT mice. There were no significant differences in electrolyte-free water clearance or fractional excretion of sodium. Under stable hydrated conditions (gelled diet feeding), the differences between the WT and TG mice were negated, but the decrease in urine osmolality persisted. When water deprived, TG mice failed to adequately concentrate urine and exhibited impaired AVP responses. However, the increases in urinary osmolalities in response to subacute dDAVP or chronic AVP treatment were similar in TG and WT mice. These observations suggest that TG mice have impaired urinary concentrating ability despite normal AVP levels. We also note impaired AVP release in response to water deprivation but that TG kidneys are responsive to exogenous dDAVP or AVP. We infer that heightened nucleotide scavenging by increased levels of CD39 altered the release of endogenous AVP in response to dehydration. We propose that ectonucleotidases and modulated purinergic signaling impact urinary concentration and indicate potential utility of targeted therapy for the treatment of water balance disorders.

Differential hypothalamic secretion of neurocrines in male common marmosets: parental experience effects?

Pregnancy and lactation produce a plethora of hormonal changes in females that promote maternal care of offspring. Males in the biparental marmoset species (Callithrix jacchus) demonstrate high levels of parenting behaviour and express enhanced circulating reproductive hormones. Furthermore, these hormonal changes are influenced by paternal experience. To determine whether the paternally experienced male marmoset has altered neurocrine hypothalamic release, as the maternal females does, we examined the release of several reproductive neurocrines, dopamine (DA), oxytocin (OT), vasopressin (AVP) and prolactin (PRL), in cultured explants of the hypothalamus of paternally experienced male marmosets compared to naïve, paternally inexperienced males. DA levels secreted from the isolated hypothalamus were significantly lower in the experienced males, whereas OT and PRL levels were significantly higher than levels found in inexperienced males. PRL levels decreased rapidly in the hypothalamic media, suggesting that PRL production occurs elsewhere. AVP levels did not change. Stimulation of the cultured explants with oestradiol significantly decreased DA levels in the inexperienced males but did not alter the other neurocrines, suggesting a direct effect of oestradiol on DA suppression in the hypothalamus. Although other factors such as age and rearing experience with siblings may play a role in hypothalamic neurocrine levels, these results demonstrate that paternal experience may impact upon the secretion of neurocrines in a male biparental primate.

Persistent elevation of urine aquaporin-2 during water loading in a child with nephrogenic syndrome of inappropriate antidiuresis (NSIAD) caused by a R137L mutation in the V2 vasopressin receptor

Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) is a novel disease caused by a gain-of-function mutation in the V2 vasopressin receptor (V2R), which results in water overload and hyponatremia. We report the effect of water loading in a 3-year old boy with NSIAD, diagnosed in infancy, to assess urine aquaporin-2 (AQP2) excretion as a marker for V2R activation, and to evaluate the progression of the disease since diagnosis. The patient is one of the first known NSIAD patients and the only patient with a R137L mutation. Patient underwent a standard water loading test in which serum and urine sodium and osmolality, serum AVP, and urine AQP2 excretion were measured. The patient was also evaluated for ad lib fluid intake before and after the test. This patient demonstrated persistent inability to excrete free water. Only 39% of the water load (20 ml/kg) was excreted during a 4-hour period (normal ≥ 80-90%). Concurrently, the patient developed hyponatremia and serum hypoosmolality. Serum AVP levels were detectable at baseline and decreased one hour after water loading; however, urine AQP2 levels were elevated and did not suppress normally during the water load. The patient remained eunatremic but relatively hypodipsic during ad lib intake. In conclusion, this is the first demonstration in a patient with NSIAD caused by a R137L mutation in the V2R that urine AQP2 excretion is inappropriately elevated and does not suppress normally with water loading. In addition, this is the first longitudinal report of a pediatric patient with NSIAD diagnosed in infancy who demonstrates the ability to maintain eunatremia during ad lib dietary intake.

GIP-Dependent Expression of Hypothalamic Genes

GIP (glucose dependent insulinotrophic polypeptide), originally identified as an incretin peptide synthesized in the gut, has recently been identified, along with its receptors (GIPR), in the brain. Our objective was to investigate the role of GIP in hypothalamic gene expression of biomarkers linked to regulating energy balance and feeding behavior related neurocircuitry. Rats with lateral cerebroventricular cannulas were administered 10 μg GIP or 10 microl artificial cerebrospinal fluid (aCSF) daily for 4 days, after which whole hypothalami were collected. Real time Taqman™ RT-PCR was used to quantitatively compare the mRNA expression levels of a set of genes in the hypothalamus. Administration of GIP resulted in up-regulation of hypothalamic mRNA levels of AVP (46.9±4.5 %), CART (25.9±2.7 %), CREB1 (38.5±4.5 %), GABRD (67.1±11 %), JAK2 (22.1±3.6 %), MAPK1 (33.8±7.8 %), NPY (25.3±5.3 %), OXT (49.1±5.1 %), STAT3 (21.6±3.8 %), and TH (33.9±8.5 %). In a second experiment the same set of genes was evaluated in GIPR(-/-) and GIPR(+/?) mice to determine the effect of lack of GIP stimulation on gene expression. In GIPR(-/-) mice expressions of the following genes were down-regulated: AVP (27.1±7.5 %), CART (28.3±3.7 %), OXT (25.2±5.8 %), PTGES (23.9±4.5 %), and STAT3 (8.8±2.3 %). These results suggest that AVP, CART, OXT and STAT3 may be involved in energy balance-related hypothalamic circuits affected by GIP.

Abstract 8563: Chronic Administration of Oral Vasopressin Type 2 Receptor Blocker, Tolvaptan Exerts Both Myocardial And Renal Protective Effects in Rats with Hypertensive Heart Failure

Background: During the diuretic therapy in heart failure (HF), the greatest concerns include additional activation of the neurohormonal cascade and renal injury. Although the recent clinical trials have shown the efficacy of the oral vasopressin (AVP) type 2 receptors (V2R) blocker, tolvaptan, the long-term effects on the myocardium and kidney in HF patients are not clear. Therefore, we tested chronic tolvaptan administration in rat hypertensive HF model and examined the chronic effects both on myocardium and kidney. Methods and Results: Dahl salt-sensitive hypertensive rats were given 8% high salt diet from 6 weeks of age. Not only circulating AVP level, but also myocardial AVP and V1a receptor (V1aR) expressions, and renal V1aR, V2R and aquaporin 2 (AQP2) expressions were significantly activated during the transition to HF (18-21 weeks of age). They were chronically treated with tolvaptan (30mg/kg/day) (Tolv group: n=21) or vehicle (n=22) from the LV hypertrophic stage (11 weeks of age) until 21 weeks. Chronic tolvaptan treatment persistently increased urine volume (94% increase) and decreased urine osmolality (43% decrease). Although there was no difference in blood pressure between the two groups, the survival rate in Tolv group was improved at 21 weeks of age from 45.5% to 81.0% (log rank test: p&lt;0.01). At HF stage, LV fractional shortening was preserved (40.2% vs. 27.5%; p&lt;0.05) and lung congestion was suppressed in Tolv group. Serum AVP level and plasma renin activity were not changed and mRNA levels of ANP, endothelin-1 (ET-1), AVP and V1aR in LV were significantly decreased in Tolv group. In contrast, renal histopathologic damage (glomerulosclerosis and tubulointerstitial fibrosis) was ameliorated, and renal function (creatinine clearance and sodium excretion) was improved in Tolv group at HF stage. Concomitantly, not only activation of AQP2, but also those of V2R, V1aR and ET-1 in kidney were significantly suppressed (p &lt;0.05 in all). Conclusions: These results indicate chronic tolvaptan treatment has beneficial effects by preventing the progressions of both LV dysfunction and renal injury in hypertensive rats with HF. The underlying mechanism may be related to the prevention of local (myocardial and renal) neurohumoral activation.