Characterization of a functional V1B vasopressin receptor in the male rat kidney: evidence for cross talk between V1B and V2 receptor signaling pathways.

Although vasopressin V1B receptor (V1BR) mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using the selective V1B agonist d[Leu4, Lys8]VP, either fluorescent or radioactive, we showed that V1BR is mainly present in principal cells of the inner medullary collecting duct (IMCD) in the male rat kidney. Protein and mRNA expression of V1BR were very low compared with the V2 receptor (V2R). On the microdissected IMCD, d[Leu4, Lys8]VP had no effect on cAMP production but induced a dose-dependent and saturable intracellular Ca2+ concentration increase mobilization with an EC50 value in the nanomolar range. This effect involved both intracellular Ca2+ mobilization and extracellular Ca2+ influx. The selective V1B antagonist SSR149415 strongly reduced the ability of vasopressin to increase intracellular Ca2+ concentration but also cAMP, suggesting a cooperation between V1BR and V2R in IMCD cells expressing both receptors. This cooperation arises from a cross talk between second messenger cascade involving PKC rather than receptor heterodimerization, as supported by potentiation of arginine vasopressin-stimulated cAMP production in human embryonic kidney-293 cells coexpressing the two receptor isoforms and negative results obtained by bioluminescence resonance energy transfer experiments. In vivo, only acute administration of high doses of V1B agonist triggered significant diuretic effects, in contrast with injection of selective V2 agonist. This study brings new data on the localization and signaling pathways of V1BR in the kidney, highlights a cross talk between V1BR and V2R in the IMCD, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.NEW & NOTEWORTHY Although V1BR mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using original pharmaceutical tools, this study brings new data on the localization and signaling pathways of V1BR, highlights a cross talk between V1BR and V2 receptor (V2R) in the inner medullary collecting duct, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.

Vasopressin V1B Receptor Antagonists as Potential Antidepressants.

Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP) is one of the primary factors in HPA axis regulation under stress situations, and AVP and its receptor subtype (V1B receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V1B receptor antagonists have been synthesized, and the efficacies of some V1B receptor antagonists have been investigated in both animals and humans. V1B receptor antagonists exert antidepressant-like effects in several animal models at doses that attenuate the hyperactivity of the HPA axis, and some of their detailed mechanisms have been delineated. These results obtained in animal models were, at least partly, reproduced in clinical trials. At least 2 V1B receptor antagonists (TS-121 and ABT-436) showed tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V1B receptor. Importantly, TS-121 showed a clearer efficacy for patients with higher basal cortisol levels than for those with lower basal cortisol levels, which was consistent with the hypothesis that V1B receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V1B receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.

Vasopressin antagonism in heart failure: a review of the hemodynamic studies and major clinical trials.

For decades, plasma arginine vasopressin (AVP) levels have been known to be elevated in patients with congestive heart failure (HF). Excessive AVP signaling at either or both the V1a and V2 receptors could contribute to the pathophysiology of HF by several mechanisms. V1a activation could cause vasoconstriction and/or direct myocardial hypertrophy as intracellular signaling pathways are closely related to those for angiotensin II. V2 activation could cause fluid retention and hyponatremia. A hemodynamic study with the pure V2 antagonist tolvaptan (TV) showed minimal hemodynamic effects. Compared with furosemide in another study, the renal and neurohormonal effects of TV were favorable. Several clinical trials with TV as adjunctive therapy in acute HF have shown beneficial effects on fluid balance and dyspnea, with no worsening of renal function or neurohormonal stimulation. Two smaller studies, one in acute and one in chronic HF, have shown comparable clinical and more favorable renal and neurohormonal effects of TV compared with loop diuretics. However, long-term treatment with TV did not alter outcomes in acute HF. No data are available other than single-dose studies of an intravenous pure V1a antagonist, which showed a vasodilating effect if plasma AVP levels were elevated. One hemodynamic study and one short-duration clinical trial with the balanced intravenous V1a/V2 antagonist conivaptan (CV) showed hemodynamic and clinical effects largely similar to those with TV in similar studies. A new orally effective balanced V1/V2 antagonist (pecavaptan) is currently undergoing phase II study as both adjunctive and alternative therapy during and after hospitalization for acute HF. The purpose of this review is to summarize what we have learned from the clinical experience with TV and CV, and to suggest implications of these findings for future work with newer agents.

An Angiotensin-Responsive Connection from the Lamina Terminalis to the Paraventricular Nucleus of the Hypothalamus Evokes Vasopressin Secretion to Increase Blood Pressure in Mice.

Blood pressure is controlled by endocrine, autonomic, and behavioral responses that maintain blood volume and perfusion pressure at levels optimal for survival. Although it is clear that central angiotensin type 1a receptors (AT1aR; encoded by the Agtr1a gene) influence these processes, the neuronal circuits mediating these effects are incompletely understood. The present studies characterize the structure and function of AT1aR neurons in the lamina terminalis (containing the median preoptic nucleus and organum vasculosum of the lamina terminalis), thereby evaluating their roles in blood pressure control. Using male Agtr1a-Cre mice, neuroanatomical studies reveal that AT1aR neurons in the area are largely glutamatergic and send projections to the paraventricular nucleus of the hypothalamus (PVN) that appear to synapse onto vasopressin-synthesizing neurons. To evaluate the functionality of these lamina terminalis AT1aR neurons, we virally delivered light-sensitive opsins and then optogenetically excited or inhibited the neurons while evaluating cardiovascular parameters or fluid intake. Optogenetic excitation robustly elevated blood pressure, water intake, and sodium intake, while optogenetic inhibition produced the opposite effects. Intriguingly, optogenetic excitation of these AT1aR neurons of the lamina terminalis also resulted in Fos induction in vasopressin neurons within the PVN and supraoptic nucleus. Further, within the PVN, selective optogenetic stimulation of afferents that arise from these lamina terminalis AT1aR neurons induced glutamate release onto magnocellular neurons and was sufficient to increase blood pressure. These cardiovascular effects were attenuated by systemic pretreatment with a vasopressin-1a-receptor antagonist. Collectively, these data indicate that excitation of lamina terminalis AT1aR neurons induces neuroendocrine and behavioral responses that increase blood pressure.SIGNIFICANCE STATEMENT Hypertension is a widespread health problem and risk factor for cardiovascular disease. Although treatments exist, a substantial percentage of patients suffer from "drug-resistant" hypertension, a condition associated with increased activation of brain angiotensin receptors, enhanced sympathetic nervous system activity, and elevated vasopressin levels. The present study highlights a role for angiotensin Type 1a receptor expressing neurons located within the lamina terminalis in regulating endocrine and behavioral responses that are involved in maintaining cardiovascular homeostasis. More specifically, data presented here reveal functional excitatory connections between angiotensin-sensitive neurons in the lamina terminals and vasopressin neurons in the paraventricular nucleus of the hypothalamus, and further indicate that activation of this circuit raises blood pressure. These neurons may be a promising target for antihypertensive therapeutics.

V1a and V1b vasopressin receptors within the paraventricular nucleus contribute to hypertension in male rats exposed to chronic mild unpredictable stress.

Depression is an independent nontraditional risk factor for cardiovascular disease and mortality. The chronic unpredictable mild stress (CMS) rat model is a validated model of depression. Within the paraventricular nucleus (PVN), vasopressin (VP) via V1aR and V1bR have been implicated in stress and neurocardiovascular dysregulation. We hypothesized that in conscious, unrestrained CMS rats versus control, unstressed rats, PVN VP results in elevated arterial pressure (MAP), heart rate, and renal sympathetic nerve activity (RSNA) via activation of V1aR and/or V1bR. Male rats underwent 4 wk of CMS or control conditions. They were then equipped with hemodynamic telemetry transmitters, PVN cannula, and left renal nerve electrode. V1aR or V1bR antagonism dose-dependently inhibited MAP after VP injection. V1aR or V1bR blockers at their ED50 doses did not alter baseline parameters in either control or CMS rats but attenuated the pressor response to VP microinjected into PVN by ∼50%. Combined V1aR and V1bR inhibition completely blocked the pressor response to PVN VP in control but not CMS rats. CMS rats required combined maximally inhibitory doses to block either endogenous VP within the PVN or responses to microinjected VP. Compared with unstressed control rats, CMS rats had higher plasma VP levels and greater abundance of V1aR and V1bR transcripts within PVN. Thus, the CMS rat model of depression results in higher resting MAP, heart rate, and RSNA, which can be mitigated by inhibiting vasopressinergic mechanisms involving both V1aR and V1bR within the PVN. Circulating VP may also play a role in the pressor response.

Sex-Specific Vasopressin Signaling Buffers Stress-Dependent Synaptic Changes in Female Mice.

In many species, social networks provide benefit for both the individual and the collective. In addition to transmitting information to others, social networks provide an emotional buffer for distressed individuals. Our understanding about the cellular mechanisms that contribute to buffering is poor. Stress has consequences for the entire organism, including a robust change in synaptic plasticity at glutamate synapses onto corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN). In females, however, this stress-induced metaplasticity is buffered by the presence of a naive partner. This buffering may be because of discrete behavioral interactions, signals in the context in which the interaction occurs (i.e., olfactory cues), or it may be influenced by local signaling events in the PVN. Here, we show that local vasopressin (VP) signaling in PVN buffers the short-term potentiation (STP) at glutamate synapses after stress. This social buffering of metaplasticity, which requires the presence of another individual, was prevented by pharmacological inhibition of the VP 1a receptor (V1aR) in female mice. Exogenous VP mimicked the effects of social buffering and reduced STP in CRHPVN neurons from females but not males. These findings implicate VP as a potential mediator of social buffering in female mice.SIGNIFICANCE STATEMENT In many organisms, including rodents and humans, social groups are beneficial to overall health and well-being. Moreover, it is through these social interactions that the harmful effects of stress can be mitigated, a phenomenon known as social buffering. In the present study, we describe a critical role for the neuropeptide vasopressin (VP) in social buffering of synaptic metaplasticity in stress-responsive corticotropin-releasing hormone (CRH) neurons in female mice. These effects of VP do not extend to social buffering of stress behaviors, suggesting this is a very precise and local form of sex-specific neuropeptide signaling.

Protective effect of tolvaptan against cyclophosphamide-induced nephrotoxicity in rat models.

Cyclophosphamide (CP) is a chemotherapeutic agent which is extensively used in the treatment of multiple neoplastic and nonneoplastic diseases like breast cancer, lymphomas, systemic lupus erythematosus, and multiple sclerosis. Dose-limiting side effects, mainly nephrotoxicity is a major problem hindering its use in the clinical practice. CP induces nephrogenic syndrome of inappropriate antidiuresis mostly via the activation of arginine vasopressin V2 receptors. Moreover, CP produces reactive metabolites which is responsible for augmentation of lipid peroxidation and oxidative stress. Tolvaptan (TOL) is a selective vasopressin V2 receptor antagonist used in the treatment of clinically significant hyponatremia, volume overload in heart failure, and liver cirrhosis with edema. The present study aimed to investigate the potential protective effect of TOL in CP-induced nephrotoxicity. Twenty-four adult male albino rats were randomly divided into four groups: the control group, TOL group that treated daily with tolvaptan (10 mg/kg/d, orally), CP group where CP was administered intraperitoneally 75 mg/kg on days 3, 4, 5, 19, 20, and 21 of study, and the CP + TOL group where animals were treated with TOL daily with (10 mg/kg/d, orally) for 22 days with concomitant administration of CP as described before. Coadministration of TOL with CP induces significant improvement in the level of urine volume, serum Na+, serum osmolarity, urinary creatinine, and free water clearance in addition to significant reduction of body weight, serum creatinine, urea, serum K+, blood pressure, urine osmolarity, and the fractional excretion of sodium as compared to CP-treated group. In addition, coadministration of TOL significantly reduced MDA, the marker of lipid peroxidation, and different pro-inflammatory cytokines. Histopathological changes showed improvement in the signs of nephrotoxicity with the coadministration of TOL. Also, co-treatment with TOL significantly decreased the level of markers of apoptosis as caspase-3 and Bax with increased expression of antiapoptotic Bcl-2 in renal tissue as compared to CP-treated group.

Electrolyte handling in the isolated perfused rat kidney: demonstration of vasopressin V2-receptor-dependent calcium reabsorption.

BACKGROUND: The most profound effect of vasopressin on the kidney is to increase water reabsorption through V2-receptor (V2R) stimulation, but there are also data suggesting effects on calcium transport. To address this issue, we have established an isolated perfused kidney model with accurate pressure control, to directly study the effects of V2R stimulation on kidney function, isolated from systemic effects. METHODS: The role of V2R in renal calcium handling was studied in isolated rat kidneys using a new pressure control system that uses a calibration curve to compensate for the internal pressure drop up to the tip of the perfusion cannula. RESULTS: Kidneys subjected to V2R stimulation using desmopressin (DDAVP) displayed stable osmolality and calcium reabsorption throughout the experiment, whereas kidneys not administered DDAVP exhibited a simultaneous fall in urine osmolality and calcium reabsorption. Epithelial sodium channel (ENaC) inhibition using amiloride resulted in a marked increase in potassium reabsorption along with decreased sodium reabsorption. CONCLUSIONS: A stable isolated perfused kidney model with computer-controlled pressure regulation was developed, which retained key physiological functions. The preparation responds to pharmacological inhibition of ENaC channels and activation of V2R. Using the model, the dynamic effects of V2R stimulation on calcium handling and urine osmolality could be visualised. The study thereby provides evidence for a stimulatory role of V2R in renal calcium reabsorption.

Osmolalidad urinaria en pacientes con poliquistosis renal: ¿medida o calculada? / Urinary osmolality in patients with polycystic kidney disease: Measured or calculated?

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Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from Conus miliaris.

Cone snails produce a fast-acting and often paralyzing venom, largely dominated by disulfide-rich conotoxins targeting ion channels. Although disulfide-poor conopeptides are usually minor components of cone snail venoms, their ability to target key membrane receptors such as GPCRs make them highly valuable as drug lead compounds. From the venom gland transcriptome of Conus miliaris, we report here on the discovery and characterization of two conopressins, which are nonapeptide ligands of the vasopressin/oxytocin receptor family. These novel sequence variants show unusual features, including a charge inversion at the critical position 8, with an aspartate instead of a highly conserved lysine or arginine residue. Both the amidated and acid C-terminal analogues were synthesized, followed by pharmacological characterization on human and zebrafish receptors and structural investigation by NMR. Whereas conopressin-M1 showed weak and only partial agonist activity at hV1bR (amidated form only) and ZFV1a1R (both amidated and acid form), both conopressin-M2 analogues acted as full agonists at the ZFV2 receptor with low micromolar affinity. Together with the NMR structures of amidated conopressins-M1, -M2 and -G, this study provides novel structure-activity relationship information that may help in the design of more selective ligands.

Effects of optogenetic stimulation of vasopressinergic retinal afferents on suprachiasmatic neurones.

Physiological circadian rhythms are orchestrated by the hypothalamic suprachiasmatic nucleus (SCN). The activity of SCN cells is synchronised by environmental signals, including light information from retinal ganglion cells (RGCs). We recently described a population of vasopressin-expressing RGCs (VP-RGC) that send axonal projections to the SCN. To determine how these VP-RGCs influence the activity of cells in the SCN, we used optogenetic tools to specifically activate their axon terminals within the SCN. Rats were intravitreally injected with a recombinant adeno-associated virus to express the channelrhodopsin-2 and the red fluorescent protein mCherry under the vasopressin promoter (VP-ChR2mCherry). In vitro recordings in acute brain slices showed that approximately 30% of ventrolateral SCN cells responded to optogenetic stimulation with an increase in firing rate that progressively increased during the first 200 seconds of stimulation and which persisted after the end of stimulation. Finally, application of a vasopressin V1A receptor antagonist dampened the response to optogenetic stimulation. Our data suggest that optogenetic stimulation of VP-RGC axons within the SCN influences the activity of SCN cells in a vasopressin-dependent manner.

Amygdala Arginine Vasopressin Modulates Chronic Ethanol Withdrawal Anxiety-Like Behavior in the Social Interaction Task.

BACKGROUND: Chronic ethanol (EtOH) exposure induces neurobehavioral maladaptations in the brain though the precise changes have not been fully explored. The central nucleus of the amygdala (CEA) regulates anxiety-like behavior induced by withdrawal from chronic intermittent EtOH (CIE) exposure, and the arginine vasopressin (AVP) system within the CEA regulates many anxiety-like behaviors. Thus, adaptations occur in the CEA AVP system due to chronic EtOH exposure, which lead to anxiety-like behaviors in rats. METHODS: Chronic exposure to a low-dose EtOH (4.5% wt/vol) induces anxiety-like behavior in rats. Wistar or Sprague Dawley rats were exposed to a modified CIE or CIE, while intra-CEA microinjections of AVP or a V1b receptor antagonist were used to elicit or block withdrawal-induced anxiety. Additionally, AVP microinjections into the CEA were given 24 hours following 15 days of continuous high-dose EtOH (7% wt/vol), a time period when rats no longer express anxiety. Chemogenetics was also used to activate the basolateral amygdala (BLA) or deactivate the dorsal periaqueductal gray=(dm/dlPAG) therefore PAG=periaqueductal gray to elicit or block withdrawal-induced anxiety. RESULTS: AVP microinjected into the CEA in lieu of exposure to the first 2 cycles of CIE was sufficient to induce anxiety-like behavior in these commonly used rat strains. The V1b receptor antagonist, but not an oxytocin receptor agonist, into the CEA during the first 2 withdrawal cycles suppressed anxiety. However, activation of the BLA in lieu of exposure to the first 2 cycles of CIE was insufficient to induce anxiety-like behavior. AVP microinjection into the CEA 24 hours into withdrawal reelicited anxiety-like behavior, and deactivation of the dm/dlPAG reduced this effect of CEA AVP. CONCLUSIONS: Taken together, this study demonstrates a role of CEA AVP and a CEA-dm/dlPAG circuit in the development of anxiety induced by CIE. Such information is valuable for identifying novel therapeutic targets for alcohol- and anxiety-associated disorders.

Arginine vasopressin attenuates dysfunction of hippocampal theta and gamma oscillations in chronic cerebral hypoperfusion via V1a receptor.

Chronic cerebral hypoperfusion (CCH) is associated with cognitive decline in aging, Alzheimer's disease and vascular dementia. Neural oscillations and their interactions support brain communication and involve in cognitive function. Although arginine vasopressin (AVP) has been linked to spatial learning and memory, the effects of AVP on CCH in terms of the hippocampal neural network is unknown. Here we investigated the dynamics of neural oscillations in the hippocampus in a rat model of permanent bilateral carotid arteries occlusion (two-vessel occlusion, 2VO) under urethane-anesthesia. Hypertonic saline (5.3%) was injected intraperitoneally to induce the endogenous AVP, and SR49059 was used as V1a receptor (an AVP receptor) antagonist. The results showed that AVP partly changed CA3 Schaffer collateral (CA3-SC) power distribution in the rat model of 2VO via V1a receptor, increased theta synchrony between CA3-SC and CA1 areas, enhanced CA3-SC theta-middle gamma phase-phase coupling, and improved spatial learning and memory performance. Biochemical fractionation further confirmed the recovery effect on N-methyl-D-aspartate receptor subunit 2B (NR2B) and postsynaptic density protein 95 (PSD-95) surface expressions after hypertonic saline injection, suggesting a possible molecular mechanism in the hippocampus. The findings shed light on a functional role of endogenous AVP from a neural network perspective that AVP improves theta synchronization and accurate coordination of theta-gamma coupling probably through upregulating NR2B and PSD-95 expressions, and further promotes neural communication in the hippocampus to some extent. As a result, the impairment of spatial learning and memory induced by CCH is significantly alleviated.

Vascular Protection and Decongestion Without Renin-Angiotensin-Aldosterone System Stimulation Mediated by a Novel Dual-Acting Vasopressin V1a/V2 Receptor Antagonist.

Increased plasma vasopressin levels have been shown to be associated with the progression of congestive heart failure. Vasopressin mediates water retention by renal tubular V2 receptor activation as well as vasoconstriction, cardiac hypertrophy, and fibrosis through V1a receptor activation. Therefore, we developed a novel, dual-acting vasopressin receptor antagonist, BAY 1753011, with almost identical Ki-values of 0.5 nM at the human V1a receptor and 0.6 nM at the human V2 receptor as determined in radioactive binding assays. Renal V2 antagonism by BAY 1753011 was compared with the loop diuretic furosemide in acute diuresis experiments in conscious rats. Similar diuretic efficacy was found with 300-mg/kg furosemide (maximal diuretic response) and 0.1-mg/kg BAY 1753011. Furosemide dose-dependently induced plasma renin and angiotensin I levels, while an equiefficient diuretic BAY 1753011 dose did not activate the renin-angiotensin system. BAY 1753011 dose-dependently decreased the vasopressin-induced expression of the profibrotic/hypertrophic marker plasminogen activator inhibitor-1 and osteopontin in rat cardiomyocytes, while the selective V2 antagonist satavaptan was without any effect. The combined vascular V1a-mediated and renal V2-mediated properties as well as the antihypertrophic/antifibrotic activity enable BAY 1753011 to become a viable treatment option for oral chronic treatment of congestive heart failure.

Vasopressin Increases Urinary Acidification via V1a Receptors in Collecting Duct Intercalated Cells.

BACKGROUND: Antagonists of the V1a vasopressin receptor (V1aR) are emerging as a strategy for slowing progression of CKD. Physiologically, V1aR signaling has been linked with acid-base homeostasis, but more detailed information is needed about renal V1aR distribution and function. METHODS: We used a new anti-V1aR antibody and high-resolution microscopy to investigate Va1R distribution in rodent and human kidneys. To investigate whether V1aR activation promotes urinary H+ secretion, we used a V1aR agonist or antagonist to evaluate V1aR function in vasopressin-deficient Brattleboro rats, bladder-catheterized mice, isolated collecting ducts, and cultured inner medullary collecting duct (IMCD) cells. RESULTS: Localization of V1aR in rodent and human kidneys produced a basolateral signal in type A intercalated cells (A-ICs) and a perinuclear to subapical signal in type B intercalated cells of connecting tubules and collecting ducts. Treating vasopressin-deficient Brattleboro rats with a V1aR agonist decreased urinary pH and tripled net acid excretion; we observed a similar response in C57BL/6J mice. In contrast, V1aR antagonist did not affect urinary pH in normal or acid-loaded mice. In ex vivo settings, basolateral treatment of isolated perfused medullary collecting ducts with the V1aR agonist or vasopressin increased intracellular calcium levels in ICs and decreased luminal pH, suggesting V1aR-dependent calcium release and stimulation of proton-secreting proteins. Basolateral treatment of IMCD cells with the V1aR agonist increased apical abundance of vacuolar H+-ATPase in A-ICs. CONCLUSIONS: Our results show that activation of V1aR contributes to urinary acidification via H+ secretion by A-ICs, which may have clinical implications for pharmacologic targeting of V1aR.

Consequences of prenatal exposure to valproic acid in the socially monogamous prairie voles.

Environmental risk factors contribute to autism spectrum disorders (ASD) etiology. In particular, prenatal exposure to the highly teratogenic anticonvulsant valproic acid (VPA) significantly increases ASD prevalence. Although significant discoveries on the embryopathology of VPA have been reported, its effects on the ability to form enduring social attachment-characteristic of ASD but uncommonly displayed by rats and mice-remains unknown. We aimed to examine the effects of prenatal VPA exposure in the social, monogamous prairie voles (Microtus ochrogaster). Compared to prenatal vehicle-exposed controls, prenatal VPA-exposed prairie voles had lower body weight throughout postnatal development, engaged in fewer social affiliative behaviors in a familial context, exhibited less social interactions with novel conspecifics, and showed enhanced anxiety-like behavior. Along these behavioral deficits, prenatal VPA exposure downregulated prefrontal cortex vasopressin receptor (V1aR) and methyl CpG-binding protein 2 (MeCP2) mRNA expression, but did not alter spine density in adults. Remarkably, adult social bonding behaviors, such as partner preference formation and selective aggression, were not disrupted by prenatal VPA exposure. Collectively, these studies suggest that, in this animal model, VPA alters only certain behavioral domains such as sex-naive anxiety and affiliative behaviors, but does not alter other domains such as social bonding with opposite sex individuals.

Management of hyponatremia: causes, clinical aspects, differential diagnosis and treatment.

INTRODUCTION: Hyponatremia is the most frequent electrolyte disorder in hospitalised patients. Acute and severe hyponatremia may be a life-threatening situation. However, also mild and chronic hyponatremia may negatively affect the health status (i.e. gait disturbances, attention deficits, falls and fractures, and bone loss) and may increase the risk of death. Therefore, it is of paramount importance for clinicians to have an in-depth knowledge on this topic, in order to appropriately manage patients affected by hyponatremia. AREAS COVERED: This review will cover different areas related to this electrolyte disorder. Because many pathologic conditions may be associated with hyponatremia, thorough investigations have to be performed in order to establish the underlying etiology. To establish the cause of hyponatremia is of great importance, because an appropriate therapeutic strategy is strictly dependent on a correct diagnosis. A description of the different available therapeutic approaches for the correction of hyponatremia, including vaptans, will follow. EXPERT COMMENTARY: Undoubtedly, the studies that have been published in recent years and the introduction of vaptans in clinical practice have contributed to increase the awareness on hyponatremia among clinicians. Nevertheless, additional studies are needed in order to clarify some partially uncovered areas.

Cligosiban, A Novel Brain-Penetrant, Selective Oxytocin Receptor Antagonist, Inhibits Ejaculatory Physiology in Rodents.

INTRODUCTION: Few treatments are available for men with premature ejaculation (PE); oxytocin (OT) receptor antagonism in the central nervous system (CNS) is a potential new approach. AIM: To determine if cligosiban selectively inhibits human OT receptors, penetrates the CNS, shows pharmacology in the CNS, and effects ejaculatory physiology in pre-clinical systems. METHODS: Experiments complied with United Kingdom legislation and were subject to local ethical review. In vitro potency and selectivity of cligosiban was assessed using recombinant and native OT receptor systems including both neuronal and non-neuronal cell types. Selectivity was determined over neighboring V1A, V1B, and V2 vasopressin receptors using a combination of recombinant and native vasopressin receptor assay systems. To determine an effect on central OT receptors and on ejaculation, cligosiban was evaluated in 2 anesthetized rat models-the electromyography model of ejaculatory physiology and a model of OT-mediated CNS neuronal firing. The CNS penetration of cligosiban was also determined by measuring cerebrospinal fluid and plasma drug concentrations following an intravenous (IV) infusion in rats. MAIN OUTCOME MEASURE: These were functional measures of pharmacology in vitro, in cell lines and tissues, and in vivo in rats. RESULTS: Cligosiban is a potent OT receptor antagonist, with a base dissociation constant of 5.7 nmol/L against native human uterine smooth muscle cell OT receptors. Cligosiban displays similar antagonistic potency against human recombinant and rat native OT receptors, including neuronal OT receptors. Cligosiban demonstrates >100-fold selectivity over human V1A, V1B, and V2 vasopressin receptors. In the electromyography model, cligosiban (0.9 mg/kg, IV bolus) reduced the bulbospongiosum burst pattern and contraction amplitude associated with ejaculation. In the anesthetized CNS neuronal firing model, the same dosing regimen of cligosiban (0.9 mg/kg IV bolus) modulated the OT-mediated response in the nucleus tractus solitarius. After systemic dosing to rats, cligosiban showed good CNS penetration. CLINICAL IMPLICATIONS: As the first highly selective and centrally penetrant OT receptor antagonist, cligosiban represents a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE. STRENGTH & LIMITATIONS: The pharmacology and selectivity of cligosiban is determined using functional assays in recombinant cell lines, native cell lines, and tissue. Functional outcomes in in vivo systems are linked to CNS measures of pharmacology. The translation of the animal models of ejaculation to PE in man is unproven. CONCLUSION: Cligosiban, a potent, selective OT receptor antagonist, demonstrated CNS penetration and pharmacology and, using the same dosing regimen, inhibited apomorphine-induced ejaculation in rats. Cligosiban is a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE. Wayman C, Russell R, Tang K, et al. Cligosiban, A Novel Brain Penetrant Selective Oxytocin Receptor Antagonist, Inhibits Ejaculatory Physiology in Rodents. J Sex Med 2018;15:1698-1706.

[The pathway of vasopressin as a pharmacological target in nephrology: a narrative review].

ADH is a hormone secreted by neurohypophysis that plays different roles based on the target organ. At the renal level, this peptide is capable of causing electrolyte-free water absorption, thus playing a key role in the hydro-electrolytic balance. There are pathologies and disorders that jeopardize this balance and, in this field, ADH receptor inhibitors such as Vaptans could play a key role. By inhibiting the activation pathway of vasopressin, they are potentially useful in euvolemic and hypervolemic hypotonic hyponatremia. However, clinical trials in heart failure have not given favourable results on clinical outcomes. Even in SIADH, despite their wide use, there is no agreement by experts on their use. Since vaptans inhibit the cAMP pathway in tubular cells, their use has been proposed to inhibit cystogenesis. A clinical trial has shown favourable effects on ADPKD progression. Because vaptans have been shown to be effective in models of renal cysts disorders other than ADPKD, their use has been proposed in diseases such as nephronophthisis and recessive autosomal polycystic disease. Other possible uses of vaptans could be in kidney transplantation and cardiorenal syndrome. Due to the activity of ADH in coagulation and haemostasis, ADH's activation pathway by Desmopressin Acetate could be a useful strategy to reduce the risk of bleeding in biopsies in patients with haemorrhagic risk.