Diagnostic Concordance between the Visual Analogue Anxiety Scale (VAS-A) and the State-Trait Anxiety Inventory (STAI) in Nursing Students during the COVID-19 Pandemic.

Anxiety is one of the most common problems among nursing students. The State-Trait Anxiety Inventory (STAI) is used to detect anxiety in this population; however, its length hinders speedy detection. For this reason, a faster and more efficient instrument is needed for early detection. This study aimed to determine the relationship between the anxiety measurement scales State-Trait Anxiety Inventory (STAI) and the Visual Analogue Scale for Anxiety (VAS-A) by establishing a discrimination threshold through the contrast of true positive rates (VPR) and false positive rates (FPR). To this end, a cross-sectional quantitative observational and analytical study was carried out on 185 fourth-year nursing students. The data collected were anxiety (STAI and VAS-A) and socio-demographic variables during the COVID-19 pandemic. The results showed a correlation between the two scales (VAS-A and STAI). The VAS-A is a useful instrument for assessing students in a crisis that could potentially generate anxiety. The study established a reasonably safe error probability range (>5%), allowing the VAS-A scale to be used as a rapid diagnostic or pre-diagnostic tool, depending on the scores. The study shows that speedy detection of anxiety using the VAS-A and an in-depth approach with the STAI by teaching staff in crises is possible.

An Octopus-Derived Peptide with Antidiuretic Activity in Rats.

Discovering new drug candidates with high efficacy and few side effects is a major challenge in new drug development. The two evolutionarily related peptides oxytocin (OXT) and arginine vasopressin (AVP) are known to be associated with a variety of physiological and psychological processes via the association of OXT with three types of AVP receptors. Over decades, many synthetic analogs of these peptides have been designed and tested for therapeutic applications; however, only a few studies of their natural analogs have been performed. In this study, we investigated the bioactivity and usefulness of two natural OXT/AVP analogs that originate from the marine invertebrate Octopus vulgaris, named octopressin (OTP) and cephalotocin (CPT). By measuring the intracellular Ca2+ or cyclic AMP increase in each OXT/AVP receptor subtype-overexpressing cell, we found that CPT, but not OTP, acts as a selective agonist of human AVP type 1b and 2 receptors. This behavior is reminiscent of desmopressin, the most widely prescribed antidiuretic drug in the world. Similar to the case for desmopressin, a single intravenous tail injection of CPT into Sprague-Dawley rats reduced urine output and increased urinary osmolality. In conclusion, we suggest that CPT has a significant antidiuretic effect and that CPT might be beneficial for treating urological conditions such as nocturia, enuresis, and diabetes insipidus.

Binding affinities of oxytocin, vasopressin and Manning compound at oxytocin and V1a receptors in male Syrian hamster brains.

Oxytocin (OT) and arginine vasopressin (AVP), as well as synthetic ligands targeting their receptors (OTR, V1aR), are used in a wide variety of research contexts, although their pharmacological properties are determined in only a few species. Syrian hamsters (Mesocricetus auratus) have a long history of use as a behavioural and biomedical model for the study of OT and AVP and, more recently, hamsters have been used to investigate behavioural consequences of OT-mediated activation of V1aR. We aimed to determine the binding affinities of OT, AVP and the selective V1aR antagonist, Manning compound, for OTR and V1aR in hamster brains. We performed saturation binding assays to determine the Kd values for the selective OTR and V1aR radioligands, [125 I]ornithine vasotocin analogue and [125 I]linear vasopressin antagonist. We then performed competition binding assays to determine Ki values for OT, AVP and Manning compound at both the OTR and V1aR. We found that OT and AVP each had the highest affinity for their canonical receptors (OT-OTR Ki = 4.28 [95% confidence interval (CI) = 2.9-6.3] nmol L-1 ; AVP-V1ar Ki = 4.70 [95% CI = 1.5-14.1] nmol L-1 ) and had the lowest affinity for their non-canonical ligands (OT-V1aR = 495.2 [95% CI = 198.5-1276] nmol L-1 ; AVP-OTR Ki = 36.1 [95% CI = 12.4-97.0] nmol L-1 ). Manning compound had the highest affinity for the V1aR (MC-V1aR Ki = 6.87 [95% CI = 4.0-11.9] nmol L-1 ; MC-OTR Ki = 213.8 [95% CI = 117.3-392.7] nmol L-1 ), although Manning compound was not as selective for the V1aR in hamsters as has been reported for the receptor in rats. When comparing these data with previously published work, we found that the promiscuity of the V1aR in hamsters with respect to OT and AVP binding is more similar to the promiscuity of the human V1aR than to the rat V1aR receptor. Moreover, the selectivity of OT at hamster receptors is more similar to the selectivity of OT at human receptors than the selectivity of OT at rat receptors. These data highlight the importance of determining the pharmacological properties of behaviourally relevant compounds in diverse model species.

Impurity identification and quantification for arginine vasopressin by liquid chromatography/high-resolution mass spectrometry.

RATIONALE: For pharmaceutical quality control, impurities may have unexpected pharmacological or toxicological effects on quality, safety, and efficacy of drugs. Arginine vasopressin (AVP) is an important cyclic peptide drug that is mainly used for the treatment of diabetes insipidus and esophageal varices bleeding. With the advancement made in analytical techniques, liquid chromatography/high-resolution mass spectrometry (LC/HRMS) has emerged as a critical technique for the identification and quantification of structurally related peptide impurities in AVP. METHODS: An LC/HRMS/MS-based method using a quadrupole ion trap-Orbitrap mass spectrometer operated in the positive ion electrospray ionization mode was developed for the determination and quantification of structurally related peptide impurities in AVP. RESULTS: Under optimized experimental conditions, three deamidation products, ([Glu4 ]AVP, [Asp5 ]AVP, and AVP acid), two amino acid deletion impurities (des-Pro7 -AVP and des-Gly9 -AVP), one amino acid insertion impurity (endo-Gly10a -AVP), one end chain reaction product (N-acetyl-AVP), and one AVP isomer were detected. Subsequent quantification using an external standard method estimated the total mass fraction of all structurally related peptide impurities in the AVP study material to be 30.3 mg/g with an expanded uncertainty of 3.0 mg/g (k = 2). CONCLUSIONS: This study complements the AVP impurity profile and improves the separation and discovery of other potential impurities in vasopressin analogues.

Comparison of the pharmacological profiles of arginine vasopressin and oxytocin analogs at marmoset, macaque, and human vasopressin 1a receptor.

Arginine vasopressin (AVP) and oxytocin (OT) are nonapeptides that bind to G-protein coupled receptors and influence social behaviors. Consensus mammalian AVP and OT (Leu8-OT) sequences are highly conserved. In marmosets, an amino acid change in the 8th position of the peptide (Pro8-OT) exhibits unique structural and functional properties. There is ∼85 % structural homology between the OT receptor (OTR) and vasopressin 1a receptor (V1aR) resulting in significant cross-reactivity between the ligands and receptors. Chinese hamster ovary (CHO) cells expressing marmoset (mV1aR), macaque (qV1aR), or human vasopressin receptor 1a (hV1aR) were used to assess AVP, Leu8-OT and Pro8-OT pharmacological profiles. To assess activation of Gq, functional assays were performed using Fluo-3 to measure ligand-induced Ca2+ mobilization. In all three V1aR-expressing cell lines, AVP was more potent than the OT ligands. To assess ligand-induced hyperpolarization, FLIPR Membrane Potential (FMP) assays were performed. In all three V1aR lines, AVP was more potent than the OT analogs. The distinctive U-shaped concentration-response curve displayed by AVP may reflect enhanced desensitization of the mV1aR and hV1aR, which is not observed with qV1aR. Evaluation of Ca2+-activated potassium (K+) channels using the inhibitors apamin, paxilline, and TRAM-34 demonstrated that both intermediate and large conductance Ca2+-activated K+ channels contributed to membrane hyperpolarization, with different pharmacological profiles identified for distinct ligand-receptor combinations. Taken together, these data suggest differences in ligand-receptor signaling that may underlie differences in social behavior. Integrative studies of behavior, genetics and ligand-receptor interaction will help elucidate the connection between receptor pharmacology and social behaviors.

AVP(4-8) Improves Cognitive Behaviors and Hippocampal Synaptic Plasticity in the APP/PS1 Mouse Model of Alzheimer's Disease.

Memory deficits with aging are related to the neurodegeneration in the brain, including a reduction in arginine vasopressin (AVP) in the brain of patients with Alzheimer's disease (AD). AVP(4-8), different from its precursor AVP, plays memory enhancement roles in the CNS without peripheral side-effects. However, it is not clear whether AVP(4-8) can improve cognitive behaviors and synaptic plasticity in the APP/PS1 mouse model of AD. Here, we investigated for the first time the neuroprotective effects of AVP(4-8) on memory behaviors and in vivo long-term potentiation (LTP) in APP/PS1-AD mice. The results showed that: (1) APP/PS1-AD mice had lower spontaneous alternation in the Y-maze than wild-type (WT) mice, and this was significantly reversed by AVP(4-8); (2) the prolonged escape latency of APP/PS1-AD mice in the Morris water maze was significantly decreased by AVP(4-8), and the decreased swimming time in target quadrant recovered significantly after AVP(4-8) treatment; (3) in vivo hippocampal LTP induced by high-frequency stimulation had a significant deficit in the AD mice, and this was partly rescued by AVP(4-8); (4) AVP(4-8) significantly up-regulated the expression levels of postsynaptic density 95 (PSD95) and nerve growth factor (NGF) in the hippocampus of AD mice. These results reveal the beneficial effects of AVP(4-8) in APP/PS1-AD mice, showing that the intranasal administration of AVP(4-8) effectively improved the working memory and long-term spatial memory of APP/PS1-AD mice, which may be associated with the elevation of PSD95 and NGF levels in the brain and the maintenance of hippocampal synaptic plasticity.

Imaging on Lung Cancer and Treatment with Targeted Therapy.

The identification of genetic mutations known as oncogenic driver mutations that lead to the growth and survival of cancer cells has been an important advance in the field of oncology. Treatment in advanced non-small-cell lung cancer (NSCLC) has transitioned from a more general approach to a more personalized approach based on genetic mutations of the cancer itself. Common mutations detected in patients with advanced NSCLC include mutations of epidermal growth factor receptor and anaplastic lymphoma kinase (ALK). Targeted therapies are aimed at the products of these gene mutations and include erlotinib (used in epidermal growth factor receptor mutant NSCLC) and crizotinib (used in anaplastic lymphoma kinase positive NSCLC). In this review, we discuss common genetic mutations in advanced NSCLC, the role of targeted therapies, and imaging findings that can be associated with various genetic mutations.

Time-Dependent Effects of Arginine-Vasopressin V1 Receptor Inhibition on Secondary Brain Damage after Traumatic Brain Injury.

Arginine-vasopressin (AVP) V1 receptors are known to mediate brain edema formation after traumatic brain injury (TBI). So far, however, AVP V1 receptors were only inhibited by genetic deletion or prior to trauma. Therefore, the current study aimed to determine the therapeutic window of AVP V1 receptor antagonization after TBI. Male C57BL/6 mice (n = 7 per group) were subjected to controlled cortical impact (CCI), and 500 ng of a selective peptide V1 receptor antagonist (V1880) were applied by intracerebroventricular injection 5 min, and 1, 3, and 6 h thereafter. After 24 h, brain water content (BWC), intracranial pressure (ICP), and secondary contusion expansion volume were assessed. Neurological function was assessed daily for 7 days after trauma. Inhibition of AVP V1 receptors within 1 h after TBI significantly reduced BWC from 81.6 ± 0.7 to 80.6 ± 0.7% (mean ± SD; p < 0.05). Reduction of brain edema resulted in a significant decrease in ICP from 25.9 ± 1.8 mm Hg to 21.0 ± 1.5 mm Hg (p < 0.05) and a reduction in contusion volume (26.1 ± 2.5 mm3 vs. 30.1 ± 2.0 mm3 in controls; p < 0.05). This reduction of brain injury resulted in a significantly improved neurological function 7 days after trauma. Treatments initiated 6 h after TBI had no effect. The results of the current study demonstrate that inhibition of AVP V1 receptors improve outcome after experimental TBI when given within a clinically relevant time window. Therefore, AVP V1 receptors may represent a therapeutic target with clinical potential.

Differential Role of Neurohypophysial Hormones in Hypotension and Nitric Oxide Production During Endotoxaemia.

Besides their well-established endocrine roles, vasopressin and oxytocin are also important regulators of immune function, participating in a complex neuroendocrine-immune network. In the present study, we investigated whether and how vasopressin and oxytocin could modulate lipopolysaccharide (LPS)-induced nitric oxide (NO) production in a well-established model of experimental endotoxaemia. Male Wistar rats were previously treated i.v. with vasopressin V1 or oxytocin receptor antagonists and then received either an i.v. LPS injection to induce endotoxaemia or a saline imjection as a control. The animals were divided into two groups: in the first group, blood was collected at 2, 4 and 6 h after LPS injection; in the second group, mean arterial blood pressure (MABP) and heart rate (HR) were recorded over 6 h. Plasma vasopressin and oxytocin values were higher in LPS- compared to saline-injected animals at 2 and 4 h but returned to basal levels at 6 h. NO levels exhibited an opposite pattern, showing a progressive increase over the entire period. The previous administration of a vasopressin V1 receptor antagonist significantly reduced NO plasma concentrations at 2 and 4 h but not at 6 h. By contrast, oxytocin receptor agonist pre-treatment had no effect on the NO plasma concentration. In relation to MABP, previous treatment with vasopressin V1 receptor antagonist reversed the LPS-induced hypotension at 4 h, although this was not the case for oxytocin antagonist-treated animals. None of the antagonists affected HR. Our findings indicate that vasopressin (but not oxytocin) has effects on NO production during endotoxaemia in rats, although they do not lend support to the proposed anti-inflammatory actions of vasopressin during endotoxaemia.

Central effect of vasotocin 4 receptor (VT4R/V1aR) antagonists on the stress response and food intake in chicks given neuropeptide Y (NPY).

Previous studies identified SR-49059 as a most effective antagonist of the avian vasotocin 4 receptor (VT4R) compared to other candidate blockers including the Manning compound using in silico 3 dimensional (3D) modeling/docking analysis of the chicken VT4R and an in vitro anterior pituitary cell culture study. The present experiments were designed to validate whether SR-49059 and the Manning compound would likewise be effective in vivo in blocking the VT4R when applied intracerebroventricularly (ICV) to chicks. Two treatments were tested, a stressor (immobilization) and administration of neuropeptide Y (NPY), a potent orexigenic compound. In the first experiment, birds were given the Manning compound, SR-49059 or physiological saline ICV followed by immobilization stress. Blood samples were taken and corticosterone (CORT) was determined by radioimmunoassay. It was hypothesized that both antagonists would reduce the stress response. A second experiment examined the role of the VT4R in food intake regulation. The Manning compound, SR-49059 or physiological saline was administered prior to NPY and food intake was monitored for 1h. It was hypothesized that each of the two antagonists coupled with NPY would augment food intake above the intake resulting from saline plus NPY administration. Related to the second experiment was a third that examined the difference between the effect of central administration of NPY versus SR-49059 in releasing CORT. Results of the first study showed that the Manning compound or SR-49059 prior to stress decreased CORT levels compared to controls while the second experiment showed that SR-49059 or the Manning compound plus NPY, enhanced food intake above that of the experimental group given saline and NPY. The last study showed that NPY increased plasma CORT above birds given SR-49059 centrally or saline administered controls. Taken together, results suggest that the avian VT4R is involved in the central neuroendocrine stress response as well as functions in appetite regulation by mediating an anorexigenic effect similar to what has been reported in mammals for the V1aR. In conclusion, similar to the past in silico and in vitro tests, the current in vivo experiments showed SR-49059 to be a most efficacious avian vasotocin receptor antagonist. Therefore based upon results of functional tests utilizing a highly specific mammalian antagonist, SR-49059, to the mammalian V1aR that likewise was most effective in blocking the avian VT4R and past reported high sequence homology between the mammalian V1aR and the VT4R, it is recommended that the chicken VT4R be renamed the avian V1aR to facilitate better communication among scientists involved in comparative studies.

Cholinergic activation of neurons in the medulla oblongata changes urinary bladder activity by plasma vasopressin release in female rats.

The central control of the micturition is dependent on cortical areas and other ascending and descending pathways in the brain stem. The descendent pathways from the pons to the urinary bladder (UB) can be direct or indirect through medullary neurons (MN). Chemical stimulation with l-glutamate of MN known for their involvement in cardiovascular regulation evokes changes in pelvic nerves activities, which innervate the urinary bladder. Different neurotransmitters have been found in medullary areas; nevertheless, their involvement in UB control is few understood. We focused to investigate if cholinergic activation of neurons in the medulla oblongata changes the urinary bladder activity. Carbachol (cholinergic agonist) or atropine (cholinergic antagonist) was injected into the 4thV in anesthetized female Wistar rats and the intravesical pressure (IP), mean arterial pressure (MAP), heart rate (HR) and renal conductance (RC) were recorded for 30 min. Carbachol injection into the 4thV increased IP with peak response at 30 min after carbachol and yielded no changes in MAP, HR and RC. Atropine injection into the 4thV decreased IP and elicited no changes in MAP, HR and RC. Plasma vasopressin levels evaluated by ELISA kit assay increased after carbachol into the 4th V. Intravenous blockade of V1 receptors prior to carbachol into the 4thV abolished the increase in IP evoked by carbachol. Therefore, our findings suggest that cholinergic activation of neurons in the medulla oblongata by carbachol injections into the 4thV increases IP due to plasma vasopressin release, which acts in V1 receptors in the UB.

Influence of thoracic epidural anesthesia on gastric oxygenation during hypothermia and hemorrhage.

OBJECTIVE: Hypothermia preserves gastric mucosal microvascular oxygenation (µHbO2) during hemorrhagic shock. Additionally, hypothermia activates the sympathetic nervous system that leads to the release of vasopressin. The aim of this study was to evaluate whether the effect of hypothermia is mediated via the sympathetic nervous system and/or via vasopressin. METHODS: In prospective and randomized experiments on five anesthetized dogs (foxhounds, cross-over design, 6 groups with n=5 per group) we analyzed the effects of hemorrhage on µHbO2 during mild hypothermia (HT, 34 °C), during additional thoracic epidural anesthesia (HT/TEA) and during additional vasopressin V1 receptor blockade (HT/VB). As control groups, effects of hemorrhage were studied under normothermia alone (NT), during additional thoracic epidural anesthesia (NT/TEA) and during additional vasopressin V1 receptor blockade (NT/VB). RESULTS: Hemorrhage decreased µHbO2 from 81 ± 3 to 49 ± 8%. In contrast, in the presence of hypothermia, µHbO2 was significantly higher during hemorrhagic shock (from 79 ± 3 to 66 ± 9%) despite a similar decrease in DO2. The effect of hypothermia on µHbO2 was reduced in the presence of thoracic epidural anesthesia or vasopressin receptor blockade. CONCLUSIONS: Hypothermia preserves µHbO2 during hemorrhagic shock. This effect is partially abolished during thoracic epidural anesthesia or during vasopressin receptor blockade. The sympathetic nervous system and the vasopressin V1 receptor are partially involved in mediating the effect of hypothermia on gastric oxygenation during hemorrhage.

Vasopressin V1a, but not V1b, receptors within the PVN of lactating rats mediate maternal care and anxiety-related behaviour.

The brain neuropeptide arginine-vasopressin (AVP) mediates a wide range of social behaviours via its V1a (V1aR) but also its V1b receptor (V1bR). With respect to maternal behaviour, V1bR are still less investigated, whereas V1aR have been shown repeatedly to trigger maternal behaviour, depending on the brain region. Here, we aimed to study the role of both V1aR and V1bR within the hypothalamic paraventricular nucleus (PVN), a major source of AVP, in maternal care (lactation day (LD) 1), maternal motivation in the pup retrieval test (LD 3) and anxiety-related behaviour on the elevated plus maze (EPM; LD 5) by acute local infusion of receptor subtype-specific antagonists for V1aR (d(CH2)5Tyr(Me)(2)AVP) or V1bR (SSR149415). Furthermore, we compared V1bR expression in the PVN of virgin versus lactating rats (LD 4). Our results demonstrate that within the PVN neither V1bR mRNA (qPCR) nor protein (Western Blot) content differed between virgin and lactating rats. Regarding behaviour, acute antagonism of V1aR, but not of V1bR, decreased the occurrence of nursing as well as anxiety-related behaviour as reflected by higher percentage of time spent on and of entries into the open arms of the EPM. Maternal motivation was not affected by any treatment. In summary, we demonstrate subtype-specific involvement of V1 receptors within the PVN in mediating various maternal behaviours. The lack of effects after V1bR blockade reveals that AVP acts mainly via V1aR in the PVN, at least in lactating rats, to mediate maternal care and anxiety.

Role of the Suprachiasmatic and Arcuate Nuclei in Diurnal Temperature Regulation in the Rat.

In mammals, daily changes in body temperature (Tb) depend on the integrity of the suprachiasmatic nucleus (SCN). Fasting influences the Tb in the resting period and the presence of the SCN is essential for this process. However, the origin of this circadian/metabolic influence is unknown. We hypothesized that, not only the SCN but also the arcuate nucleus (ARC), are involved in the Tb setting through afferents to the thermoregulatory median preoptic nucleus (MnPO). Therefore, we investigated by neuronal tracing and microdialysis experiments the possible targeting of the MnPO by the SCN and the ARC in male Wistar rats. We observed that vasopressin release from the SCN decreases the temperature just before light onset, whereas α-melanocyte stimulating hormone release, especially at the end of the dark period, maintains high temperature. Both peptides have opposite effects on the brown adipose tissue activity through thermoregulatory nuclei such as the dorsomedial nucleus of the hypothalamus and the dorsal raphe nucleus. The present study indicates that the coordination between circadian and metabolic signaling within the hypothalamus is essential for an adequate temperature control. SIGNIFICANCE STATEMENT: When circadian and metabolic systems are not well synchronized, individuals may develop metabolic diseases. The underlying mechanisms are unknown. Here, we demonstrate that the balance between the releases of neuropeptides derived from the biological clock and from a metabolic sensory organ as the arcuate nucleus, are essential for an adequate temperature control. These observations show that brain areas involved in circadian and metabolic functions of the body need to interact to produce a coherent arrangement of physiological processes associated with temperature control.

Arginine-, D-arginine-vasopressin, and their inverso analogues in micellar and liposomic models of cell membrane: CD, NMR, and molecular dynamics studies.

We describe the synthesis, pharmacological properties, and structures of antidiuretic agonists, arginine vasopressin (AVP) and [D-Arg(8)]-vasopressin (DAVP), and their inverso analogues. The structures of the peptides are studied based on micellar and liposomic models of cell membranes using CD spectroscopy. Additionally, three-dimensional structures in mixed anionic-zwitterionic micelles are obtained using NMR spectroscopy and molecular dynamics simulations. NMR data have shown that AVP and DAVP tend to adopt typical of vasopressin-like peptides ß-turns: in the 2-5 and 3-6 fragments. The inverso-analogues also adopt ß-turns in the 3-6 fragments. For this reason, their inactivity seems to be due to the difference in side chains orientations of Tyr(2), Phe(3), and Arg(8), important for interactions with the receptors. Again, the potent antidiuretic activity of DAVP can be explained by CD data suggesting differences in mutual arrangement of the aromatic side chains of Tyr(2) and Phe(3) in this peptide in liposomes rather than of native AVP. In the presence of liposomes, the smallest conformational changes of the peptides are noticed with DPPC and the largest with DPPG liposomes. This suggests that electrostatic interactions are crucial for the peptide-membrane interactions. We obtained similar, probably active, conformations of the antidiuretic agonists in the mixed DPC/SDS micelles (5:1) and in the mixed DPPC/DPPG (7:3) liposomes. Thus it can be speculated that the anionic-zwitterionic liposomes as well as the anionic-zwitterionic micelles, mimicking the eukaryotic cell membrane environment, partially restrict conformational freedom of the peptides and probably induce conformations resembling those of biologically relevant ones.

Neuronal-derived nitric oxide and somatodendritically released vasopressin regulate neurovascular coupling in the rat hypothalamic supraoptic nucleus.

The classical model of neurovascular coupling (NVC) implies that activity-dependent axonal glutamate release at synapses evokes the production and release of vasoactive signals from both neurons and astrocytes, which dilate arterioles, increasing in turn cerebral blood flow (CBF) to areas with increased metabolic needs. However, whether this model is applicable to brain areas that also use less conventional neurotransmitters, such as neuropeptides, is currently unknown. To this end, we studied NVC in the rat hypothalamic magnocellular neurosecretory system (MNS) of the supraoptic nucleus (SON), in which dendritic release of neuropeptides, including vasopressin (VP), constitutes a key signaling modality influencing neuronal and network activity. Using a multidisciplinary approach, we investigated vasopressin-mediated vascular responses in SON arterioles of hypothalamic brain slices of Wistar or VP-eGFP Wistar rats. Bath-applied VP significantly constricted SON arterioles (Δ-41 ± 7%) via activation of the V1a receptor subtype. Vasoconstrictions were also observed in response to single VP neuronal stimulation (Δ-18 ± 2%), an effect prevented by V1a receptor blockade (V2255), supporting local dendritic VP release as the key signal mediating activity-dependent vasoconstrictions. Conversely, osmotically driven magnocellular neurosecretory neuronal population activity leads to a predominant nitric oxide-mediated vasodilation (Δ19 ± 2%). Activity-dependent vasodilations were followed by a VP-mediated vasoconstriction, which acted to limit the magnitude of the vasodilation and served to reset vascular tone following activity-dependent vasodilation. Together, our results unveiled a unique and complex form of NVC in the MNS, supporting a competitive balance between nitric oxide and activity-dependent dendritic released VP, in the generation of proper NVC responses.

Arginine vasopressin inhibits adipogenesis in human adipose-derived stem cells.

Intracellular Ca(2+) signaling is important for stem cell differentiation and there is evidence it may coordinate the process. Arginine vasopressin (AVP) is a neuropeptide hormone secreted mostly from the posterior pituitary gland and increases Ca(2+) signals mainly via V1 receptors. However, the role of AVP in adipogenesis of human adipose-derived stem cells (hASCs) is unknown. In this study, we identified the V1a receptor gene in hASCs and demonstrated that AVP stimulation increased intracellular Ca(2+) concentration during adipogenesis. This effect was mediated via V1a receptors, Gq-proteins and the PLC-IP3 pathway. These Ca(2+) signals were due to endoplasmic reticulum release and influx from the extracellular space. Furthermore, AVP supplementation to the adipogenic medium decreased the number of adipocytes and adipocyte marker genes during differentiation. The effect of AVP on adipocyte formation was reversed by the V1a receptor blocker V2255. These findings suggested that AVP may function to inhibit adipocyte differentiation.

Corticotropin-releasing hormone and the sympathoadrenal system are major mediators in the effects of peripherally administered exendin-4 on the hypothalamic-pituitary-adrenal axis of male rats.

Glucagon-like peptide-1 (GLP-1) and the GLP-1 receptor agonist, exendin-4 (Ex-4), potently stimulate hypothalamic-pituitary-adrenal (HPA) axis activity after either central or peripheral administration. Because several GLP-1 derivative drugs, including synthetic Ex-4, are currently in use to treat patients with type II diabetes mellitus, the characterization of Ex-4 effects on the HPA axis is highly relevant. Herein, the roles of CRH and AVP on these effects were investigated by administering the antagonists astressin and d(CH2)5Tyr(Me)AVP, respectively. The role of the sympathoadrenal system (SAS) was explored in bilateral adrenal enucleated and guanethidine-treated rats, whereas primary pituitary cell cultures were used to study direct effects on the corticotropes. Astressin completely abrogated (P < .05) the effects of Ex-4 central administration on ACTH secretion but only slightly reduced (by 35%) the ACTH response to Ex-4 peripheral administration. Moreover, astressin significantly (P < .05) decreased the corticosterone response to centrally but not peripherally administered Ex-4, suggesting different mechanisms depending on the route of administration. Pretreatment with d(CH2)5Tyr(Me)AVP failed to diminish either the ACTH or corticosterone response to Ex-4 and no direct effect of Ex-4 or GLP-1 was observed on pituitary cell cultures. In contrast, a significant (P < .05) reduction in the corticosterone response elicited by Ex-4 peripheral administration was observed in enucleated and guanethidine-treated rats, indicating a role of the SAS in the glucocorticoid stimulatory effects of Ex-4. Our data demonstrate that the effects of Ex-4 on the HPA axis are partially mediated by CRH and the sympathoadrenal system, and stress the relevance of Ex-4 as a corticosterone secretagogue.

Social preference and maternal defeat-induced social avoidance in virgin female rats: sex differences in involvement of brain oxytocin and vasopressin.

BACKGROUND: Research concerning non-reproductive sociability in rodents is mainly restricted to assessing the effects of oxytocin (OXT) and arginine-vasopressin (AVP) in male rats and mice. Comparable studies on natural social preference and social avoidance in females are substantially lacking. NEW METHOD: Here, we adapted a behavioral paradigm for monitoring social preference of female rats consisting of two consecutive exposures to either non-social or social stimuli. Further, to induce stimulus-specific social avoidance, female rats were exposed to a single 10-min maternal defeat by a lactating dam. RESULTS: Social preference towards same-sex conspecifics in female rats was shown to be independent of the estrous cycle and even more pronounced than in male rats. Intracerebroventricular (icv) application of OXT, AVP, or their selective receptor antagonists or agonists, did not alter naturally-occurring social preference in female rats. Stimulus-specific social avoidance could be induced by prior exposure to a lactating rat: an effect that could not be reversed/overcome by icv OXT. COMPARISON WITH EXISTING METHOD(S): The female social preference paradigm for rats established in this study detected subtle sex differences in social preference behavior of rats. Further, stimulus-specific social deficits could be induced in female rats using an acute exposure to social defeat - as previously observed in male rodents. CONCLUSIONS: Female rats show strong social preference behavior, which can be prevented by social defeat, but does not seem to be regulated by the OXT or AVP systems. Accordingly, icv application of synthetic OXT does not reverse maternal defeat-induced social avoidance in female rats.