Arginine vasopressin activates serotonergic neurons in the dorsal raphe nucleus during neonatal development in vitro and in vivo.

Birth stress is a risk factor for psychiatric disorders and associated with exaggerated release of the stress hormone arginine vasopressin (AVP) into circulation and in the brain. In perinatal hippocampus, AVP activates GABAergic interneurons which leads to suppression of spontaneous network events and suggests a protective function of AVP on cortical networks during birth. However, the role of AVP in developing subcortical networks is not known. Here we tested the effect of AVP on the dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT, serotonin) system in male and female neonatal rats, since early 5-HT homeostasis is critical for the development of cortical brain regions and emotional behaviors. We show that AVP is strongly excitatory in neonatal DRN: it increases excitatory synaptic inputs of 5-HT neurons via V1A receptors in vitro and promotes their action potential firing through a combination of its effect on glutamatergic synaptic transmission and a direct effect on the excitability of these neurons. Furthermore, we identified two major firing patterns of neonatal 5-HT neurons in vivo, tonic regular firing and low frequency oscillations of regular spike trains and confirmed that these neurons are also activated by AVP in vivo. Finally, we show that the sparse vasopressinergic innervation in neonatal DRN originates exclusively from cell groups in medial amygdala and bed nucleus of stria terminalis. Hyperactivation of the neonatal 5-HT system by AVP during birth stress may impact its own functional development and affect the maturation of cortical target regions, which may increase the risk for psychiatric conditions later on.

Ionic mechanisms involved in arginine vasopressin-mediated excitation of auditory cortical and thalamic neurons.

The axons containing arginine vasopressin (AVP) from the hypothalamus innervate a variety of structures including the cerebral cortex, thalamus, hippocampus and amygdala. A plethora amount of evidence indicates that activation of the V1a subtype of the vasopressin receptors facilitates anxiety-like and fear responses. As an essential structure involved in fear and anxiety responses, the amygdala, especially the lateral nucleus of amygdala (LA), receives glutamatergic innervations from the auditory cortex and auditory thalamus where high density of V1a receptors have been detected. However, the roles and mechanisms of AVP in these two important areas have not been determined, which prevents the understanding of the mechanisms whereby V1a activation augments anxiety and fear responses. Here, we used coronal brain slices and studied the effects of AVP on neuronal activities of the auditory cortical and thalamic neurons. Our results indicate that activation of V1a receptors excited both auditory cortical and thalamic neurons. In the auditory cortical neurons, AVP increased neuronal excitability by depressing multiple subtypes of inwardly rectifying K+ (Kir) channels including the Kir2 subfamily, the ATP-sensitive K+ channels and the G protein-gated inwardly rectifying K+ (GIRK) channels, whereas activation of V1a receptors excited the auditory thalamic neurons by depressing the Kir2 subfamily of the Kir channels as well as activating the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and a persistent Na+ channel. Our results may help explain the roles of V1a receptors in facilitating fear and anxiety responses. Categories: Cell Physiology.

Atrial Natriuretic Peptide Alleviates Motion Sickness Potentially through Regulating Endolymph Volume in the Inner Ear Increased by Arginine Vasopressin.

INTRODUCTION: Dimenhydrinate and scopolamine are frequently used drugs, but they cause drowsiness and performance decrement. Therefore, it is crucial to find peripheral targets and develop new drugs without central side effects. This study aimed to investigate the anti-motion sickness action and inner ear-related mechanisms of atrial natriuretic peptide (ANP). METHODS: Endolymph volume in the inner ear was measured with magnetic resonance imaging and expression of AQP2 and p-AQP2 was detected with Western blot analysis and immunofluorescence method. RESULTS: Both rotational stimulus and intraperitoneal arginine vasopressin (AVP) injection induced conditioned taste aversion (CTA) to 0.15% sodium saccharin solution and an increase in the endolymph volume of the inner ear. However, intraperitoneal injection of ANP effectively alleviated the CTA behaviour and reduced the increase in the endolymph volume after rotational stimulus. Intratympanic injection of ANP also inhibited rotational stimulus-induced CTA behaviour, but anantin peptide, an inhibitor of ANP receptor A (NPR-A), blocked this inhibitory effect of ANP. Both rotational stimulus and intraperitoneal AVP injection increased the expression of AQP2 and p-AQP2 in the inner ear of rats, but these increases were blunted by ANP injection. In in vitro experiments, ANP addition decreased AVP-induced increases in the expression and phosphorylation of AQP2 in cultured endolymphatic sac epithelial cells. CONCLUSION: Therefore, the present study suggests that ANP could alleviate motion sickness through regulating endolymph volume of the inner ear increased by AVP, and this action of ANP is potentially mediated by activating NPR-A and antagonising the increasing effect of AVP on AQP2 expression and phosphorylation.

Effects of arginine vasopressin on human anxiety and associations with sex, dose, and V1a-receptor genotype.

RATIONALE: Arginine vasopressin (AVP) has dose- and sex-specific effects on social behavior, and variation in social responses is related to variation in the V1a receptor gene in animals. Whether such complexity also characterizes AVP effects on anxiety in humans, or whether V1a genotype is related to anxiety and/or AVP's ability to affect it, remains to be determined. OBJECTIVE: To test if AVP has dose-dependent effects on anxiety in men and/or women and if a particular allele within the RS3 promoter region of the V1a receptor gene is associated with anxiety and/or AVP effects on anxiety. METHOD: Men and women self-administered 20 IU or 40 IU intranasal arginine vasopressin (AVP) and placebo in a double-blind, within-subjects design, and State (SA) and Trait (TA) anxiety were measured 60 min later. PCR was used to identify allelic variation within the RS3 region of the V1a receptor gene. RESULTS: AVP decreased SA in men across both doses, whereas only the lower dose had the same effect, across sexes, in individuals who carry at least one copy of a previously identified "risk" allele in the RS3 promoter of the V1a receptor gene. Additionally, after placebo, women who carried a copy of the allele displayed lower TA than women who did not, and AVP acutely increased TA scores in those women. CONCLUSIONS: Exogenous AVP has modest sex- and dose-dependent effects on anxiety/affect in humans. Further, allelic variation in the V1a promoter appears associated with responsiveness to AVP's effects and, at least in women, to stable levels of anxiety/affect.

Subcutaneous therapy for portal hypertension: PHIN-214, a partial vasopressin receptor 1A agonist.

Cirrhosis is a liver disease that leads to increased intrahepatic resistance, portal hypertension (PH), and splanchnic hyperemia resulting in ascites, variceal bleeding, and hepatorenal syndrome. Terlipressin, a prodrug that converts to a short half-life vasopressin receptor 1 A (V1a) full agonist [8-Lys]-Vasopressin (LVP), is an intravenous treatment for PH complications, but hyponatremia and ischemic side effects require close monitoring. We developed PHIN-214 which converts into PHIN-156, a more biologically stable V1a partial agonist. PHIN-214 enables once-daily subcutaneous administration without causing ischemia or tissue necrosis and has a 10-fold higher therapeutic index than terlipressin in healthy rats. As V1a partial agonists, PHIN-214 and PHIN-156 exhibited maximum activities of 28 % and 42 % of Arginine vasopressin (AVP), respectively. The potency of PHIN-156 and LVP relative to AVP is comparable for V1a (5.20 and 1.65 nM, respectively) and V1b (102 and 115 nM, respectively) receptors. However, the EC50 of PHIN-156 to the V2 receptor was 26-fold higher than that of LVP, indicating reduced potential for dilutional hyponatremia via V2 agonism compared to terlipressin/LVP. No significant off-target binding to 87 toxicologically relevant receptors were observed when evaluated in vitro at 10 µM concentration. In bile duct ligated rats with PH, subcutaneous PHIN-214 reduced portal pressure by 13.4 % ± 3.4 in 4 h. These collective findings suggest that PHIN-214 could be a novel pharmacological treatment for patients with PH, potentially administered outside of hospital settings, providing a safe and convenient alternative for managing PH and its complications.

Discovery and Characterization of RGH-122, a Potent, Selective, and Orally Bioavailable V1a Receptor Antagonist.

The V1a receptor is a major contributor in mediating the social and emotional effects of arginine-vasopressin (AVP); therefore it represents a promising target in the treatment of several neuropsychiatric conditions. The aim of this research was to design and synthesize novel and selective V1a antagonists with improved in vitro and in vivo profiles. Through optimization and detailed SAR studies, we developed low nanomolar antagonists, and further characterizations led to the discovery of the clinical candidate compound 43 (RGH-122). The CNS activity of the compound was determined in a 3-chamber social preference test of autism in which RGH-122 successfully enhanced social preference with the lowest effective dose of 1.5 mg/kg.

Hesperidin improves physiological outcomes in an arginine vasopressin rat model of pre-eclampsia.

BACKGROUND: Hesperidin, a flavanone commonly found in citrus fruits and herbal formulations, has emerged as a potential new therapeutic agent for modulating several diseases. Since pre-eclampsia is a growing public health threat, it may negatively impact the economy and increase the disease burden of South Africa. Phytocompounds are easily accessible, demonstrate minimal side effects, and may confer novel medicinal options as a treatment and preventive preference. OBJECTIVE: To investigate the physiological, biochemical, and hematological outcomes of hesperidin in an arginine vasopressin (AVP)-induced rodent model of pre-eclampsia. METHODS: Female Sprague-Dawley rats were surgically implanted with mini-osmotic pumps to deliver AVP (200 ng/h) subcutaneously. Animals were treated with hesperidin at 200 mg/kg.b.w via oral gavage for 14 days. Systolic and diastolic blood pressures were measured on GD 7, 14, and 18 using a non-invasive tail-cuff method and were euthanized on GD 21. RESULTS: The findings showed that hesperidin administration significantly decreased blood pressure (P < 0.05) and urinary protein levels in pregnant rats (P < 0.001). Placental and individual pup weight also increased significantly in the pregnant hesperidin-treated groups compared to AVP untreated groups (P < 0.001). Biochemical and hematological markers such as white blood cell count and lymphocyte levels differed significantly (P < 0.05) in AVP groups treated with and without hesperidin. CONCLUSION: Our results suggest that hesperidin is an antihypertensive agent with modes of action associated with its diuretic and blood pressure lowering effects and reduction of proteinuria in AVP-induced pre-eclamptic rats.

Arginine vasopressin injection rescues delayed oviposition in cyp19a1b-/- mutant female zebrafish.

In zebrafish, estrogens produced in the ovaries via Cyp19a1a activity are required for both sexual differentiation of the ovary during early development as well as maintenance of the ovarian state during adulthood. The importance of Cyp19a1b that is highly expressed in the brain for female reproduction is still under study. We previously reported that female cyp19a1b -/- mutant zebrafish have significantly lower brain estradiol levels and impaired spawning behavior characterized by an increased latency to oviposition during dyadic sexual behavior encounters. In the current study, we provide evidence that the delayed oviposition in female cyp19a1b -/- mutants is linked to impaired arginine vasopressin (Avp) signaling. Droplet digital PCR experiments revealed that levels of the estrogen receptors, avp, and oxytocin (oxt) are lower in the hypothalamus of mutant females compared to wildtype fish. We then used acute intraperitoneal injections of Avp and Oxt, along with mixtures of their respective receptor antagonists, to determine that Avp can uniquely rescue the delayed oviposition in female cyp19a1b -/- mutants. Using immunohistochemistry, we demonstrated that Cyp19a1b-expressing radial glial cell (RGC) fibers surround and are in contact with Avp-immunopositive neurons in the preoptic areas of the brain. This could provide the neuroanatomical proximity for RGC-derived estrogens to diffuse to and activate estrogen receptors and regulate avp expression levels. Together these findings identify a positive link between Cyp19a1b and Avp for female zebrafish sexual behavior. They also suggest that the female cyp19a1b -/- mutant behavioral phenotype is likely a consequence of impaired processing of Avp-dependent social cues important for mate identification and assessment.

Intranasal oxytocin does not change partner preference in female titi monkeys (Plecturocebus cupreus), but intranasal vasopressin decreases it.

Strong social bonds are critical to human health; however, the mechanisms by which social bonds are formed and maintained are still being elucidated. The neurohormones oxytocin (OT) and vasopressin (AVP) are considered likely candidates. Primate females, both human and nonhuman, remain understudied populations. Here, we conducted a pharmacological study coupled with a behavioral partner preference test (PPT) to better understand the mechanistic basis of attachment in adult female titi monkeys (Plecturocebus cupreus). This pair-bonding species shares a conserved form of oxytocin with humans and is an excellent model organism to study the neural basis of social bonding. We performed intranasal administration of three doses of oxytocin (IN-OT), two doses of vasopressin (IN-AVP), one dose of an oxytocin antagonist (IN-OTA) and one dose of a saline treatment. We found that compared to the saline control, the IN-AVP treatment (lower dose, 40 IU/kg) decreased the time spent in proximity to the partner and increased lip-smacking toward the stranger. We found no effects of IN-OT or IN-OTA manipulation on partner preference. In contrast, low-dose IN-AVP weakened the partner preference in female titi monkeys.

Characterization of rat gastric myogenic contractions and modulation by oxytocin and arginine-vasopressin.

BACKGROUND: Interstitial cells of Cajal generate slow wave gastric electrical activity, initiating spontaneous muscle contractions. This becomes dysrhythmic during nausea when [Arg8]-vasopressin (AVP) is also released. In human stomach AVP increased spontaneous contraction activity and muscle tone, not neuronally-mediated contractions. Rodents cannot vomit, releasing the related hormone, oxytocin (OT) instead. We hypothesised that rat stomach would behave differently. EXPERIMENTAL APPROACH: Spontaneous and electrically-evoked (EFS) contractions were measured in rat forestomach and antrum circular muscle. Custom software defined spontaneous contractions by analysing eight motility parameters. RESULTS: The forestomach was quiescent. Irregular antrum contractions became regular adjacent to the pylorus (1.7 ± 0.4 mN; 1.2 ± 0.1 contractions/min, n = 12). These were unaffected by tetrodotoxin (10-6 M), atropine (10-6 M) and L-NAME (3 × 10-4 M). In both regions, AVP (pEC50∼9.0) and OT (∼0.5 log10-unit less potent) caused contraction (greater in antrum), competitively antagonized by, respectively, SR49059 (pKB∼9.5) and L371257 (pKB∼9.0), reduced by tetrodotoxin but unaffected by atropine. In the antrum, AVP and OT (∼2 log10-units less potent/efficacious) regularized and increased spontaneous contraction amplitude, frequency, rates of contraction/decay. In both regions, EFS-evoked contractions, abolished by atropine/tetrodotoxin, were reduced by AVP and OT, with AVP more potent and efficacious, particularly in forestomach. CONCLUSION: Irregular spontaneous contractions of gastric antrum suggest variable ICC-muscle coupling. AVP and less potently, OT, enhanced frequency and force of contractions via V1A and OT receptors. Compared with human, differences in contraction regularity, potency and ability of AVP/OT to affect neuronal function suggests caution when using rat stomach to model ICC functions and nauseagenic stimuli.

Assessment of the hypothalamic-pituitary-adrenocortical axis function using a vasopressin stimulation test in neonatal foals.

BACKGROUND: Bacterial sepsis is the leading cause of death in foals and is associated with hypothalamic-pituitary-adrenocortical axis (HPAA) dysfunction. HPAA function can be evaluated by an arginine-vasopressin (AVP) stimulation test. HYPOTHESES/OBJECTIVES: Administration of AVP will stimulate a dose-dependent rise in systemic adrenocorticotropin-releasing hormone (ACTH) and cortisol in neonatal foals. There will be no response seen in corticotropin-releasing hormone (CRH) and baseline AVP will be within reference interval. ANIMALS: Twelve neonatal foals, <72 hours old. METHODS: HPAA function was assessed in foals utilizing 3 doses of AVP (2.5, 5, and 7.5 IU), administered between 24 and 48 hours of age in this randomized cross-over study. Cortisol, ACTH, CRH and AVP were measured at 0 (baseline), 15, 30, 60 and 90 minutes after AVP administration with immunoassays. The fold increase in cortisol and ACTH was calculated at 15 and 30 minutes compared to baseline. RESULTS: All doses of AVP resulted in a significant increase in cortisol concentration over time, and a dose-dependent increase in ACTH concentration over time. ACTH and cortisol were significantly increased at 15 and 30 minutes, respectively after all 3 doses of AVP compared to baseline (P < .01). There was no change in endogenous CRH after stimulation with AVP. CONCLUSION AND CLINICAL IMPORTANCE: Administration of AVP is safe and results in a significant rise in ACTH and cortisol in neonatal foals. A stimulation test with AVP (5 IU) can be considered for HPAA assessment in septic foals.

Arginine vasopressin potentiates inspiratory bursting in hypoglossal motoneurons of neonatal mice.

Vasopressin (AVP) acts as a neurotransmitter and its activity can potentiate respiratory activity. Hypoglossal (XII) motoneurons that innervate the tongue express V1a vasopressin receptors, which are excitatory. Therefore, we hypothesized that V1a receptor activation at XII motoneurons would potentiate inspiratory bursting. We developed this study to determine whether AVP can potentiate inspiratory bursting in rhythmic medullary slice preparations in neonatal (postnatal, P0-5) mice. Bath or local application of AVP potentiated inspiratory bursting compared to baseline XII inspiratory burst amplitude. Antagonizing V1a receptors revealed significant attenuation of the AVP-mediated potentiation of inspiratory bursting, while antagonism of oxytocin receptors (at which AVP has similar binding affinity) revealed a trend to attenuate AVP-mediated potentiation of inspiratory bursting. Finally, we discovered that the AVP-mediated potentiation of inspiratory bursting increases significantly with postnatal maturation from P0-5. Overall, these data support that AVP potentiates inspiratory bursting directly at XII motoneurons.

Arginine vasopressin effects on membrane potentials of preoptic area temperature-sensitive and -insensitive neurons in rat hypothalamic tissue slices.

Arginine vasopressin (AVP) plays a hypothermic regulatory role in thermoregulation and is an important endogenous mediator in this mechanism. In the preoptic area (POA), AVP increases the spontaneous firing and thermosensitivity of warm-sensitive neurons and decreases those of cold-sensitive and temperature-insensitive neurons. Because POA neurons play a crucial role in precise thermoregulatory responses, these findings indicate that there is an association between the hypothermia and changes in the firing activity of AVP-induced POA neurons. However, the electrophysiological mechanisms by which AVP controls this firing activity remain unclear. Therefore, in the present study, using in vitro hypothalamic brain slices and whole-cell recordings, we elucidated the membrane potential responses of temperature-sensitive and -insensitive POA neurons to identify the applications of AVP or V1a vasopressin receptor antagonists. By monitoring changes in the resting potential and membrane potential thermosensitivity of the neurons before and during experimental perfusion, we observed that AVP increased the changes in the resting potential of 50% of temperature-insensitive neurons but reduced them in others. These changes are because AVP enhances the membrane potential thermosensitivity of nearly 50% of the temperature-insensitive neurons. On the other hand, AVP changes both the resting potential and membrane potential thermosensitivity of temperature-sensitive neurons, with no differences between the warm- and cold-sensitive neurons. Before and during AVP or V1a vasopressin receptor antagonist perfusion, no correlation was observed between changes in the thermosensitivity and membrane potential of all neurons. Furthermore, no correlation was observed between the thermosensitivity and membrane potential thermosensitivity of the neurons during experimental perfusion. In the present study, we found that AVP induction did not result in any changes in resting potential, which is unique to temperature-sensitive neurons. The study results suggest that AVP-induced changes in the firing activity and firing rate thermosensitivity of POA neurons are not controlled by resting potentials.

The Role of Oxytocin and Vasopressin in Drug-Induced Reward-Implications for Social and Non-Social Factors.

Drug abuse is a worldwide problem that leads to negative physical, mental, and economic consequences. Although pharmacological strategies for drug addiction management have been widely studied, therapeutic options with high efficacy and a low side-effects profile are still limited. Recently, there has been a growing interest in oxytocin (OT) and vasopressin (AVP) systems as potential therapeutic targets for the treatment of drug abuse. OT and AVP are hypothalamic neuropeptides involved in numerous physiological processes. Additionally, studies show that these neurohormones are highly implicated in the modulation of a wide range of behaviors. Interestingly, ample evidence has shown that both, OT and AVP are able to decrease the consumption of different drugs of abuse, as well as to ameliorate their rewarding and reinforcing effects. Furthermore, OT and AVP have been strongly involved in prosocial effects and social reward. In particular, OT has been shown to be able to shift drug-induced reward into social-induced reward, mainly due to its interaction with the dopaminergic system. This phenomenon is also reflected in the results of clinical trials where intranasal OT shows promising efficacy in managing substance use disorder. Therefore, the aim of this review is to comprehensively characterize the involvement of OT and AVP in the rewarding and other behavioral effects of drugs of abuse in animal models, with a particular highlight on the impact of social factors on the observed effects. Understanding this relationship may contribute to higher drug development success rates, as a result of a more profound and deliberate studies design.

Arginine vasopressin deficiency and conivaptan (a V1a-V2 receptor antagonist) treatment reverses liver damage and fibrosis in rats with chronic portocaval anastomosis.

Arginine vasopressin (AVP) is a naturally occurring hormone synthesized in the hypothalamus. AVP demonstrates pro-fibrotic effects as it stimulates hepatic stellate cells to secrete transforming growth factor-ß (TGF-ß) and collagen. Previous work in liver cirrhotic (CCL4 -induced) hamsters demonstrated that AVP deficiency induced by neurointermediate pituitary lobectomy (NIL) can restore liver function. Therefore, we hypothesized that liver fibrosis would decrease in portocaval anastomosis (PCA) rats, which model chronic liver diseases, when they are treated with the V1a-V2 AVP receptor antagonist conivaptan (CV). In this study, changes in liver histology and gene expression were analysed in five experimental groups: control, PCA, NIL, PCA + NIL and PCA + CV, with NIL surgery or CV treatment administered 8 weeks after PCA surgery. Body weight gain was assessed on a weekly basis, and serum liver function, liver weight and liver glycogen content were assessed following euthanasia. Most PCA-induced phenotypes were reverted to normal levels following AVP-modelled deficiency, though hypoglycemia and ammonium levels remained elevated in the PCA + CV group. Liver histopathological findings showed a significant reversal in collagen content, less fibrosis in the triad and liver septa and increased regenerative nodules. Molecular analyses showed that the expression of fibrogenic genes (TGF-ß and collagen type I) decreased in the PCA + CV group. Our findings strongly suggest that chronic NIL or CV treatment can induce a favourable microenvironment to decrease liver fibrosis and support CV as an alternative treatment for liver fibrosis.

ß-arrestin2 Mediates the Arginine Vasopressin-Induced Expression of IL-1ß in Murine Hearts.

BACKGROUND: Circulating levels of arginine vasopressin (AVP) are elevated during cardiac stress and this could be a factor in cardiac inflammation and fibrosis. Herein, we studied the effects of AVP on interleukin-1ß (IL-1ß) production and the role(s) of ß-arrestin2-dependent signaling in murine heart. METHODS: The levels of IL-1ß mRNA and protein in adult rat cardiofibroblasts (ARCFs) was measured using quantitative PCR and ELISA, respectively. The activity of ß-arrestin2 was manipulated using either pharmacologic inhibitors or through recombinant ß-arrestin2 over-expression. These experiments were conducted to determine the roles of ß-arrestin2 in the regulation of AVP-induced IL-1ß and NLRP3 inflammasome production. The phosphorylation and activation of NF-κB induced by AVP was measured by immunoblotting. ß-arrestin2 knockout (KO) mice were used to investigate whether ß-arrestin2 mediated the AVP-induced production of IL-1ß and NLRP3, as well as the phosphorylation of the NF-κB p65 subunitin mouse myocardium. Prism GraphPad software(version 8.0), was used for all statistical analyses. RESULTS: AVP induced the expression of IL-1ß in a time-dependent manner in ARCFs but not in cultured adult rat cardiomyocytes (ARCMs). The inhibition of NF-κB with pyrrolidinedithiocarbamic acid (PDTC) prevented the AVP-induced phosphorylation of NF-κB and production of IL-1ß and NLRP3 in ARCFs. The deletion of ß-arrestin2 blocked the phosphorylation of p65 and the expression of NLRP3 and IL-1ß induced by AVP in both mouse hearts and in ARCFs. CONCLUSIONS: AVP promotes IL-1ß expression through ß-arrestin2-mediated NF-κB signaling in murine heart.

Aquaporin-2 is not alone.

Arginine-vasopressin induces water reabsorption in collecting duct principal cells through the water channels aquaporin (AQP) 2, 3, and 4. Only the presence of these AQPs allows for short-term adjustments of plasma osmolality by arginine-vasopressin. How principal cells maintain the expression of the AQPs is unclear. Zhang et al., for the first time, identify a mechanism that explains the expression of the AQPs under resting conditions. They show that the transcription coregulator, yes-associated protein, is responsible for the coordinated expression of the 3 AQPs.

Effects of maternal hypertension on cord blood Arginine vasopressin receptor expression.

Arginine vasopressin (AVP) signaling is altered in preeclampsia and physiologic stress. AVP is implicated in fluid homeostasis and cardiovascular (CV) function, which is disrupted in some progeny from preeclamptic pregnancies. However, whether altered fetal AVP signaling occurs in preeclampsia is unknown. Here, we measured CV-related transcripts (e.g., AVP receptors) in cord blood via quantitative PCR. Chronic hypertension decreased AVPR1b, AVPR2, OXTR, LNPEP, and CUL5. AVPR1a, AVPR1b, and AVPR2 were decreased while OXTR was increased in preeclamptic cord blood. In sum, we found prenatal exposure to hypertension in pregnancy alters fetal AVP signaling and may thereby prime offspring CV disease risk.

Phosphorylation of CaMK and CREB-Mediated Cardiac Aldosterone Synthesis Induced by Arginine Vasopressin in Rats with Myocardial Infarction.

Both aldosterone and arginine vasopressin (AVP) are produced in the heart and may participate in cardiac fibrosis. However, their relationship remains unknown. This study aims to demonstrate the regulation and role of AVP in aldosterone synthesis in the heart. Rats were subjected to a sham operation or myocardial infarction (MI) by ligating the coronary artery. Cardiac function and fibrosis were assessed using echocardiography and immunohistochemical staining, respectively. In addition, the effects of AVP stimulation on cardiac microvascular endothelial cells (CMECs) were studied using ELISA, real-time PCR, and Western blotting. Compared with the rats having undergone a sham operation, the MI rats had an increased LVMI, type I collagen composition, and concentrations of aldosterone and AVP in the heart but decreased cardiac function. As the MI rats aged, the LVMI, type I collagen, aldosterone, and AVP increased, while the LVMI decreased. Furthermore, AVP time-dependently induced aldosterone secretion and CYP11B2 mRNA expression in CMECs. The p-CREB levels were significantly increased by AVP. Nevertheless, these effects were completely blocked by SR49059 or partially inhibited by KN93. This study demonstrated that AVP could induce the secretion of local cardiac aldosterone, which may involve CaMK and CREB phosphorylation and CYP11B2 upregulation through V1 receptor activation.

Influence of arginine vasopressin on the ultradian dynamics of Hypothalamic-Pituitary-Adrenal axis.

Numerous studies on humans and animals have indicated that the corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) stimulate both individually and synergistically secretion of adrenocorticotropic hormone (ACTH) by corticotropic cells in anterior pituitary. With aim to characterize and better comprehend the mechanisms underlying the effects of AVP on Hypothalamic-Pituitary-Adrenal (HPA) axis ultradian dynamics, AVP is here incorporated into our previously proposed stoichiometric model of HPA axis in humans. This extended nonlinear network reaction model took into account AVP by: reaction steps associated with two separate inflows of AVP into pituitary portal system, that is synthesized and released from hypothalamic parvocellular and magnocellular neuronal populations, as well as summarized reaction steps related to its individual and synergistic action with CRH on corticotropic cells. To explore the properties of extended model and its capacity to emulate the effects of AVP, nonlinear dynamical systems theory and bifurcation analyses based on numerical simulations were utilized to determine the dependence of ultradian oscillations on rate constants of the inflows of CRH and AVP from parvocellular neuronal populations, the conditions under which dynamical transitions occur due to their synergistic action and, moreover, the types of these transitions. The results show that under certain conditions, HPA system could enter into oscillatory dynamic states from stable steady state and vice versa under the influence of synergy reaction rate constant. Transitions between these dynamical states were always through supercritical Andronov-Hopf bifurcation point. Also, results revealed the conditions under which amplitudes of ultradian oscillations could increase several-fold due to CRH and AVP synergistic stimulation of ACTH secretion in accordance with results reported in the literature. Moreover, results showed experimentally observed superiority of CRH as a stimulator of ACTH secretion compared to AVP in humans. The proposed model can be very useful in studies related to the role of AVP and its synergistic action with CRH in life-threatening circumstances such as acute homeostasis dynamic crisis, autoimmune inflammations or severe hypovolemia requiring instant or several-days sustained corticosteroid excess levels. Moreover, the model can be helpful for investigations of indirect AVP-induced HPA activity by exogenously administered AVP used in therapeutic treatment.