Action Of Arginine Vasopressin Research Articles

PILOT STUDY OF THE RELATIONSHIP OF AMBIENT COPEPTIN TO THE AQUARETIC EFFECTS OF TOLVAPTAN IN PATIENTS WITH HEART FAILURE

Tolvaptan, an arginine vasopressin (AVP) antagonist, may be a novel therapy for congestive heart failure (CHF) but AVP activation is not uniform and results have been variable in previous trials of unselected CHF patients. Copeptin, c-terminal pre-provasopressin, reflects AVP activation. We

Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates

Central arginine vasopressin (AVP) plays a critical role in mammalian social behavior and has been hypothesized to be a biomarker of certain human neurodevelopmental disorders, including autism. However, opportunities to collect post-mortem brain tissue or cerebrospinal fluid (CSF) from children are extremely limited, and the use of less invasive peripheral assessments (e.g., blood, urine, or saliva) of AVP as a proxy for more invasive central measures has not been well validated. Further, almost nothing is known about AVP biology in very young infants. Therefore in the present study we concomitantly collected basal CSF and plasma samples from N=20 neonates undergoing clinical sepsis evaluation (all were sepsis negative) and quantified AVP concentrations via well-validated enzyme-immunoassay methodology. Plasma AVP concentrations significantly and positively predicted CSF AVP concentrations (r=0.73, p=0.0021), and this relationship persisted when variance attributed to sex, gestational age, and sample collection time was controlled for in the statistical model (r=0.75, p=0.0047). These findings provide preliminary support for the use of basal plasma AVP measurement as a proxy for basal brain AVP activity in pediatric populations. Future studies are now required to determine the relationship between behavioral measures and AVP concentrations in both central and peripheral compartments in young infants and older children.

Riding the waves: evidence for a beneficial effect of increased water intake in autosomal dominant polycystic kidney disease patients?

Autosomal dominant polycystic kidney disease (ADPKD) can lead to end-stage kidney disease and accounts for ∼10% of people receiving renal replacement therapy. Until recently, no treatment had been proven to effectively postpone kidney failure. Interestingly, experimental studies that have been published over the past decades have suggested a detrimental role for the antidiuretic hormone arginine vasopressin (AVP) in ADPKD. V2 receptor activation by AVP was discovered to result in an increase of 30,50-cyclic adenosine monophosphate (cAMP) [1]. In turn, cAMP stimulates cell proliferation and fluid secretion, leading to cyst formation and cyst growth [2–4]. ADPKD patients appeared to have high serum levels of AVP, and AVP levels were, in cross-sectional studies, associated with disease severity [5] and, in longitudinal studies, with disease progression [6, 7]. These observations formed the rationale to study interventions that block this cAMP-mediated pathway using V2 receptor antagonists. In various animal models for cystic kidney disease, these interventions were successful to reduce cyst growth [8–10]. Subsequently, the selective AVP V2 receptor antagonist tolvaptan was tested for its efficacy in ADPKD patients in the TEMPO 3:4 trial. For the first time, a medical treatment proved to be beneficial with respect to kidney outcomes. In 1445 ADPKD patients, relatively early in the disease, treatment with tolvaptan slowed the rate of growth in total kidney volume by ∼50% and the rate of estimated glomerular filtration rate (eGFR) loss by ∼30% compared with placebo. In 2013, however, the US Food and Drug Administration (FDA) decided against approval of tolvaptan for the indication of slowing disease progression in ADPKD (http:// www.fda.gov/downloads/advisorycommittees/committeesmeeting materials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ ucm373520.pdf). This decision was based, amongst others, upon questions relating to the effectiveness of the drug and to tolvaptan’s risk of drug-induced liver injury. This decision felt surprising for some, because the effect on eGFR loss with tolvaptan is comparable with that of, for instance, angiotensin-II receptor blockers that are registered for diabetic nephropathy [11], a disease for which other treatments are available, whereas for ADPKD there is no renoprotective alternative. In addition, all liver function abnormalities that occurred in the TEMPO 3:4 trial were reversible after drug withdrawal. The FDA, however, extrapolated from these data that 1 per 3.000 treated ADPKD patients may develop hepatic failure for which a liver transplant would be needed (http://www.fda.gov/downloads/Advisory Committees/CommitteesMeetingMaterials/Drugs/Cardiovascular andRenalDrugsAdvisoryCommittee/UCM364582.pdf ). This should be weighed against the need for liver transplantation due to the cystic disease which occurs in a number of ADPKD patients anyway [12, 13]. Notwithstanding these considerations, the FDA decided not to register tolvaptan for the indication ADPKD, but to ask for additional evidence. The decision of the European Medicines Agency is expected late in 2014. With tolvaptan at present not being available for clinical care, other options that lower AVP activity should be considered. An alternative might be to lower AVP concentration by increasing water intake [14]. In a rat model for polycystic kidney disease, a 3.5-fold increased water intake reduced urinary osmolality, renal expression of the AVP V2 receptor and reduced kidney weight compared with normal water intake [15] (Figure 1). Given the theoretical background and the promising animal data, Higashihara et al. investigated the effects of increased water intake on disease progression in ADPKD, a clinically important and very timely topic. In their study, published in this issue of NDT, 34 ADPKD patients with a relatively preserved kidney function were divided based upon their preference into a high and a free water intake group.

Copulation or sensory cues from the female augment Fos expression in arginine vasopressin neurons of the posterodorsal medial amygdala of male rats.

BackgroundThe posterodorsal part of the medial amygdala is essential for processing reproductively salient sensory information in rodents. This is the initial brain structure where information from olfactory system and male hormones intersect. The neurochemical identity of the neurons participating in the sensory processing in medial amygdala remains presently undetermined. Many neurons in this brain structure express arginine vasopressin in a testosterone-dependent manner, suggesting that this neuropeptide is maintained by the androgenic milieu.MethodHere we use Fos, a protein expressed by recently active neurons, to quantify activation of arginine vasopressin neurons after exposure to odor from physically inaccessible female. We compare it to mating with accessible female and to reproductively innocuous odor.ResultsWe show that inaccessible female activate arginine vasopressin neurons in the male posterodorsal medial amygdala. The magnitude of activation is not further enhanced when physical access with resultant mating is granted, even though it remains undetermined if same population of AVP neurons is activated by both inaccessible female and copulation. We also show that arginine vasopressin activation cannot be fully accounted for by mere increase in the number of Fos and AVP neurons.ConclusionThese observations posit a role for the medial amygdala arginine vasopressin in reproductive behaviors, suggesting that these neurons serve as integrative node between the hormonal status of the animal and the availability of reproductive opportunities.

Effects of Atrial Natriuretic Peptide on Bicarbonate Transport in Long- and Short-Looped Medullary Thick Ascending Limbs of Rats

Atrial natriuretic peptide (ANP) is known to influence NaCl transport in the medullary thick ascending limbs (MAL), where the largest NaCl reabsorption occurs among distal nephron segments in response to arginine vasopressin (AVP). In the present study, we investigated the effect of ANP on bicarbonate (HCO3 −) transport in the MAL using an isolated tubule perfusion technique. The HCO3 − concentration was measured using free-flow ultramicro-fluorometer. We first observed basal HCO3 − reabsorption in both long- and short-looped MALs (lMALs, and sMALs, respectively). AVP inhibited HCO3 − reabsorption in both lMALs and sMALs, whereas ANP did not change HCO3 − transport. However, in the presence of AVP, ANP restored the HCO3 − reabsorption inhibited by AVP both in lMAL and sMAL. The effects of ANP on HCO3 − transport was mimicked by cyclic GMP. The mRNA expression level of the vasopressin V2 receptor in lMALs was significantly higher than in sMALs, whereas expression of the V1a receptor was unchanged. In summary, AVP inhibits HCO3 − transport, and ANP counteracts the action of AVP on HCO3 − transport both in lMALs and sMALs.

Synergistic Interactions between Cytokines and AVP at the Blood-CSF Barrier Result in Increased Chemokine Production and Augmented Influx of Leukocytes after Brain Injury

Several lines of evidence indicate that the blood-cerebrospinal fluid barrier (BCSFB), which primarily resides in the choroid plexus (CP), plays a significant pathophysiological role not only in neuroinflammatory diseases, such as multiple sclerosis, but also in traumatic brain injury (TBI). Here we investigated how arginine vasopressin (AVP) regulates function of the BCSFB in the context of post-traumatic neuroinflammation. It has previously been shown that AVP exacerbates various forms of brain injury, but the mechanisms underlying this AVP action are poorly understood. Type 1A AVP receptor is highly expressed on the CP epithelium and the CP synthesizes AVP. Using the controlled cortical impact model of TBI, we demonstrated decreased post-traumatic production of proinflammatory mediators by the CP and reduced influx of inflammatory cells across the BCSFB in AVP-deficient Brattleboro rats when compared with Long-Evans rats, a parental strain for Brattleboro rats. Arginine vasopressin was also found to play an important role in post-traumatic activation of c-Jun N-terminal kinase (JNK) in the CP. In the CP epithelial cell cultures, AVP augmented the tumor necrosis factor-α– and interleukin-1β–dependent increase in synthesis of proinflammatory mediators, including neutrophil chemoattractants, an action largely dependent on the JNK signaling pathway. Under in vivo conditions, a selective JNK inhibitor decreased the post-traumatic production of neutrophil chemoattractants by the CP and reduced the influx of neutrophils across the BCSFB. These results provide evidence for the synergistic interactions between proinflammatory cytokines and AVP, a ligand for G protein-coupled receptors, and support a pathophysiological role of AVP in post-traumatic neuroinflammation.

English

Introduction Arginine vasopressin has become an important part of the armamentarium available to paediatric cardiac intensive care physicians managing complex infants and children recovering from cardiovascular surgery. This therapy must be applied cautiously, however, as excessive afterload from its vasoconstrictive effects could be potentially detrimental to this patient population. Relative arginine vasopressin deficiency has been identified in some children recovering from cardiovascular surgery, and these children likely represent the ideal candidates for arginine vasopressin therapy. The aim of this critical review is to discuss arginine vasopressin and paediatric cardiovascular surgery. Conclusion Knowledge of endogenous plasma arginine vasopressin activity prior to initiation of therapy could therefore be helpful in clinical bedside decision making and should be the goal of future research.

Site of origin of and sex differences in the vasopressin innervation of the mouse (Mus musculus) brain

Defining how arginine vasopressin (AVP) acts centrally to regulate homeostasis and behavior is problematic, as AVP is made in multiple nuclei in the hypothalamus (i.e., paraventricular [PVN], supraoptic [SON], and suprachiasmatic [SCN]) and extended amygdala (i.e., bed nucleus of the stria terminalis [BNST] and medial amygdala [MeA]), and these groups of neurons have extensive projections throughout the brain. To understand the function of AVP, it is essential to know the site of origin of various projections. In mice, we used gonadectomy to eliminate gonadal steroid hormone-dependent expression of AVP in the BNST and MeA and electrolytic lesions to eliminate the SCN, effectively eliminating those AVP-immunoreactive projections; we also quantified AVP-immunoreactive fiber density in gonadectomized and sham-operated male and female mice to examine sex differences in AVP innervation. Our results suggest that the BNST/MeA AVP system innervates regions containing major modulatory neurotransmitters (e.g., serotonin and dopamine) and thus may be involved in regulating behavioral state. Furthermore, this system may be biased toward the regulation of male behavior, given the numerous regions in which males have a denser AVP-immunoreactive innervation than females. AVP from the SCN is found in regions important for the regulation of hormone output and behavior. Innervation from the PVN and SON is found in brain regions that likely work in concert with the well-known peripheral AVP actions of controlling homeostasis and stress response; female-biased sex differences in this system may be related to the heightened stress response observed in females.

The effect of vasopressin 1b receptors (V1bRs) blockade on the HPA axis activity in rats exposed to acute heat stress

Thermal stressors such as low and high ambient temperature elicit an abundance of neuroendocrine responses including activation of the hypothalamo-pituitary-adrenal (HPA) axis and arginine vasopressin (AVP) release. The exposure to heat is a particularly interesting model for studying AVP action because this kind of stressor represents not only an unpleasant experience but also a threat to osmotic homeostasis. As AVP has long been recognized as a hormone involved in the modulation of HPA axis activity, the aim of this study was to elucidate the role of AVP in acutely heat-exposed rats using Nelivaptan, a selective vasopressin 1b receptor (V1bR) antagonist. Rats were exposed to high ambient temperature (38°C) for 60 min. The circulating hormones were determined by ELISA or chemiluminescence, and intrapituitary adrenocorticotropic hormone (ACTH) and V1bR level were determined by western blot. The results obtained show that V1bR blockade negatively affected the increase in blood ACTH caused by heat exposure. This treatment alone, or in combination with Nelivaptan, decreased intrapituitary V1bR levels while circulating AVP concentration was increased under the same conditions. Furthermore, a strong correlation was observed between blood ACTH and corticosterone concentration. In conclusion, our results directly confirm the positive role of AVP in the regulation of ACTH secretion from the pituitary in animals exposed to heat. Moreover, the results suggest that AVP from the general circulation influences pituitary V1bR.

Age-dependent regulation of renal vasopressin V1A and V2 receptors in rats with genetic hypertension: implications for the treatment of hypertension

The role of arginine vasopressin (AVP) as a hypertensive hormone remains controversial. We have previously reported that intervention with a V1A receptor antagonist in 6-week-old prehypertensive spontaneously hypertensive rats (SHR) for 4 weeks attenuated the subsequent development of hypertension in adult SHR. This study assessed the age-dependent regulation of plasma AVP levels and kidney V1A and V2 receptor expression during the development of hypertension in SHR and in normotensive Sprague Dawley rats. Systolic blood pressure (SBP), plasma AVP, and plasma renin activity (PRA) and kidney V1A and V2 receptor expression were assessed. SHR were studied at three ages: prehypertensive (6 weeks), developed hypertension (10 weeks), and established hypertension (16 weeks). SBP increased with age in SHR (P < .01) and both plasma AVP (P < .01) and PRA (P < .05) were increased in 10-week-old SHR. Renal medulla V1A receptor gene expression decreased in 10-week and 16-week-old SHR (P < .01), with a reduction in V1A receptor protein in the inner medulla of 16-week-old SHR (P < .05) compared with young SHR. There was no change in V2 receptor expression during the development of hypertension. In normotensive rats, plasma AVP, PRA, and kidney V1A and V2 receptor expression were unchanged over time. These data suggest that in SHR, activation of plasma AVP and the renal V1A receptor occurs during developing hypertension, with downregulation when hypertension is established. The use of V1A receptor antagonists in prehypertension may provide a unique opportunity for the prevention of hypertension in high-risk individuals.

Vasopressin inhibits apoptosis in renal collecting duct cells

The peptide hormone arginine vasopressin (AVP) plays a critical role in regulating salt and water transport in the mammalian kidney. Recent studies have also demonstrated that AVP can promote cell survival in neuronal cells through V1 receptors. The current study addresses whether AVP can inhibit apoptosis in kidney collecting duct cells via V2 receptors and also explores the downstream signaling pathways regulating this phenomenon. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling analysis and caspase cleavage assays demonstrated that 1-desamino-8-d-arginine vasopressin (dDAVP) inhibited apoptosis induced by various agents (staurosporine, actinomycin D, and cycloheximide) in cultured mouse cortical collecting duct cells (mpkCCD). Incubation with dDAVP also inhibited apoptosis induced by the phosphatidylinositol 3-kinase (PI3K) pathway inhibitor LY294002, suggesting that the antiapoptotic effects of dDAVP are largely independent of PI3K signaling. The V2 receptor antagonist SR121463 completely abolished the antiapoptotic effects of dDAVP. In addition, incubation with 8-cpt-cAMP, a cell-permeable analog of cAMP, reproduced the antiapoptotic effects of dDAVP. Both dDAVP and 8-cpt-cAMP increased phosphorylation of proapoptotic Bcl-2 family members Bad and Bok. Bad phosphorylation at Ser-112 and Ser-155 is known to inhibit its proapoptotic activity. Preincubation with H89 blocked dDAVP-induced phosphorylation of both Bad and Bok, suggesting dependence on protein kinase A (PKA). This study provides evidence that AVP can inhibit apoptosis through the V2 receptor and downstream cAMP-mediated pathways in mammalian kidney. The antiapoptotic action of AVP may be relevant to a number of physiological and pathophysiological conditions including osmotic tolerance in the inner medulla, escape from AVP-induced antidiuresis, and polycystic kidney disease.

Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems

The neurohypophysial hormone arginine vasopressin (AVP) is essential for a wide range of physiological functions, including water reabsorption, cardiovascular homeostasis, hormone secretion, and social behavior. These and other actions of AVP are mediated by at least three distinct receptor subtypes: V1a, V1b, and V2. Although the antidiuretic action of AVP and V2 receptor in renal distal tubules and collecting ducts is relatively well understood, recent years have seen an increasing understanding of the physiological roles of V1a and V1b receptors. The V1a receptor is originally found in the vascular smooth muscle and the V1b receptor in the anterior pituitary. Deletion of V1a or V1b receptor genes in mice revealed that the contributions of these receptors extend far beyond cardiovascular or hormone-secreting functions. Together with extensively developed pharmacological tools, genetically altered rodent models have advanced the understanding of a variety of AVP systems. Our report reviews the findings in this important field by covering a wide range of research, from the molecular physiology of V1a and V1b receptors to studies on whole animals, including gene knockout/knockdown studies.

Diagnosis and Management of Hyponatremia in Cancer Patients

Hyponatremia, a common electrolyte abnormality in oncology practice, may be a negative prognostic factor in cancer patients based on a systematic analysis of published studies. The largest body of evidence comes from small-cell lung cancer (SCLC), for which hyponatremia was identified as an independent risk factor for poor outcome in six of 13 studies. Hyponatremia in the cancer patient is usually caused by the syndrome of inappropriate antidiuretic hormone (SIADH), which develops more frequently with SCLC than with other malignancies. SIADH may be driven by ectopic production of arginine vasopressin (AVP) by tumors or by effects of anticancer and palliative medications on AVP production or action. Other factors may cause hypovolemic hyponatremia, including diarrhea and vomiting caused by cancer therapy. Hyponatremia may be detected on routine laboratory testing before or during cancer treatment or may be suggested by the presence of mostly neurological symptoms. Treatment depends on several factors, including symptom severity, onset timing, and extracellular volume status. Appropriate diagnosis is important because treatment differs by etiology, and choosing the wrong approach can worsen the electrolyte abnormality. When hyponatremia is caused by SIADH, hypertonic saline is indicated for acute, symptomatic cases, whereas fluid restriction is recommended to achieve a slower rate of correction for chronic asymptomatic hyponatremia. Pharmacological therapy may be necessary when fluid restriction is insufficient. The orally active, selective AVP receptor 2 (V(2))-receptor antagonist tolvaptan provides a mechanism-based option for correcting hyponatremia caused by SIADH or other conditions with inappropriate AVP elevations. By blocking AVP effects in the renal collecting duct, tolvaptan promotes aquaresis, leading to a controlled increase in serum sodium levels.

Role of Estrogen in the Urinary Concentrating Mechanism

The anti‐diuretic hormone, arginine vasopressin (AVP) concentrates urine by enhancing water, salt and urea re‐absorption in the renal collecting duct. We hypothesized that estrogen may play a key role in the response of the renal collecting duct to AVP. We used CD1 male and female mice (8‐weeks old, n=8–10) and water restricted (WR, 48 hr) to increase endogenous AVP levels. In another study, we used CD1 female mice which were ovariectomized (OVX) for 5 weeks. Urine osmolality in WR female mice (4874 mOsm/kg.H20) compared to WR males (3962 mOsm/kg.H2O) was significantly higher (25%). Consistent with elevated AVP levels during WR, medullary AQP2 was significantly increased in females (mRNA, 2.12‐fold and protein, 151%). However, following ovariectomy neither AQP2 nor AQP3 mRNA expression levels were altered versus control mice. WR had a similar response in either gender in increasing medullary mRNA expression of the urea transporters (UTA1, UTA3) but decreasing the sodium channels (ENaCβ and ENaCγ). Our data suggests that females are more sensitive to the actions of AVP in the renal medulla which results in higher water re‐absorption from urine possibly through increased expression of AQP2 channels leading to higher urine osmolality. However loss of estrogen (OVX) is not associated with a change in AQP2 expression in females. Support: DK073611 (HLB), NSF ADVANCE (HLB, JF) and HL07249 (SC).

Scientific Basis of Hyponatremia and Its Clinical Presentations

Purpose To describe causes, pathophysiologic mechanisms, and classifications of hyponatremia, and to describe clinical symptoms and underlying disease states associated with different levels of hyponatremia. Summary The key to comprehending hyponatremia is to understand body water content and plasma osmolality and accurately assess arterial volume. Hyponatremia results from sodium dilution because of retained water or sodium depletion because of electrolyte loss in excess of water loss. Body sodium, water, and extracellular fluid (ECF) volume are tightly regulated by mechanisms that act to maintain a closely controlled concentration of solutes in the ECF. These forces act to regulate water content and sodium excretion to maintain normal intravascular volume. The body closely defends normal plasma osmolality within a narrow range primarily by controlling the release of arginine vasopressin (AVP) and via the thirst mechanism. A number of factors can stimulate inappropriate AVP release and cause or worsen hyponatremia. Dysregulation of AVP plays an important role in heart failure and cirrhosis, common causes of hypervolemic hyponatremia. Conclusion Body water content and plasma osmolality are tightly regulated by the action of AVP. A variety of disease states are associated with hyponatremia related to inappropriate AVP release. The cause of the electrolyte disturbance must be determined, because it can have profound implications for treatment. Differential diagnosis can be guided by observation of the rapidity of onset as well as volume status changes. If untreated or treated inappropriately, hyponatremia can impact morbidity and mortality.

Increasing expression of oxytocin and vasopressin receptors in the equine conceptus between Days 10 and 16 of pregnancy

Oxytocin (OT) and arginine vasopressin (AVP) have been detected in the yolk sac of the pre-attachment equine conceptus. Therefore, we have assessed the presence of OT and AVP receptors in equine conceptuses between Days 10 and 16 of pregnancy by qualitative PCR, quantitative PCR and immunohistochemistry. Expression of OT receptor and of the AVP receptors V1aR and V2R could be verified after sequencing the RT-PCR products of the expected length. The size of conceptuses used for quantitative PCR significantly increased with day of pregnancy (P<0.01) as did their quantitative expression of OTR (P<0.01). Immunohistochemistry of OTR resulted in weak trophectodermal abundance on Day 10, increasing at Day 12. On Day 14, staining intensity increased in individual cells of the trophectoderm while it decreased in other cells; this trend became more apparent on Day 16. The endoderm of the trophoblast and surrounding subtrophoblastic compartments always showed moderate staining for OTR. On Day 10 immunoreactive V2R protein was localised in the trophectodermal apical membrane; on Day 12 it was also present in the basal membrane and weakly in the cytoplasm. On Day 14 only individual trophectodermal cells showed positive supranuclear cytoplasmic areas or V2R, whereas on Day 16 about one-third of the trophectodermal cells were stained entirely and intensely positive. These results suggest an involvement of OT and AVP action in the development and expansion of the early equine conceptus.

Genetic deletion of the P2Y2receptor offers significant resistance to development of lithium-induced polyuria accompanied by alterations in PGE2signaling

Lithium (Li)-induced polyuria is due to resistance of the medullary collecting duct (mCD) to the action of arginine vasopressin (AVP), apparently mediated by increased production of PGE(2). We previously reported that the P2Y(2) receptor (P2Y(2)-R) antagonizes the action of AVP on the mCD and may play a role in Li-induced polyuria by enhancing the production of PGE(2) in mCD. Hence, we hypothesized that genetic deletion of P2Y(2)-R should ameliorate Li-induced polyuria. Wild-type (WT) or P2Y(2)-R knockout (KO) mice were fed normal or Li-added diets for 14 days and euthanized. Li-induced polyuria, and decreases in urine osmolality and AQP2 protein abundance in the renal medulla, were significantly less compared with WT mice despite the lack of differences in Li intake or terminal serum or inner medullary tissue Li levels. Li-induced increased urinary excretion of PGE(2) was not affected in KO mice. However, prostanoid EP(3) receptor (EP3-R) protein abundance in the renal medulla of KO mice was markedly lower vs. WT mice, irrespective of the dietary regimen. The protein abundances of other EP-Rs were not altered across the groups irrespective of the dietary regimen. Ex vivo stimulation of mCD with PGE(2) generated significantly more cAMP in Li-fed KO mice (130%) vs. Li-fed WT mice (100%). Taken together, these data suggest 1) genetic deletion of P2Y(2)-R offers significant resistance to the development of Li-induced polyuria; and 2) this resistance is apparently due to altered PGE(2) signaling mediated by a marked decrease in EP3-R protein abundance in the medulla, thus attenuating the EP3-mediated decrease in cAMP levels in mCD.

Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine

The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are evolutionarily highly conserved mediators in the regulation of complex social cognition and behaviour. Recent studies have investigated the effects of OXT and AVP on human social interaction, the genetic mechanisms of inter-individual variation in social neuropeptide signalling and the actions of OXT and AVP in the human brain as revealed by neuroimaging. These data have advanced our understanding of the mechanisms by which these neuropeptides contribute to human social behaviour. OXT and AVP are emerging as targets for novel treatment approaches--particularly in synergistic combination with psychotherapy--for mental disorders characterized by social dysfunction, such as autism, social anxiety disorder, borderline personality disorder and schizophrenia.

Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease

Tolvaptan and related V(2)-specific vasopressin receptor antagonists have been shown to delay disease progression in animal models of polycystic kidney disease. Slight elevations in serum creatinine, rapidly reversible after drug cessation, have been found in clinical trials involving tolvaptan. Here, we sought to clarify the potential renal mechanisms to see whether the antagonist effects were dependent on underlying renal function in 20 patients with autosomal dominant polycystic kidney disease (ADPKD) before and after 1 week of daily split-dose treatment. Tolvaptan induced aquaresis (excretion of solute-free water) and a significant reduction in glomerular filtration rate (GFR). The serum uric acid increased because of a decreased uric acid clearance, and the serum potassium fell, but there was no significant change in renal blood flow as measured by para-aminohippurate clearance or magnetic resonance imaging (MRI). No correlation was found between baseline GFR, measured by iothalmate clearance, and percent change in GFR induced by tolvaptan. Blinded post hoc analysis of renal MRIs showed that tolvaptan significantly reduced total kidney volume by 3.1% and individual cyst volume by 1.6%. Preliminary analysis of this small cohort suggested that these effects were more noticeable in patients with preserved renal function and with larger cysts. No correlation was found between changes of total kidney volume and body weight or estimated body water. Thus, functional and structural effects of tolvaptan on patients with ADPKD are likely due to inhibition of V(2)-driven adenosine cyclic 3',5'-monophosphate generation and its aquaretic, hemodynamic, and anti-secretory actions.

The Science Behind Hyponatremia and Its Clinical Manifestations

Body sodium, water, and extracellular fluid volume are tightly regulated by neural, humoral, and renal mechanisms to maintain osmolality in extracellular fluid and to maintain normal intravascular volume. This is accomplished by controlling sodium content in extracellular fluid. In the normal physiologic state, total body water (which accounts for ~60% of body weight) is distributed among three compartments: intracellular, interstitial, and intravascular spaces. About two thirds of total body water is intracellular fluid. Potassium is the major intracellular cation, and sodium is the major extracellular cation. Body water content and plasma osmolality are tightly regulated by the action of arginine vasopressin on renal tubules. A wide variety of disease states are associated with a nonosmotic response of arginine vasopressin, also known as the antidiuretic hormone. Determination of the serum sodium concentration is the most direct measure of hyponatremia. The vasopressin V(2)-receptor antagonists are effective aquaretic agents and correct hyponatremia in several hyponatremic disorders.