Plasma Arginine Vasopressin Levels Research Articles

A cAMP-biosensor-based assay for measuring plasma arginine–vasopressin levels

Arginine–vasopressin (AVP), a cyclic peptide hormone composed of nine amino acids, regulates water reabsorption by increasing intracellular cyclic adenosine monophosphate (cAMP) concentrations via the vasopressin V2 receptor (V2R). Plasma AVP is a valuable biomarker for the diagnosis of central diabetes insipidus (CDI) and is commonly measured using radioimmunoassay (RIA). However, RIA has several drawbacks, including a long hands-on time, complex procedures, and handling of radioisotopes with special equipment and facilities. In this study, we developed a bioassay to measure plasma AVP levels using HEK293 cells expressing an engineered V2R and a cAMP biosensor. To achieve high sensitivity, we screened V2R orthologs from 11 various mammalian species and found that the platypus V2R (pV2R) responded to AVP with approximately six-fold higher sensitivity than that observed by the human V2R. Furthermore, to reduce cross-reactivity with desmopressin (DDAVP), a V2R agonist used for CDI treatment, we introduced a previously described point mutation into pV2R, yielding an approximately 20-fold reduction of responsiveness to DDAVP while maintaining responsiveness to AVP. Finally, a comparison of plasma samples from 12 healthy individuals demonstrated a strong correlation (Pearson's correlation value: 0.90) between our bioassay and RIA. Overall, our assay offers a more rapid and convenient method for quantifying plasma AVP concentrations than existing techniques.

The role of arginine vasopressin in the pathophysiology of microvascular dysfunction after ST-elevation myocardial infarction

Abstract Background Coronary microvascular dysfunction (CMD) after ST-elevation myocardial infarction (STEMI), in part due to impaired vasomotor tone, predicts heart failure and mortality at one year. Arginine vasopressin (AVP) may be implicated in CMD as it is released during MI and has known vasoconstrictor effects, but data in humans are lacking. We examined the role of copeptin, a stable plasma surrogate marker of AVP, in humans with STEMI. Methods We included three cohorts. The first cohort prospectively recruited patients presenting with STEMI eligible for primary percutaneous coronary intervention (PPCI) (n= 55). In this cohort, the index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured in the culprit artery at the end of the procedure. The second cohort included 45 patients from a sub-study of the CAPRI trial (Evaluating the effectiveness of intravenous Ciclosporin on reducing reperfusion injury in pAtients undergoing PRImary PCI; NCT02390674). In this cohort, patients underwent cardiac magnetic resonance (CMR) imaging at one and 12 weeks post-MI, allowing precise measurement of infarct size and microvascular obstruction (MVO), the imaging hallmark of CMD. Both cohorts had serum copeptin measured at four time points. The 3rd cohort included two patients undergoing trans-coronary alcohol ablation of septal hypertrophy (TASH). Serial copeptin measurements were performed in this cohort to assess copeptin release in an induced ischaemia setting. Results One hundred patients were included from both STEMI cohorts. Copeptin levels paralleled AVP plasma levels closely, with mean levels falling in the 24 hours after reperfusion from 92.5 pmol/L to 6.4 pmol/L, and this was mirrored in the TASH patients. Copeptin release wasinversely linked to admission diastolic blood pressure (DBP) (Spearman’s rho r= -0.431, p=0.001), but did not correlate with systolic blood pressure. Copeptin levels at 24 hours were significantly associated with high IMR (r=0.372, p=0.011) and low CFR (r=-0.467, p=0.001). Patients with IMR >40 also had significantly higher mean copeptin concentration at 24 hours than those with lower IMR (19.1 vs 7.1pmol/L, p=0.019, Figure 1). Finally, patients with MVO on early CMR showed a trend towards higher mean copeptin concentration at baseline, although this was not statistically significant. Notably, copeptin levels were not associated with infarct size on either early or late CMR. Conclusions Copeptin, and therefore AVP, is released secondary to acute myocardial ischaemia, particularly in response to reduced coronary perfusion, as evidenced by the inverse correlation with DBP, and normalises by 24 hours. However, evidence of CMD was seen in patients with persistently elevated copeptin at 24 hours, suggesting AVP may contribute to microcirculatory dysfunction. AVP receptor antagonists may represent a novel therapeutic option in patients with STEMI and evidence of microvascular dysfunction.

THU115 Sex-Specific And Shared Associations Between Vasopressin Levels And Body Composition In Adults With Obesity

Abstract Disclosure: F. Galbiati: None. M. Wronski: None. A. Aulinas Maso: None. M. Muhammed: None. R. Boutin: None. K. Liya: None. S. Carter: None. H. Nazarloo: None. J.M. Davis: None. K. Holman: None. J. Gydus: None. S. Smith: None. E. Asanza: None. M. Bredella: None. M. Torriani: None. F. Plessow: None. E.A. Lawson: Advisory Board Member; Self; OXT Therapeutics. Grant Recipient; Self; Tonix Pharmaceuticals. Background: Arginine-vasopressin (AVP) is a sexually dimorphic neurohormone shown in preclinical studies to have relevant metabolic effects, including reducing food intake, inducing lipolysis, and promoting muscle regeneration in male mice. However, findings are inconsistent, possibly due to the opposing effects of AVP at different receptor subtypes, and little is known about the effects of AVP on metabolism in humans. We hypothesized that AVP may act as signal of energy availability, such that in adults with obesity, integrated AVP levels around a standardized meal would be positively associated with BMI, adiposity, and lean mass. We also predicted that relationships between AVP and body composition measures would differ by sex. Methods: We performed a cross-sectional study of 53 adults with obesity (56% females; age [mean±SD] 33.7±6.2 years; BMI 36.9±4.9 kg/m2). We obtained plasma AVP levels fasting and 30, 60, and 120 minutes after a standardized meal. We computed area under the curve with respect to ground (AUC) for an integrated measure of AVP levels around the meal. Participants underwent body composition assessment by dual-energy X-ray absorptiometry (total fat, truncal fat, and lean mass) and magnetic resonance imaging (abdominal visceral and subcutaneous fat). We performed Pearson’s correlation (normally distributed variables) and Spearman’s correlation (non-normally distributed variables) to investigate the relationship between AVP levels and body composition parameters. Fisher’s Z test was performed to analyze the difference between correlation coefficients across sexes. Results: Age and AVP AUC did not differ based on sex (p=0.300). Total fat mass (p=0.013) was higher while total lean mass (p<0.0001) and abdominal visceral fat (p=0.001) were lower in females than males; BMI, truncal fat, and abdominal subcutaneous fat did not differ by sex (p’s≥0.09). Across all participants, AVP AUC levels were positively correlated with BMI (rs=0.36, p=0.008), total fat mass (r=0.33, p=0.013), truncal fat (r=0.35; p=0.010), abdominal subcutaneous fat (r=0.30, p=0.028), and total lean mass (r=0.38, p=0.005), but not with abdominal visceral fat (p=0.331). Within sex-based group, a robust positive correlation between AVP AUC and abdominal subcutaneous fat mass was present in males (r=0.56, p=0.004), but not females (r=0.04, p=0.592) [(by Fisher’s Z test, p=0.024). There were no other sex differences in correlations (by Fisher’s Z test, p≥0.108). Conclusions: Our data in humans showing a link between integrated AVP and body composition support preclinical data indicating that AVP is a metabolically active hormone. Additionally, we identified sex differences in the relationship between AVP and subcutaneous fat mass. Further investigation of sex-specific and shared metabolic effects of AVP in humans will be important. Presentation: Thursday, June 15, 2023

Effects of a high-salt diet on MAP and expression levels of renal ENaCs and aquaporins in SHR.

An increase in blood pressure by a high-salt (HS) diet may change the expression levels of renal epithelial sodium channels (ENaCs) and aquaporins (AQPs). Spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats were exposed to HS and regular-salt (RS) diets for 6 weeks. Mean arterial pressure (MAP) and plasma atrial natriuretic peptide (ANP), angiotensin II (Ang II), aldosterone, and arginine vasopressin (AVP) levels were determined. Expression of mRNA levels of ENaCs and AQPs were quantified by real-time PCR. The MAP was higher in SHRs on the HS diet. Plasma Ang II and aldosterone levels were low while plasma ANP level was high in both strains of rats. Renal expression of mRNA levels of α-, β-, and γ-ENaCs was lowered in SHRs on the HS diet. Meanwhile, renal AQP1, AQP2, and AQP7 mRNA expression levels were lowered in both strains of rats on the HS diet. Suppression of mRNA expression levels of ENaC and AQP subunits suggests that the high-salt-induced increase in the MAP of SHR may not be solely due to renal sodium and water retention.

Relationship between postpartum depression and plasma vasopressin level at 6–8 weeks postpartum: a cross-sectional study

Postpartum depression (PPD) is the most important postpartum mood disorder due to its significant effect on both the infant and family health. Arginine vasopressin (AVP) has been suggested as a hormonal agent involved in the development of depression. The purpose of this study was to investigate the relationship between the plasma concentrations of AVP and the score of Edinburgh Postnatal Depression Scale (EPDS). This cross-sectional study was conducted in 2016–2017 in Darehshahr Township, Ilam Province, Iran. In the first phase, 303 pregnant women, who were at 38 weeks, met the inclusion criteria, and were not depressed (according to their EPDS scores) were included in the study. In the 6–8 week postpartum follow-up, using the EPDS, 31 depressed individuals were diagnosed and referred to a psychiatrist for confirmation. The maternal venous blood samples of 24 depressed individuals still meeting the inclusion criteria and 66 randomly selected non-depressed subjects were obtained to measure their AVP plasma concentrations with ELISA assay. There was a significant positive relationship between plasma AVP levels and the EPDS score (P = 0.000, r = 0.658). Also the mean plasma concentration of AVP was significantly higher in the depressed group (41.35 ± 13.75 ng/ml) than in the non-depressed group (26.01 ± 7.83 ng/ml) (P < 0.001). In a multiple logistic regression model for various parameters, increased vasopressin levels were associated with increased odds of PPD (OR = 1.15, 95% CI = 1.07–1.24, P = 0.000). Furthermore, multiparity (OR = 5.45, 95% CI = 1.21–24.43, P = 0.027) and non-exclusive breastfeeding (OR = 13.06, 95% CI = 1.36–125, P = 0.026) were associated with increased odds of PPD. Maternal gender preference (having a baby of desired and desired sex) decreased the odds of PPD (OR = 0.13, 95% CI = 0.02–0.79, P = 0.027 and OR = 0.08, 95% CI = 0.01–0.5, P = 0.007). AVP seems to be a contributor to clinical PPD by affecting the hypothalamic–pituitary–adrenal (HPA) axis activity. Furthermore, primiparous women had significantly lower EPDS scores.

PS-BPB10-1: INVOLVEMENT OF RENAL TUBULAR NFAT5 IN THE REGULATION OF BLOOD PRESSURE AND BODY FLUID VOLUME

Objective: Nuclear factor of activated T-cells 5 (NFAT5) is an osmoresponsive transcription factor that activates osmoprotective genes to protect cells against hypertonicity. Renal tubular cell-specific NFAT5 knockout (KO) mice have been shown to exhibit polyuria, hypernatremia, low urinary sodium excretion, and increased expression of the epithelial sodium channel (ENaC) in the kidney. In the present study, regulation of blood pressure (BP) as well as that of body fluid volume were examined in the wild type (WT) mice and NFAT5 KO mice. Methods: The BP of KO mice and WT mice was measured using radiotelemetry method. The mice were fed with regular salt diet (RSD, 0.3% NaCl chow) or high salt diet (HSD, 8% NaCl chow) followed by the treatment with amiloride, an ENaC blocker. To assess body fluid volume, the plasma renin activity (PRA) and the plasma aldosterone concentration (PAC) were measured at the condition of RSD and HSD, together with plasma arginine vasopressin (AVP) and hematocrit (Ht) levels. Results: Compared to WT mice, the mean BP was significantly higher in KO mice both at the condition with RSD and that with HSD in dark period, but not in light period. Treatment with amiloride significantly decreased the mean BP in KO mice with HSD to the level of WT mice with HSD in dark period. PRA, PAC, and AVP levels were not significantly different between in WT and KO mice with RSD. HSD significantly decreased PRA and PAC and tended to increase the AVP level both in WT and KO mice. The Ht level was significantly lower in KO mice than in WT mice regardless of RSD or HSD (WT with RSD, 42.6 ± 0.5%; WT with HSD, 42.8 ± 0.6%; KO with RSD, 38.3 ± 0.4%; KO with HSD, 39.0 ± 0.4%, n = 4). Conclusions: The results suggest that the renal tubular cell-specific NFAT5 KO mice exhibit excess body fluid retention induced by sodium reabsorption through ENaC, leading to salt-sensitive hypertension. Such phenotypes seem to be independent of the systemic renin-angiotensin-aldosterone and AVP systems. Renal tubular NFAT5 could integrate urine concentration and sodium reabsorption in the kidney, thus preventing salt-dependent hypertension.

Pathophysiology of Drug-Induced Hyponatremia

Drug-induced hyponatremia caused by renal water retention is mainly due to syndrome of inappropriate antidiuresis (SIAD). SIAD can be grouped into syndrome of inappropriate antidiuretic hormone secretion (SIADH) and nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The former is characterized by uncontrolled hypersecretion of arginine vasopressin (AVP), and the latter is produced by intrarenal activation for water reabsorption and characterized by suppressed plasma AVP levels. Desmopressin is useful for the treatment of diabetes insipidus because of its selective binding to vasopressin V2 receptor (V2R), but it can induce hyponatremia when prescribed for nocturnal polyuria in older patients. Oxytocin also acts as a V2R agonist and can produce hyponatremia when used to induce labor or abortion. In current clinical practice, psychotropic agents, anticancer chemotherapeutic agents, and thiazide diuretics are the major causes of drug-induced hyponatremia. Among these, vincristine and ifosfamide were associated with sustained plasma AVP levels and are thought to cause SIADH. However, others including antipsychotics, antidepressants, anticonvulsants, cyclophosphamide, and thiazide diuretics may induce hyponatremia by intrarenal mechanisms for aquaporin-2 (AQP2) upregulation, compatible with NSIAD. In these cases, plasma AVP levels are suppressed by negative feedback. In rat inner medullary collecting duct cells, haloperidol, sertraline, carbamazepine, and cyclophosphamide upregulated V2R mRNA and increased cAMP production in the absence of vasopressin. The resultant AQP2 upregulation was blocked by a V2R antagonist tolvaptan or protein kinase A (PKA) inhibitors, suggestive of the activation of V2R-cAMP-PKA signaling. Hydrochlorothiazide can also upregulate AQP2 in the collecting duct without vasopressin, either directly or via the prostaglandin E2 pathway. In brief, nephrogenic antidiuresis, or NSIAD, is the major mechanism for drug-induced hyponatremia. The associations between pharmacogenetic variants and drug-induced hyponatremia is an area of ongoing research.

Evaluating the neuropeptide-social cognition link in ageing: the mediating role of basic cognitive skills.

The roles of oxytocin (OT) and arginine-vasopressin (AVP) as crucial modulators of social cognition and related behaviours have been extensively addressed in the literature. The involvement of these neuropeptides in social cognition in ageing, however, and a potential mediating effect of basic cognitive capacities on this link, are not well understood. To fill these research gaps, this study assessed associations of plasma OT and AVP levels with dynamic emotion identification accuracy in generally healthy older men (aged 55-95 years) and probed the underlying roles of crystallized and fluid cognition in these associations. Higher plasma OT levels were associated with lower accuracy in dynamic emotion identification, with this negative relationship fully mediated by cognition. For plasma AVP levels, in contrast, there was no association with dynamic emotion identification accuracy. Integrated within existing theoretical accounts, results from this study advance understanding of the neuropeptide-social cognition link in ageing and support basic cognitive capacities as mediators in this association. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'.

Altered arginine vasopressin-cyclic AMP-aquaporin 2 pathway in patients with chronic kidney disease.

In the collecting ducts of the kidney, arginine vasopressin (AVP), cyclic adenosine monophosphate (cAMP), and aquaporin 2 (AQP2) play a pivotal role in maintaining fluid volume and serum osmolality in humans. However, their association among those with chronic kidney disease (CKD) remains uncertain. We prospectively included the out-patients with CKD and measured osmolality-related biomarkers including plasma AVP, urine cAMP, urine AQP2, and urine osmolality levels. Association among these parameters at each CKD stage was investigated. A total of 121 patients were included (median age 71years old [61-78], 89 men, estimated glomerular filtration ratio 28.6 [16.4-45.3] mL/min/1.73m2). Serum osmolality increased as CKD progression, accompanying incremental plasma AVP levels, whereas urine cAMP, urine AQP2, and urine osmolality decreased as CKD progression. At advanced CKD stage, urine cAMP remained low irrespective of the AVP stimulation, whereas urine cAMP levels varied according to the levels of plasma AVP at less advanced CKD stage. The associations between urine cAMP and urine AQP2 and between urine AQP2 and urine osmolality remained preserved irrespective of the CKD stages. Vasopressin type-2 receptor seems to be particularly impaired in patients with advanced CKD, whereas the signal cascade of the downstream of vasopressin type-2 receptor is relatively preserved. Urine cAMP might be a promising marker to estimate the residual function of the collecting duct.

Alterations in oxytocin and vasopressin in men with problematic pornography use: The role of empathy.

BackgroundAddictive behaviors share clinical, genetic, neurobiological and phenomenological parallels with substance addictions. Despite the prevalence of compulsive sexual behaviors, particularly problematic pornography use (PPU), how neuroendocrine systems relate to PPU is not well understood. Preclinical studies demonstrate alterations in oxytocin and arginine vasopressin (AVP) function in animal models of addiction, but no human study has tested their involvement in PPU.MethodParticipants included 122 males; 69 reported PPU, and 53 were demographically-matched participants without PPU. Plasma oxytocin and AVP levels and oxytocin-to-AVP balance were measured at baseline. Salivary oxytocin was assessed at baseline and in response to four videos depicting neutral/positive social encounters. Participants reported on empathy and psychiatric symptoms.ResultsBaseline plasma AVP levels were elevated in men with PPU, and the ratio of oxytocin-to-vasopressin suggested AVP dominance. Men with PPU reacted with greater oxytocin increases to presentation of neutral/positive social stimuli. Decreased empathic tendencies were found in men with PPU, and this reduced empathy mediated links between oxytocin and pornography-related hypersexuality. Structural equation modeling revealed three independent paths to pornography-related hypersexuality; two direct paths via increased AVP and higher psychiatric symptoms and one indirect path from oxytocin to pornography-related hypersexuality mediated by diminished empathy.ConclusionsFindings are among the first to implicate neuropeptides sustaining mammalian attachment in the pathophysiology of pornography-related hypersexuality and describe a neurobiological mechanism by which oxytocin-AVP systems and psychiatric symptomatology may operate to reduce empathy and lead to pornography-related hypersexuality.

Hypothalamic kinin B1 receptor mediates orexin system hyperactivity in neurogenic hypertension

Brain orexin system hyperactivity contributes to neurogenic hypertension. We previously reported upregulated neuronal kinin B1 receptor (B1R) expression in hypertension. However, the role of central B1R activation on the orexin system in neurogenic hypertension has not been examined. We hypothesized that kinin B1R contributes to hypertension via upregulation of brain orexin-arginine vasopressin signaling. We utilized deoxycorticosterone acetate (DOCA)-salt hypertension model in wild-type (WT) and B1R knockout (B1RKO) mice. In WT mice, DOCA-salt-treatment increased gene and protein expression of orexin A, orexin receptor 1, and orexin receptor 2 in the hypothalamic paraventricular nucleus and these effects were attenuated in B1RKO mice. Furthermore, DOCA-salt- treatment increased plasma arginine vasopressin levels in WT mice, but not in B1RKO mice. Cultured primary hypothalamic neurons expressed orexin A and orexin receptor 1. B1R specific agonist (LDABK) stimulation of primary neurons increased B1R protein expression, which was abrogated by B1R selective antagonist R715 but not by the dual orexin receptor antagonist, ACT 462206, suggesting that B1R is upstream of the orexin system. These data provide novel evidence that B1R blockade blunts orexin hyperactivity and constitutes a potential therapeutic target for the treatment of salt-sensitive hypertension.

Nephrogenic Syndrome of Inappropriate Antidiuresis Mimicking Hyporeninemic Hypoaldosteronism: Case Report of Two Infants

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an X-linked disease caused by activating mutations in the arginine vasopressin (AVP) receptor-2 (AVPR2) gene. Affected patients excrete concentrated urine despite very low levels of AVP, and consequently develop euvolemic hyponatremia. Due to its low frequency, patients may be misdiagnosed and treated incorrectly. We report two related male infants with NSIAD that was initially confused with hyporeninemic hypoaldosteronism (HH). First, a 2-month-old male presented with hyponatremia, low plasma osmolality, relatively high urine osmolality, and low plasma renin-aldosterone levels. These clinical and laboratory findings were compatible with syndrome of inappropriate antidiuretic hormone (ADH) secretion without apparent cause. Consequently, fludrocortisone was initiated with a presumptive diagnosis of HH. While correcting hyponatremia, fludrocortisone treatment led to hypertension and was discontinued promptly. The second patient, aged one year, was admitted with a history of oligohydramnios, had been hospitalized four times due to hyponatremia since birth, and had a diagnosis of epilepsy. Similarly, the second infant had clinical and laboratory findings compatible with syndrome of inappropriate ADH secretion with no apparent cause. Fluid restriction normalized his serum sodium despite the plasma AVP level being undetectable. In both infants, AVPR2 gene analysis revealed a known mutation (c.409C>T; p.R137C) and confirmed the diagnosis of NSIAD. In conclusion, NSIAD should be considered in all patients with unexplained euvolemic hyponatremia despite high urine osmolality. If NSAID is not considered, the plasma reninaldosterone profile can be confused with HH, especially in infants.

Peak Lag Between Plasma Vasopressin and Urine Aquaporin-2 Following Cardiac Surgery.

Tolvaptan, a vasopressin type-2 receptor antagonist, is utilized to ameliorate fluid retention following cardiac surgery. However, the optimal timing of tolvaptan administration considering novel biomarkers remains unknown. We prospectively included patients who underwent cardiac surgery between 2016 and 2020. We measured perioperative trends of free water reabsorption mediators including plasma arginine vasopressin and urine aquaporin-2. A total of 20 patients (68 [60, 75] years old, 18 men) were included. Urine volume decreased gradually after the initial 3 hours following cardiac surgery. The plasma arginine vasopressin level increased significantly with a peak at postoperative 6 hours, whereas the urine aquaporin-2 level increased later with a delayed peak at postoperative 12 hours. As a result, urine aquaporin-2 relative to the plasma arginine vasopressin level, which represents the activity of the collecting ducts and indicates predicted responses to tolvaptan, was a minimum at postoperative 6 hours. Tolvaptan administration immediately after cardiac surgery might not be recommended given the transient refractoriness to tolvaptan probably due to the stunning of kidney collecting ducts.

Endolymphatic Sac Drainage Surgery and Plasma Stress Hormone Vasopressin Levels in Meniere's Disease.

Meniere's disease is a common inner ear disorder accompanied by vertigo attacks and fluctuating hearing loss that some believe is due to a stressful lifestyle. To elucidate the scientific relationship in neuro-endocrinology between Meniere's disease and stress, we examined the surgical results of endolymphatic sac drainage surgery and changes in stress-induced plasma arginine-vasopressin levels. We enrolled 100 intractable Meniere's patients and examined surgical results and plasma vasopressin levels. Fifty-four chronic otitis media patients who underwent tympano-mastoidectomy formed a control group. We assessed surgical results during a 2-year follow-up period, including vertigo and hearing loss. We examined plasma vasopressin levels just before surgery and 1 week, 1 year, and 2 years after surgery. In patients with intractable Meniere's disease, plasma vasopressin levels were significantly reduced 1 week after surgery compared to the decrease observed in chronic otitis media patients after tympano-mastoidectomy. In intractable Meniere's disease, long-lasting low plasma vasopressin levels after surgery were associated with significantly good surgical results. In recurrent Meniere's disease, a gradual plasma vasopressin level elevation was observed after surgery, followed by recurrent vertigo attacks and sensorineural hearing loss. It is suggested that long-lasting high levels of plasma vasopressin could have adverse effects on inner ear water metabolism and the subsequent Meniere's disease symptoms. Effective treatments for Meniere's disease might be best based on the maintenance of low plasma vasopressin levels.

Psychoendocrinology: arginine vasopressin and resilience in patients with major depressive disorder.

There is a burgeoning body of evidence suggesting that arginine vasopressin (AVP) acts as a neuromodulator of the stress response. AVP stimulates the release of adrenocorticotropic hormone, synergistic to corticotropin-releasing hormone, which might explain AVP's role in resilience. Personal hardiness is the bedrock of resilience. Numerous studies have demonstrated elevated plasma levels of AVP in patients with major depressive disorder (MDD), suggesting an etiopathogenetic role as well as a novel therapeutic target. The aim of this study was to examine the relationship between AVP and resilience in patients with MDD and to determine AVP levels in serum of patients with MDD. Forty patients with MDD and 40 healthy control subjects were studied using the Dispositional Resilience (Hardiness) Scale by Barton, the Quality of Life Scale, the Social Readjustment Rating Scale, and the Beck Depression Inventory. Biochemical analysis of plasma levels of AVP, using the enzyme-linked immunosorbent assay (ELISA), was performed for all participants. Levels of AVP were statistically significantly elevated in patients with MDD compared with healthy controls. Psychological hardiness was decreased in patients with MDD compared with healthy controls, a finding also statistically significant. There was a negative correlation between plasma AVP level and psychological hardiness. AVP and psychological hardiness are negatively correlated, reflecting lower stress resilience. AVP levels are indeed higher in patients struggling with MDD.

Effects of firibastat in combination with enalapril and hydrochlorothiazide on blood pressure and vasopressin release in hypertensive DOCA-salt rats

In the brain, aminopeptidase A (APA) generates angiotensin III, one of the effector peptides of the brain renin-angiotensin system (RAS), exerting tonic stimulatory control over blood pressure (BP) in hypertensive rats. Oral administration of firibastat, an APA inhibitor prodrug, in hypertensive rats, inhibits brain APA activity, blocks brain angiotensin III formation and decreases BP. In this study, we evaluated the efficacy of firibastat in combination with enalapril, an angiotensin I-converting enzyme inhibitor, and hydrochlorothiazide (HCTZ), in conscious hypertensive deoxycorticosterone acetate (DOCA)-salt rats, which display high plasma arginine-vasopressin levels, low circulating renin levels and resistance to treatment by systemic RAS blockers. We determined mean arterial BP, heart rate, plasma arginine-vasopressin levels and renin activity in DOCA-salt rats orally treated with firibastat, enalapril or HCTZ administered alone or in combination. Acute oral firibastat administration (30 mg/kg) induced a significant decrease in BP, whereas enalapril (10 mg/kg) or HCTZ (10 mg/kg) administered alone induced no significant change in BP in conscious DOCA-salt rats. The BP decrease induced by acute and nine-day chronic tritherapy [Firibastat+Enalapril+HCTZ] was significantly greater than that observed after bitherapy [Enalapril+HCTZ]. Interestingly, the chronic administration of a combination of firibastat with [Enalapril+HCTZ] reduced plasma arginine-vasopressin levels by 62% relative to those measured in DOCA-salt rats receiving bitherapy. Our data show that tritherapy with firibastat, enalapril and HCTZ improves BP control and arginine-vasopressin release in an experimental salt-dependent model of hypertension, paving the way for the development of new treatments for patients with currently difficult-to-treat or resistant hypertension.

Signaling of Phoenixin via GPR173 and the Paradox of Increased Vasopressin Secretion in Preeclampsia

Preterm birth affects over 15 million pregnancies annually worldwide, and is associated with severe health risks for both mother and child. The leading cause of clinically indicated, non-spontaneous preterm delivery is preeclampsia, which can lead to maternal and fetal morbidity and mortality if not appropriately and promptly managed. At this time, the only “cure” for preeclampsia is delivery of the fetus and associated products of conception, which presents the clinical challenge of weighing the risks versus benefits of delivery if the pregnancy is preterm. The etiology of preeclampsia is multifactorial and incompletely understood. However, several carefully conducted studies have implicated the paradoxical secretion of the posterior pituitary hormone, arginine vasopressin (AVP) as a potential causative factor. Women with preeclampsia exhibit elevated plasma levels of AVP even in the face of the ongoing hypertension and hyponatremia, and infusion of AVP into pregnant rodents recapitulated multiple features of preeclampsia. The reason for the inappropriately elevated AVP in preeclampsia is unknown. Using a bioinformatic algorithm, our group identified a novel peptide that is conserved across multiple species, and named it phoenixin (PNX) (PMID 22963497). Our published data demonstrate a reproductive role of the peptide, and indicate that hypothalamic and pituitary PNX expression is modulated by sex hormones (PMID 27440717). Likewise, we recently have demonstrated that cerebroventrcular administration of PNX elevated plasma AVP levels in rats (PMID 29364701). Using the RNAscope approach we have now demonstrated that the receptor for PNX, identified by our group as GPR173 (PMID 27440717), is expressed by AVP neurons. Importantly expression of GPR173 increased across pregnancy in the rat hypothalamus coincident with increased AVP production and release (PMID 27330717). These data strongly suggest that PNX, acting through GPR173, could act as a molecular link between sex hormones and AVP secretion. In addition, we now demonstrate that central injection of PNX increases blood pressure, likely through PNX-induced elevation in AVP secretion. We hypothesize that the paradox of increased AVP secretion in the hyponatremic and hypervolemic state of preeclampsia is due to exaggerated PNX signaling in hypothalamus via GPR173 on AVP neurons and possibly on GPR173 expressing neurons in autonomic centers in hindbrain.

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

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

Excessive maternal salt intake gives rise to vasopressin-dependent salt sensitivity of blood pressure in male offspring

Salt sensitivity of blood pressure (SSBP) is a trait carrying strong prognostic implications for various cardiovascular diseases. To test the hypothesis that excessive maternal salt intake causes SSBP in offspring through a mechanism dependent upon arginine-vasopressin (AVP), we performed a series of experiments using offspring of the rat dams salt-loaded during pregnancy and lactation with 1.5% saline drink (“experimental offspring”) and those with normal perinatal salt exposure (“control offspring”). Salt challenge, given at 7–8 weeks of age with either 2% saline drink (3 days) or 8% NaCl-containing chow (4 weeks), had little or no effect on systolic blood pressure (SBP) in female offspring, whereas the salt challenge significantly raised SBP in male offspring, with the magnitude of increase being greater in experimental, than control, rats. Furthermore, the salt challenge not only raised plasma AVP level more and caused greater depressor responses to V1a and V2 AVP receptor antagonists to occur in experimental, than control, males, but it also made GABA excitatory in a significant proportion of magnocellular AVP neurons of experimental males by depolarizing GABA equilibrium potential. The effect of the maternal salt loading on the salt challenge-elicited SBP response in male offspring was precluded by maternal conivaptan treatment (non-selective AVP receptor antagonist) during the salt-loading period, whereas it was mimicked by neonatal AVP treatment. These results suggest that the excessive maternal salt intake brings about SSBP in male offspring, both the programming and the expression of which depend on increased AVP secretion that may partly result from excitatory GABAergic action.

Oestrogen inhibits salt-dependent hypertension by suppressing GABAergic excitation in magnocellular AVP neurons.

Abundant evidence indicates that oestrogen (E2) plays a protective role against hypertension. Yet, the mechanism underlying the antihypertensive effect of E2 is poorly understood. In this study, we sought to determine the mechanism through which E2 inhibits salt-dependent hypertension. To this end, we performed a series of in vivo and in vitro experiments employing a rat model of hypertension that is produced by deoxycorticosterone acetate (DOCA)-salt treatment after uninephrectomy. We found that E2 prevented DOCA-salt treatment from inducing hypertension, raising plasma arginine-vasopressin (AVP) level, enhancing the depressor effect of the V1a receptor antagonist (Phenylac1,D-Tyr(Et)2,Lys6,Arg8,des-Gly9)-vasopressin, and converting GABAergic inhibition to excitation in hypothalamic magnocellular AVP neurons. Moreover, we obtained results indicating that the E2 modulation of the activity and/or expression of NKCC1 (Cl- importer) and KCC2 (Cl- extruder) underpins the effect of E2 on the transition of GABAergic transmission in AVP neurons. Lastly, we discovered that, in DOCA-salt-treated hypertensive ovariectomized rats, CLP290 (prodrug of the KCC2 activator CLP257, intraperitoneal injections) lowered blood pressure, and plasma AVP level and hyperpolarized GABA equilibrium potential to prevent GABAergic excitation from emerging in the AVP neurons of these animals. Based on these results, we conclude that E2 inhibits salt-dependent hypertension by suppressing GABAergic excitation to decrease the hormonal output of AVP neurons.