Arginine Vasopressin Receptor Antagonists Research Articles

Arginine vasopressin in mood disorders: A potential biomarker of disease pathology and a target for pharmacologic intervention.

Vasopressin or arginine-vasopressin (AVP) is a neuropeptide molecule known for its antidiuretic effects and serves to regulate plasma osmolality and blood pressure. The existing literature suggests that AVP plays a multifaceted-though less well-known-role in the central nervous system (CNS), particularly in relation to the pathophysiology and treatment of mood disorders. Animal models have demonstrated that AVP is implicated in regulating social cognition, affiliative and prosocial behaviors, and aggression, often in conjunction with oxytocin. In humans, AVP is implicated in mood disorders through its effects on the hypothalamic-pituitary-adrenal (HPA) axis as well as on the serotoninergic and glutamatergic systems. Measuring plasma AVP has yielded interesting but mixed results in mood and stress-related disorders. Recent advances have led to the development of copeptin as a stable and reliable surrogate biomarker for AVP. Another interesting but relatively unexplored issue is the interaction between the osmoregulatory system and mood disorder pathophysiology, given that psychotropic medications often cause dysregulation of AVP receptor expression or signaling that can subsequently lead to clinical syndromes like syndrome of inappropriate diuresis and diabetes insipidus. Finally, pharmaceutical trials of agents that act on V1a and V1b receptor antagonists are still underway. This narrative review summarizes: (1) the neurobiology of the vasopressinergic system in the CNS; (2) the interaction between AVP and the monoaminergic and glutamatergic pathways in the pathophysiology and treatment of mood disorders; (3) the iatrogenic AVP dysregulation caused by psychotropic medications; and (4) the pharmaceutical development of AVP receptor antagonists for the treatment of mood disorders.

ARGININE VASOPRESSIN DEFICIENCY INDUCES DECREASED CARDIAC FIBROSIS RATE AND MEAN ARTERIAL BLOOD PRESSURE IN RATS WITH EXPERIMENTAL ABDOMINAL AORTIC STENOSIS

Cardiac fibrosis (CF) involves the accumulation of extracellular matrix proteins in the interstitial space, often seen in various cardiac pathologies. Each year, cardiovascular diseases claim the lives of 17.9 million people worldwide. Cardiac fibroblasts and myofibroblasts, equipped with vasopressin receptors (AVP), play a crucial role in regulating cell signaling pathways associated with CF development. AVP, an immunomodulatory hormone, influences immune responses, and its deficiency results in a decrease in immune activity. Abdominal aortic stenosis (AS) serves as an experimental model for left cardiac overload hypertension and CF. Neurointermediate pituitary lobectomy (NIL) induces a permanent decrease in circulating AVP levels, showcasing regression of hepatic fibrosis in liver damage models. The quest for effective alternative treatments for cardiac fibrosis poses a substantial challenge for researchers. In this experiment, groups of male Wistar rats weighing approximately 250 g (8/group) were categorized into: 1) Intact Control (IC), 2) Abdominal Aortic Stenosis (AS), 3) Neurointermediate pituitary lobectomy (NIL), and 4) AS+NIL. The AS and AS+NIL groups underwent abdominal aortic stenosis surgery on day one of the experiment. By week 5, the NIL and NIL+AS groups underwent NIL surgery. Prior to sacrifice at week 10, intracarotid mean blood pressure (MBP) was assessed in all groups. Following sacrifice, the hearts were removed, fixed in neutral formalin, and processed in paraffn for histopathological examination using H-E, Masson's trichrome, and Sirius red staining. Results revealed an elevated MBP in the AS group (156 ± 27.1 vs. 114 ± 30 mmHg in the IC), normalized in the AS+NIL group (110 ± 40.9 mmHg), and a mild decrease in the NIL group (87 ± 7.6 mmHg). The evaluation of CF in histological slides concurred with the MBP findings; a significant increase in CF occurred in the AS group compared to the IC, NIL, and AS+NIL groups, with almost complete reversion of CF observed in the AS+NIL group. In summary, this study demonstrates that AVP deficiency induces arterial hypotension, and in the AS+NIL group, AVP deficiency led to: 1) a decrease in blood pressure to normal levels and 2) reversion of cardiac fibrosis. Further experiments are warranted to determine if the decrease in blood pressure and cardiac overload are suffcient to inhibit profibrogenic mechanisms and/or activate antifibrogenic mechanisms. Additionally, investigations are needed to explore whether AVP deficiency, beyond inhibiting the inflammatory process, promotes the activation of antifibrogenic mechanisms. The present results offer new avenues for a deeper understanding of the molecular and cellular mechanisms through which AVP deficiency or the use of AVP receptor antagonists significantly influences fibrosis regulation in organ fibrotic diseases. Funding by Autonomous University of Aguascalientes (PIFF22-1). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Arginine Vasopressin Plays a Role inMicrovascular Dysfunction After ST-Elevation Myocardial Infarction.

Background Coronary microvascular dysfunction (CMD) predicts mortality after ST-elevation-myocardial infarction (STEMI). Arginine vasopressin (AVP) may be implicated, but data in humans are lacking, and no study has investigated the link between arginine vasopressin and invasive measures of CMD. Methods and Results We invasively assessed CMD in 55 patients with STEMI treated with primary percutaneous coronary intervention (PPCI), by measuring the index of microcirculatory resistance after PPCI. In a separate group of 45 patients with STEMI/PPCI, recruited for a clinical trial, we measured infarct size and microvascular obstruction with cardiac magnetic resonance (CMR) imaging at 1 week and 12 weeks post-STEMI. Serum copeptin was measured at 4 time points before and after PPCI in all patients with STEMI. Plasma copeptin levels fell from 92.5 pmol/L before reperfusion to 6.4 pmol/L at 24 hours. Copeptin inversely correlated with diastolic, but not systolic, blood pressure (r=-0.431, P=0.001), suggesting it is released in response to myocardial ischemia. Persistently raised copeptin at 24 hours was correlated with higher index of microcirculatory resistance (r=0.372, P=0.011). Patients with microvascular obstruction on early CMR imaging showed a trend toward higher admission copeptin, which was not statistically significant. Copeptin levels were not associated with infarct size on either early or late CMR. Conclusions Patients with CMD after STEMI have persistently elevated copeptin at 24 hours, suggesting arginine vasopressin may contribute to microvascular dysfunction. Arginine vasopressin receptor antagonists may represent a novel therapeutic option in patients with STEMI and CMD.

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.

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-β (TGF-β) 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-β 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.

The Role of Arginine-Vasopressin in Stroke and the Potential Use of Arginine-Vasopressin Type 1 Receptor Antagonists in Stroke Therapy: A Narrative Review.

Stroke is a life-threatening condition in which accurate diagnoses and timely treatment are critical for successful neurological recovery. The current acute treatment strategies, particularly non-invasive interventions, are limited, thus urging the need for novel therapeutical targets. Arginine vasopressin (AVP) receptor antagonists are emerging as potential targets to treat edema formation and subsequent elevation in intracranial pressure, both significant causes of mortality in acute stroke. Here, we summarize the current knowledge on the mechanisms leading to AVP hyperexcretion in acute stroke and the subsequent secondary neuropathological responses. Furthermore, we discuss the work supporting the predictive value of measuring copeptin, a surrogate marker of AVP in stroke patients, followed by a review of the experimental evidence suggesting AVP receptor antagonists in stroke therapy. As we highlight throughout the narrative, critical gaps in the literature exist and indicate the need for further research to understand better AVP mechanisms in stroke. Likewise, there are advantages and limitations in using copeptin as a prognostic tool, and the translation of findings from experimental animal models to clinical settings has its challenges. Still, monitoring AVP levels and using AVP receptor antagonists as an add-on therapeutic intervention are potential promises in clinical applications to alleviate stroke neurological consequences.

The management and outcome of hyponatraemia following transsphenoidal surgery: a retrospective observational study

PurposeHyponatraemia is a common complication following transsphenoidal surgery. However, there is sparse data on its optimal management and impact on clinical outcomes. The aim of this study was to evaluate the management and outcome of hyponatraemia following transsphenoidal surgery.MethodsA prospectively maintained database was searched over a 4-year period between January 2016 and December 2019, to identify all patients undergoing transsphenoidal surgery. A retrospective case-note review was performed to extract data on hyponatraemia management and outcome.ResultsHyponatraemia occurred in 162 patients (162/670; 24.2%) with a median age of 56 years. Female gender and younger age were associated with hyponatraemia, with mean nadir sodium being 128.6 mmol/L on postoperative day 7. Hyponatraemic patients had longer hospital stay than normonatraemic group with nadir sodium being inversely associated with length of stay (p < 0.001). In patients with serum sodium ≤ 132 mmol/L, syndrome of inappropriate antidiuretic hormone secretion (SIADH) was the commonest cause (80/111; 72%). Among 76 patients treated with fluid restriction as a monotherapy, 25 patients (25/76; 32.9%) did not achieve a rise in sodium after 3 days of treatment. Readmission with hyponatraemia occurred in 11 cases (11/162; 6.8%) at a median interval of 9 days after operation.ConclusionHyponatraemia is a relatively common occurrence following transsphenoidal surgery, is associated with longer hospital stay and risk of readmission and the effectiveness of fluid restriction is limited. These findings highlight the need for further studies to better identify and treat high-risk patients, including the use of arginine vasopressin receptor antagonists.

Effects of Vasopressin (AVP) Deficiency and Conivaptan (an AVP Receptors Antagonist) on Liver Physiology and Fibrosis in Rats with Protracted Portacaval Anastomosis

Liver fibrosis is due to the over deposition of collagens on the extracellular matrix, causing fibrotic septa and liver failure. Portocaval anastomosis (PCA) is a model of liver disease. Fibrogenesis is stimulated by AVP. We have described the healthy effect of the AVP deficiency, induced by neurointermediate pituitary lobectomy (NIL), on liver functions and cirrhosis. We hypothesize that blocking the AVP receptors with the V1a-V2 AVP receptor antagonist conivaptan (CV) will induce the same healthy effects of NIL on liver fibrosis. Male Wistar rats were divided in 6 groups (8-10 each): Sham surgery (SHAM), PCA, NIL, PCA+NIL, CV and PCA+CV. SHAM, NIL and the 4 groups with PCA were operated at week 0, whereas NIL surgery in the PCA+NIL group was done at week 8. CV treatments (30 mg/day/im/8 weeks) in the CV group started at week 0, whereas in the PCA+CV group started at week 8. NIL and CV groups were sacrificed at week 8, whereas SHAM, PCA, PCA+NIL and PCA+CV groups were sacrificed at week 16. At sacrifice, serum levels of ALT, AST, bilirubin, NH4, urea, albumin and glucose were assessed. Livers were weighed and samples were processed for glycogen content and the other processed for light microscopy analysis (slide tissues stained with H-E, Masson and Sirius red). Results are summarized in Table 1. Table 1. Comparative effects of sham surgery (SHAM), portocaval anastomosis (PCA), neurointermediate pituitary lobectomy (NIL), PCA+NIL, conivaptan (CV) and PCA+CV on body weight, liver weight, glycogen liver content and serum biochemical parameters of liver functions GROUPS SHAM PCA NIL PCA+NIL CV PCA+CV (Basal values) Body weight = ↓ (-29%) ↓ (-22%) (- ↓(-29%) = ↓ (23%) (g) NS vs SHAM NS vs SHAM NS vs SHAM NS vs SHAM Liver weight = ↓ (-54%) = = = ↓ (-22%) (g) p<0.05 vsSHAM NS vsSHAM ALT(U/L) = ↑↑↑ ↑↑↑ = = = AST(U/L) = ↑↑↑ ↑↑↑ ↑↑ = = Total bilirubin (mg/dL) = ↑↑↑ = = = = Unconjugated bilirubin (mg/dL) = ↑↑↑ = = = = Albumin(g/dL) = = = = = = Glucose (mg/dL) = = = = = ↓↓↓ NH4(µg/dL) = ↑↑↑ = = = ↑↑↑ Urea(mg/dL) = ↓↓↓ = = = = Liver glycogen(mg/gr of tissue) = ↓↓↓ = = = = Liver histopathology. In the PCA group, mainly in the periportal areas, small inflammatory infiltrates and big deposits of collagen were developed. Compared with the PCA, PCA+NIL and PCA+CV groups showed less inflammatory areas and much less collagen deposits. Conclusions, all results showed that: 1) AVP deficiency restores to normality the liver physiology and histology in the protracted liver disease, 2) Except the alterations in glycemia and NH4 metabolism, similar restored effects in liver histophysiology were induced by CV, suggesting that similar cellular mechanisms are involved, 3) Results strongly support that AVP is an important role in the pathophysiology of the liver fibrosis and possibly other fibrotic diseases.

Regulation and role of arginine vasopressin in myocardial infarction/reperfusion

Abstract Background Little attention is paid to the coronary microvasculature when treating acute myocardial infarction (MI). Microvascular obstruction contributes to ischaemia-reperfusion (I-R) injury. One proposed mechanism is a persistent vasoconstrictor tone during MI/reperfusion. Arginine vasopressin (AVP) has a vasoactive effect on the coronary microvessels. Moreover, cardiac AVP synthesis was found in an animal model. To exert vasoconstriction, AVP binds to its receptor 1a (AVPR1a). Aims (i) To analyse the AVP levels during MI/reperfusion (ii) To assess cardiac AVP and AVPR1a expressions in MI/reperfusion mouse models. Methods We took arterial blood samples from ST elevation MI (STEMI) patients admitted to our hospital over the course of MI/reperfusion for AVP levels quantification. We also measured AVP through its more stable surrogate biomarker, copeptin. Cardiac MRI was done to evaluate coronary microvasculature, infarct size, and left ventricular ejection fraction (LVEF) 1 week post-admission. Cardiac AVP and AVPR1a expressions were assessed by polymerase chain reaction (PCR) in mouse models. Results STEMI patients displayed bothAVPand copeptinlevels elevation at baseline (130.8±20.5 pmol/l, n=23) until 90 min post-reperfusion (55.7±6.2 pmol/l, n=23). Their concentrations began to approach normal levels at 24h. Patients with poorer reperfusion outcomes had copeptin concentrations that remained above normal level after 24h following reperfusion. Copeptin levels at 24h post-reperfusion were significantly higher in patients who developed larger infarct size (p=0.004) and lower LVEF (p=0.009). Patients with microvascular obstruction tended to have higher copeptin levels from admission until 24h post-reperfusion. Mouse models showed no cardiac AVP expression but significantly high AVPR1a expression at 2h post-reperfusion. Conclusion In STEMI patients, circulating AVP level is elevated over the course of MI/reperfusion. In MI/reperfusion mouse models, cardiac AVP synthesis is absent but cardiac AVPR1a is upregulated. The combination of delayed decline in AVP concentrations and AVPR1a upregulation may increase the possibility for AVP to mediate I-R injury through microvascular disturbance. Increased AVP levels at 24h post-reperfusion are significantly associated with poor reperfusion outcome. These results warrant further studies concerning the use of AVP receptor antagonist in STEMI patients undergoing reperfusion therapy Copeptin levels and reperfusion outcomes Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Newcastle University MRes Programme

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.

Blockade of Arginine Vasopressin receptors prevents blood-brain barrier breakdown in Experimental Autoimmune Encephalomyelitis

The blood-brain barrier (BBB) plays a significant pathophysiological role in multiple sclerosis (MS). Vasopressin (AVP) is released after brain injury and contributes to the inflammatory response. We propose that AVP may be modulating BBB permeability and hence affecting EAE clinical signs. Female Lewis rats were immunized s.c. with guinea-pig brain extract suspended in complete Freund’s adjuvant. Prior to that, animals were subjected to Neurointermediate pituitary lobectomy (NIL) or treated with AVP receptor antagonist (conivaptan). BBB permeability assays were performed. Western blot for claudin-5 and histological analysis were performed in conivaptan treated EAE rats. EAE increase in BBB permeability to Evans blue was reverted by the NIL surgery. AVP receptor blockade reverted the EAE BBB hyperpermeability to Evans blue and 10-kDa FITC-dextran in almost all brain regions. Both, AVP low levels and AVP receptor blockade attenuated EAE clinical signs. Conivaptan reduced perivascular cuffs in EAE rats. A decrease in claudin-5 expression was observed in EAE rats and conivaptan treatment partially restored normal levels. Our data indicate that V1a and V2 AVP receptors can modulate BBB permeability and consequently are involved in the CNS inflammatory process during EAE. Future research is required to characterize the utility of vasopressin antagonist in MS treatment.

241 “From SIAD to Happy”: a Case of Effective Use of Tolvaptan for Hyponatremia in an Older Person

Abstract Background Hyponatremia commonly affects the older person, leading to morbidity and mortality. Tolvaptan use is rare in this cohort, but may have benefit in select cases of syndrome of inappropriate antidiuresis (SIAD). Methods An 84-year-old gentleman presented with a history of increasing confusion, fatigue and lethargy attributed to symptomatic hyponatremia. He had background of a recent prolonged admission with small bowel obstruction, treated conservatively. That hospital course was complicated by hypovolaemic hyponatremia, sepsis and clostridium difficile colitis. On this admission, he had no clinical symptoms or signs of infection and his septic screen was negative. He had a Rockwood clinical frailty scale score of 7. His biochemical abnormality was a persistent hyponatremia of 129 mmol/L. Clinically, he was euvolaemic. Further biochemical work up revealed serum osmolality of 263 mmol/kg, serum urea of 6.3 umol/L, urine sodium 108 mmol/L and urine osmolality 541 mmol/kg. Thyroid function, cortisol, and HbA1c were normal. CT brain and chest x ray were unremarkable. A diagnosis of SIAD was made. Fluid restriction was ineffective and Tolvaptan (a selective non-peptide arginine vasopressin receptor antagonist) was commenced on consultation with Endocrinology. Results With initiation of Tolvaptan there was significant clinical improvement. Sodium normalised to 134 mmol/L. He became alert, less confused and more engaged with the multidisciplinary team. He was discharged home well, and on follow up four months later, his clinical frailty scale score was 4 with significant improvement in his mobility on continued Tolvaptan therapy. An underlying colonic neoplasm is the clinically suspected driver of his SIAD but he is declining further investigation at present. Conclusion This case reflects the positive benefits of careful selected use of Tolvaptan in the older population with refractory SIAD, resulting in improved functional status and quality of life.

Arginine vasopressin infusion is sufficient to model clinical features of preeclampsia in mice.

Copeptin, a marker of arginine vasopressin (AVP) secretion, is elevated throughout human pregnancies complicated by preeclampsia (PE), and AVP infusion throughout gestation is sufficient to induce the major phenotypes of PE in mice. Thus, we hypothesized a role for AVP in the pathogenesis of PE. AVP infusion into pregnant C57BL/6J mice resulted in hypertension, renal glomerular endotheliosis, intrauterine growth restriction, decreased placental growth factor (PGF), altered placental morphology, placental oxidative stress, and placental gene expression consistent with human PE. Interestingly, these changes occurred despite a lack of placental hypoxia or elevations in placental fms-like tyrosine kinase-1 (FLT1). Coinfusion of AVP receptor antagonists and time-restricted infusion of AVP uncovered a mid-gestational role for the AVPR1A receptor in the observed renal pathologies, versus mid- and late-gestational roles for the AVPR2 receptor in the blood pressure and fetal phenotypes. These findings demonstrate that AVP is sufficient to initiate phenotypes of PE in the absence of placental hypoxia, and indicate that AVP may mechanistically (independently, and possibly synergistically with hypoxia) contribute to the development of clinical signs of PE in specific subtypes of human PE. Additionally, they identify divergent and gestational time-specific signaling mechanisms that mediate the development of PE phenotypes in response to AVP.

Vasopressin Antagonists Regulate Immune Responses in Preeclampsia

The early pathogenesis of preeclampsia (PreE) involves altered T helper (TH) cell populations and elevated inflammatory cytokine production. Consistent with current mouse and human literature, we observed an increase in TH1 and TH17 inflammatory cytokine production with a reduction in the TH2‐associated cytokine IL‐4 in our novel, chronic infusion of vasopressin (AVP) mouse model of PreE. The mechanisms of immune modulation by AVP in pregnancy have not been elucidated. As increased CD4+ T cell activity is involved in the development of PreE, the objective of this study was to determine AVP receptor expression in CD4+ T cells and which receptors play a role in the PreE immune phenotype.Splenic CD4+ T cells were negatively purified on gestational day 18 from wild‐type C57BL/6J female mice infused with AVP (24 ng/hr or saline s.c.) throughout pregnancy. AVP receptor (AVPR) 1a, 1b, and 2 expression was determined via qPCR normalized to 18S rRNA endogenous control. Mouse CD4+ T cells express all AVP receptors. AVPR2 is the highest expressed receptor in CD4+ T cells isolated from saline (N=7, p&lt;0.05 and AVP‐infused (N=10, p&lt;0.05) dams. Maternal mid‐gestation mononuclear cells isolated from healthy human control or PreE‐affected pregnancies were obtained from the University of Iowa Maternal‐Fetal Tissue Bank (IRB #200910784) and similarly analyzed. As in mouse CD4+ T cells, human control (N=27, p&lt;0.05) and PreE‐affected (N=26, p&lt;0.05) CD4+ T cells most highly express AVPR2. AVPR1a is also highly expressed while AVPR1b is the least expressed. CD4+ T cells from human PreE‐affected women express significantly lower AVPR1a (N=0.23, p&lt;0.05) versus controls.To evaluate the contribution of specific AVPRs to the PreE immune phenotype, AVP and the AVPR antagonists conivaptan (blocks AVPR1a and AVPR2), relcovaptan (blocks AVPR1a), or nelivaptan (blocks AVPR1b) were infused (22 ng/hour) into dams throughout gestation and cytokines were analyzed via ELISA. Conivaptan (N=5, p&lt;0.05) and nelivaptan (N=5, p&lt;0.05) correct the IL‐4 deficiency in the maternal kidney of PreE dams while relcovaptan (N=5, p=NS) does not. The reduction of IL‐4 production in the placenta of AVP‐infused dams is also corrected by conivaptan (N=5, p&lt;0.05) and nelivaptan (N=5, p&lt;0.05), but not relcovaptan (N=5, p=NS). Interestingly, only relcovaptan (N=5, p&lt;0.05) corrects the increased IL‐17 induced by AVP in the placenta while nelivaptan (N=5, p&lt;0.05) further enhances placental IL‐17.Here, we demonstrate human and mouse CD4+ T cells express AVPRs and inhibition of AVPRs attenuates the TH2 cytokine suppression and elevated TH17 cytokine production observed in PreE. Although the actions of AVP on the vascular and renal systems are well documented, these novel data suggest AVP differentially acts through specific AVP receptors to mediate immune responses in target organs during PreE.Support or Funding InformationDepartment of Obstetrics &amp; Gynecology at the University of Iowa Hospitals &amp;Clinics, The Maternal Fetal Tissue Bank, University of Iowa Hospitals &amp; Clinics, Institute for Clinical and Translational Science (NIH KL2 RR024980‐2 to MKS), The Reproductive Scientist Development Program: NIH K12 HD000849 (MKS), NIHK99/R00 HL098276, and PPG HL084207 (JLG), University of Iowa Carver Collaborative Science Grant (MKS &amp; JLG), University of Iowa Immunology Postdoctoral Training Grant (SMS), AHA Innovation Grant (MKS &amp; JLG), AHA Strategically Focused Research Network Grant (MKS &amp; JLG), AHA Predoctoral Research Fellowship (JAS), AHA Postdoctoral Research Fellowship (SMS), John Warner Maternal Health Grant, Shelly Bridgewater Dreams Foundation Grant (SMS)

Endothelin ETA Receptor Blockade, by Activating ETB Receptors, Increases Vascular Permeability and Induces Exaggerated Fluid Retention.

Endothelin (ET) receptor antagonists have been associated with fluid retention. It has been suggested that, of the two endothelin receptor subtypes, ETB receptors should not be blocked, because of their involvement in natriuresis and diuresis. Surprisingly, clinical data suggest that ETA-selective antagonists pose a greater risk of fluid overload than dual antagonists. The purpose of this study was to evaluate the contribution of each endothelin receptor to fluid retention and vascular permeability in rats. Sitaxentan and ambrisentan as ETA-selective antagonists and bosentan and macitentan as dual antagonists were used as representatives of each class, respectively. ETA-selective antagonism caused a dose-dependent hematocrit/hemoglobin decrease that was prevented by ETB-selective receptor antagonism. ETA-selective antagonism led to a significant blood pressure reduction, plasma volume expansion, and a greater increase in vascular permeability than dual antagonism. Isolated vessel experiments showed that ETA-selective antagonism increased vascular permeability via ETB receptor overstimulation. Acutely, ETA-selective but not dual antagonism activated sympathetic activity and increased plasma arginine vasopressin and aldosterone concentrations. The hematocrit/hemoglobin decrease induced by ETA-selective antagonism was reduced in Brattleboro rats and in Wistar rats treated with an arginine vasopressin receptor antagonist. Finally, the decrease in hematocrit/hemoglobin was larger in the venous than in the arterial side, suggesting fluid redistribution. In conclusion, by activating ETB receptors, endothelin receptor antagonists (particularly ETA-selective antagonists) favor edema formation by causing: 1) fluid retention resulting from arginine vasopressin and aldosterone activation secondary to vasodilation, and 2) increased vascular permeability. Plasma volume redistribution may explain the clinical observation of a hematocrit/hemoglobin decrease even in the absence of signs of fluid retention.

Effects of Arginine Vasopressin and V1 Receptor Antagonist on Cerebral Vasospasm Secondary to Subarachnoid Hemorrhage: An Experimental Study.

To examine morphological, radiological and biochemical effects of arginine vasopressin (AV) and V1 receptor antagonist on cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) in rabbits. Forty male New Zealand white rabbits were randomly divided into four groups comprising 10 rabbits each. The groups were; 1) Control group, 2) SAH group, 3) SAH+AV group, 4) SAH+V1 antagonist group. Diameters of the basilar artery in all groups were measured on angiograms. All animals were sacrificed two days following basilar angiography and tissue samples of basilar artery were obtained under microscope immediate after craniectomy for ultrastructural and biochemical examinations. The artery diameters were found to be 50% and 50% at the 30th minute in the groups 2 and 3 respectively. In group 3, CVS was 13% more in comparison with the 2nd group. In group 4, vascular constriction was 34.5% at the 30th minute and about 30.9% at the 300th minute. Despite the increase in regional blood flow, AV did not provide morphological change. Histological appearance was related to vascular stenosis due to CVS. Histological outcome was the best in group 4 because of less CVS. Arginine vasopressin plays an important role in CVS. We detected morphological and radiological recovery in basilar artery, besides moderate improvement due to AV receptor antagonist in CVS.

Stones: Tolvaptan might prevent kidney stone formation.

Tolvaptan, an arginine vasopressin receptor antagonist, decreases urinary supersaturation in kidney stone formers by considerably increasing diuresis, suggesting that this drug might be an effective therapy for reducing the risk of developing kidney stones in these patients.

Arginine Vasopressin Injected into the Dorsal Motor Nucleus of the Vagus Inhibits Gastric Motility in Rats.

Background. Until now, the effect of arginine vasopressin (AVP) in the DMV on gastric motility and the possible modulating pathway between the DMV and the gastrointestinal system remain poorly understood. Objectives. We aimed to explore the role of AVP in the DMV in regulating gastric motility and the possible central and peripheral pathways. Material and Methods. Firstly, we microinjected different doses of AVP into the DMV and investigated its effects on gastric motility in rats. Then, the possible central and peripheral pathways that regulate gastric motility were also discussed by microinjecting SR49059 (a specific AVP receptor antagonist) into the DMV and intravenous injection of hexamethonium (a specific neuronal nicotinic cholinergic receptor antagonist) before AVP microinjection. Results. Following microinjection of AVP (180 pmol and 18 pmol) into the DMV, the gastric motility (including total amplitude, total duration, and motility index of gastric contraction) was significantly inhibited (P < 0.05). Moreover, the inhibitory effect of AVP (180 pmol) on gastric motility could be blocked completely by both SR49059 (320 pmol) and hexamethonium (8 μmol). Conclusions. It is concluded that AVP inhibits the gastric motility by acting on the specific AVP receptor in the DMV, with the potential involvement of the parasympathetic preganglionic cholinergic fibers.

Synthesis and biological evaluation of novel phenothiazine derivatives as non-peptide arginine vasopressin V2 receptor antagonists

Abstract A series of novel phenothiazine derivatives was synthesized and tested for arginine vasopressin receptor antagonist activity. They were synthesized as novel arginine vasopressin receptor antagonists from phenothiazine as a scaffold via successive acylation, reduction and acylation reactions. Their structures were characterized by 1 H NMR, 13 C NMR and HRMS, and biological activity was evaluated by in vitro and in vivo studies. The in vitro binding assay indicated that several compounds are potent selective V2 receptor antagonists. Compounds with promising binding affinity to V2 receptors were selected to conduct the in vivo diuretic studies on Sprague-Dawley rats. Among them, 1n , 1r , 1t and 1v exhibited excellent diuretic activity, especially 1r and 1v . Therefore, 1r and 1v are potent novel AVP V2 receptor antagonist candidates.