Vasopressin Levels Research Articles

Correlation Between Serum Copeptin and NTproBNP Levels in Heart Failure

Introduction: Heart Failure is a leading cause of morbidity and mortality worldwide. It is associated with upregulation and dysfunction of the renin-angiotensin aldosterone system, the sympathetic nervous system and the vasopressin system. In heart failure, the levels of vasopressin are elevated and out of sync with the osmotic status. Arginine Vasopressin has a half-life of only 20 minutes and is bound to circulating platelets. Hence, it is not useful as a biomarker. Copeptin, a by-product of vasopressin metabolism has been used as a surrogate marker for Arginine Vasopressin in clinical practice. Thus, our study aims to find the use of copeptin in studying heart failure and its use in predicting severity. We also sought to correlate copeptin with NTproBNP the standard biomarker used in heart failure. Methods: Our study was a single-centre cross-sectional observational study involving 90 admitted heart failure patients over 18 months. NYHA Class was used to assess the severity of heart failure. Copeptin levels were measured using Human Copeptin ELISA Kit. Results: In these patients, elevated levels of copeptin and NTproBNP were found. In patients with higher NYHA Class, a greater rise in serum copeptin and NTproBNP levels was noted. Moreover, a strong positive correlation between NTproBNP and copeptin (rho = 0.7) was found in our study. Conclusion: Our study puts forward copeptin as a simple additional cost-effective biomarker for predicting the severity of heart failure.

Phase I clinical trial evaluating the safety, tolerance, pharmacokinetics and pharmacodynamics of HSK21542 injection in healthy volunteers.

HSK21542 injection is a new peripheral kappa opioid receptor (KOR) agonist. To evaluate its safety, tolerability, pharmacokinetics and pharmacodynamics, this study was conducted in healthy volunteers, consisting of two parts: a single ascending dose (0.2-3.375 μg/kg, 15-min infusion) and different infusion durations (0.2 and 1μg/kg, 2- or 15-min infusion). The area under the plasma concentration-time curve (AUC) and peak concentration (Cmax) of HSK21542 were dose-linear among 0.2-3.375 μg/kg. After intravenous injection, HSK21542 was rapidly eliminated with a half-life (t1/2) of 1.5h, and the majority (48.02%) of the dose was excreted unchanged in urine. Pharmacodynamic results showed that HSK21542 increased prolactin release and reached a peak at 1-2h after administration but had no significant effect on vasopressin levels. There was a brief increase in urine volume within the initial 2h after administration. HSK21542 was well tolerated; most of the adverse effects (AEs) in the trial group were grade 1, and only 2 cases (4.0%) were grade 2. The main AE was paresthesia, which appeared in 42% (21/50) in the trial group. No serious adverse event (SAE) was observed. No subject withdrew early due to AEs. These results suggest that HSK21542 may be a potential treatment for pain and pruritic conditions.

Efficacy of an Animal-Assisted Therapy Program in the Development of Children With Down Syndrome

ABSTRACT This study aimed to evaluate the efficacy of a dog-assisted intervention program in occupational therapy (OT) sessions in the treatment of children with Down syndrome (DS). A randomized clinical trial was conducted with 14 children with DS (9–12 years old) randomly distributed into two groups: control and experimental. Both received 12 OT sessions, one per week. The experimental group also received dog-assisted therapy. To evaluate the effects of the program, the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI), the Test of Playfulness (ToP), an ethogram of positive and negative social behaviors, and comparisons of vasopressin levels in the urine of children upon awakening and after sessions were used. The results showed that after the conventional intervention, the control group had a significant increase in visual perception and attention scores. The experimental group showed a significantly higher frequency of satisfaction and interactivity behaviors. We found that the presence of the dog maximizes the social skills of children with DS and increases their engagement in positive social interactions; however, conventional OT sessions were more effective with visual-motor performance. No physiological changes were observed in either group after the intervention.

Effects of diluted seawater in drinking water on physiological responses, feeding, drinking patterns, and water balance in crossbred dairy goats

Background and Aim: In tropical regions, the intrusion of saline from seawater (SW) due to global warming and sea level rise in recent years is an important natural factor influencing goat well-being. This study aimed to determine the effects of diluted SW in drinking water on the physiological responses and eating and drinking patterns of crossbred dairy goats under tropical conditions. Materials and Methods: Twenty dairy goats were divided into four groups (five animals each) based on body weight and milk yield. Animals received either fresh drinking water (SW0.0, control) or diluted SW at concentrations of 0.5% (SW0.5, low salinity), 1% (SW1.0, moderate salinity), and 1.5% (SW1.5, high salinity). The experiment was performed for 49 days (1st–7th week). Throughout this period, daily food and water intake were measured every day. In addition, blood collection was performed on day 25. Total urine and feces were collected from days 25 to 29. Meal and drinking patterns were determined on days 31 and 32. Results: Salinity did not influence dry matter intake throughout the experiment (p > 0.05). However, SW had a significant effect on eating patterns. The effect of SW on water intake (WI) was pronounced from the 2nd to 7th weeks of this experiment (p < 0.05). The water balance decreased and plasma antidiuretic hormone levels increased from SW1.5 to SW2.5 compared to the other treatments. Rectal temperature and respiration rate increased from 15:00 to 17:00 in SW1.5 patients. The concentrations of plasma electrolyte, creatinine, and heat shock protein 70 did not differ between treatments (p > 0.05). The urinary excretion of Na+ from SW1.5 and K+ and Cl- from SW1.0 was higher than that from SW0.0 and SW0.5 (p < 0.01). Conclusion: Lactating crossbred goats adapted to low and moderate SW by increasing urine volume and urinary electrolyte excretion (Uex), whereas animals responded to high SW by either increasing Uex or altering drinking patterns to minimize salt stress. Keywords: antidiuretic hormone, dairy goat, kidney, saline water, water balance.

The relationship between cardiac activity, behaviour and endogenous oxytocin and vasopressin in Prader-Willi Syndrome: An exploratory study

This study aimed to increase our understanding of cardiac activity abnormalities in Prader-Willi Syndrome (PWS) and the relationship between cardiac activity, PWS behaviours thought to be associated with cardiac vagal tone and endogenous oxytocin and vasopressin levels. We compared cardiac activity (respiratory sinus arrhythmia (RSA), low-frequency heart rate variability (LF-HRV), heart period) in 30 adolescents and adults with PWS to 30 typically developing age-matched controls. RSA, LF-HRV, and heart period were lower in individuals with PWS than in the control group. In the control group, RSA was higher for females than males. However, for those with PWS, there was no difference between the sexes. Individuals with the mUPD genetic subtype had lower RSA and LF-HRV than participants with the PWS deletion subtype and compared to typically developing controls, no difference was found between the latter two groups. Heart period was also lower for those with mUPD compared to controls. Higher RSA reduced the odds of having temper outbursts and skin-picking. RSA was lower in those with PWS and psychosis compared to those with PWS without psychosis. Finally, we found RSA correlated with vasopressin for those with mUPD but not deletion. There was no relationship between RSA and oxytocin plasma or saliva levels. Our findings suggest autonomic dysfunction in PWS that is more marked in mUPD than deletion and potentially due to greater loss of parasympathetic activity in mUPD.

Neuroendocrinology of bone.

The past decade has witnessed significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone in primary and secondary osteoporosis. Recent breakthroughs have primarily emerged from identifying disease-causing mutations and phenocopying human bone disease in rodents. Notably, using genetically-modified rodent models, disrupting the reciprocal relationship with tropic pituitary hormone and effector hormones, we have learned that pituitary hormones have independent roles in skeletal physiology, beyond their effects exerted through target endocrine glands. The rise of follicle-stimulating hormone (FSH) in the late perimenopause may account, at least in part, for the rapid bone loss when estrogen is normal, while low thyroid-stimulating hormone (TSH) levels may contribute to the bone loss in thyrotoxicosis. Admittedly speculative, suppressed levels of adrenocorticotropic hormone (ACTH) may directly exacerbate bone loss in the setting of glucocorticoid-induced osteoporosis. Furthermore, beyond their established roles in reproduction and lactation, oxytocin and prolactin may affect intergenerational calcium transfer and therefore fetal skeletal mineralization, whereas elevated vasopressin levels in chronic hyponatremic states may increase the risk of bone loss.. Here, we discuss the interaction of each pituitary hormone in relation to its role in bone physiology and pathophysiology.

Peptides and primate personality: Central and peripheral oxytocin and vasopressin levels and social behavior in two baboon species (Papio hamadryas and Papio anubis)

The neurohormones oxytocin (OT) and arginine vasopressin (AVP) are involved in social behaviors and psychiatric conditions. However, more research on nonhuman primates with complex social behaviors is needed. We studied two closely-related primate species with divergent social and mating systems; hamadryas baboons (Papio hamadryas, n=38 individuals) and anubis baboons (Papio anubis, n=46). We measured OT in cerebrospinal fluid (CSF, n=75), plasma (n=81) and urine (n=77), and AVP in CSF (n=45), and we collected over 250 hours of focal behavioral observations. Using Bayesian multivariate models, we found no clear species difference in hormone levels; the strongest support was for hamadryas having higher CSF OT levels than anubis (posterior probability [PP] for females = 0.75, males = 0.84). Looking at nine specific behaviors, OT was associated with affiliative behaviors (approach, proximity, grooming, PP ∼ 0.85 – 1.00), albeit inconsistently across sources of measurement (CSF, plasma, and urine, which were uncorrelated with each other). Most behaviors had low repeatability (R ∼ 0 – 0.2), i.e. they did not exhibit stable between-individual differences (or “personality”), and different behaviors did not neatly coalesce into higher-order factors (or “behavioral syndromes”), which cautions against the use of aggregate behavioral measures and highlights the need to establish stable behavioral profiles when testing associations with baseline hormone levels. In sum, we found some associations between peptides and social behavior, but also many null results, OT levels from different sources were uncorrelated, and our behavioral measures did not indicate clear individual differences in sociability.

The effect of liver surgery and fluid strategy on renin activity and aldosterone and anti-diuretic hormone levels: a secondary analysis of the GALILEO trial

BackgroundIt is unknown whether liver surgery leads to increased RAAS activity and anti-diuretic hormone (ADH) levels and subsequent fluid accumulation. Furthermore, it is unknown whether the peri-operative fluid strategy changes this effect. MethodsThis is a pre-planned post hoc analysis of a randomised controlled trial which compared restrictive (n = 20) versus liberal fluid strategy (n = 20) in patients undergoing liver surgery. Primary outcomes for the current study were the difference in hormone levels after anaesthesia induction and after liver resection. Fluid overload was defined as a ≥10% increase in weight. ResultsRenin activity (6 [2.1–15.5] vs. 12 [4.6–33.5]) and ADH levels (6.0 [1.7–16.3] vs. 3.8 [1.6–14.7]) did not differ significantly before and after resection. However, aldosterone levels were significantly higher after resection (0.30 [0.17–0.49] vs. 0.69 [0.31–1.21] ). Renin activity and aldosterone levels did not differ between the groups. ADH was significantly higher in the restrictive strategy group (1.6 [1.1–2.1] vs 5.9 [3.8–16.0]). No differences in hormone levels were found in patients with and without fluid overload. DiscussionAldosterone levels increased after liver surgery but renin activity and ADH levels did not. ADH levels were higher in the restrictive group. Development of post-operative fluid overload was not associated with RAAS activity or ADH levels.

HYDROALCOHOLIC EXTRACT OF Lepidium draba L. AMELIORATES CAPECITABINE -INDUCED ENTEROCOLITIS IN RATS

This study investigated the protective properties of Lepidium draba L. hydroalcoholic extract (LDHE) against enterocolitis induced by Capecitabine (CT), utilizing biochemical, molecular, and histopathological analyses. A study was conducted involving 50 Wistar rats divided into 5 groups of ten rats over 60 days: healthy, 400 mg/kg LDHE, 20 mg/kg CT, and two co-treatment groups receiving both CT and 200 and 400 mg/kg LDHE groups. On the 61st day, serum nitric oxide, antidiuretic hormone (ADH), arginine vasopressin (AVP), tumor necrosis factor-α, interleukin-6, chemokine C-X-C motif ligand 1 (CXCL-1), and interleukin-1β levels were measured, along with the activity of glutathione peroxidase, catalase, and superoxide dismutase enzymes. To evaluate tissue oxidative stress in the intestine, measurements were taken for FRAP, thiol, and TBARS levels. Apoptosis in the intestine was assessed by examining the Bax/Bcl-2, caspase-3, and p53 expression via real-time PCR. Furthermore, real-time PCR was employed to evaluate water homeostasis by examining the AQP3, AQP8, and AQP10 expression, while protein expression was analyzed using western blotting. LDHE extract effectively regulates inflammatory cytokine levels and modulates ADH and AVP levels, thereby preserving serum and intestinal osmotic balance. Furthermore, it attenuated the Bax/Bcl-2, caspase-3, and p53 mitochondrial apoptotic pathways while enhancing the expression of AQP3, AQP8, and AQP10 genes in intestinal tissue. The study suggests that LDHE holds promise in the treatment of enterocolitis in chemotherapy patients. Keywords: Lepidium draba L., Capecitabine, Intestine, Enterocolitis, Apoptosis, Aquaporins

Elevated arginine vasopressin levels surrogate acute lung injury in acute decompensated heart failure.

Activated arginine vasopressin (AVP) pathway worsens congestion in heart failure (HF), but its potential to relieve pulmonary congestion is also reported. The pathophysiological role and prognostic utility of AVP elevation in acute decompensated HF (ADHF) are poorly understood. We prospectively enrolled 52 hospitalized patients for ADHF to investigate the association between acute lung injury (ALI) in ADHF and AVP levels on admission. ALI was defined as respiratory failure leading to death, or requiring a respirator or a more than 12-h non-invasive intermittent positive pressure ventilation (NIPPV) support. In addition, we investigated the prognostic value of AVP levels on admission for cardiovascular death or recurrence of ADHF after discharge. ALI was documented in 7 patients (13.5%) during a median hospital stay of 14days. And the patients with ALI demonstrated significantly higher AVP levels than those without (32.5 ± 21.6 vs. 6.4 ± 8.7pg/ml, p = 0.018). Besides, the patients with ALI demonstrated significantly higher heart rates (HR) and lower E/e' on admission (HR: 127 ± 24 vs. 97 ± 28bpm; E/e': 10.6 ± 3.7 vs. 17.4 ± 6.2, all p < 0.05, respectively). Of note, significant hemodilution assessed by hemoglobin and hematocrit values were observed in the patients with ALI 48h after admission. A receiver operating characteristic curve analysis showed that higher than 7.2pg/ml surrogate ALI in ADHF (AUC: 0.897, p = 0.001, Sensitivity: 85.7%, and Specificity: 77.8%). In contrast, increased AVP levels on admission could not predict cardiovascular events after discharge. Elevated AVP levels on admission are associated with ALI in ADHF but not cardiovascular events after discharge.

Hypoalbuminemia contributes to ascites formation via sodium and water retention: Evidence from clinical date and albumin deficient mice

Albumin infusions improve circulatory and renal function in patients with decompensated cirrhosis. However, there is no convincing evidence that hypoalbuminemia contributes to ascites formation in liver cirrhosis. The aim of our study is to determine the exact role of hypoalbuminemia in the formation of ascites caused by liver cirrhosis and its underlying mechanism. Clinical profiles of patients with liver cirrhosis retrospectively analyzed. The details of albumin involved in ascites formation were investigated in rat model and murine model. Statistical analysis demonstrated hypoalbuminemia was an independent risk factor for ascites formation in patients with liver cirrhosis (OR = 0.722, P < 0.001). In carbon tetrachloride (CCl4)-induced rat model of liver cirrhosis, a significant reduction in serum albumin was observed in rats with ascites (13.37 g/L) compared with rats without ascites (21.43 g/L, P < 0.001). In thioacetamide (TAA)-treated mice, ascites amount of heterozygous albumin (Alb+/−) mice (112.0 mg) was larger than that of wild-type (Alb+/+) mice (58.46 mg, P < 0.001). In CCl4-induced chronic liver injury, ascites amounts of Alb+/− or Alb+/+ mice were 80.00 mg or 48.46 mg (P = 0.001). Further study demonstrated 24-h urinary sodium excretion in Alb+/− mice was lower than that of Alb+/+ mice in TAA/CCl4-induce murine models of liver cirrhosis. Additionally, serum sodium concentration of Alb+/− mice was lower than that of Alb+/+ mice. In cirrhotic mice, higher level of antidiuretic hormone was observed in Alb+/− mice compared with the control; and renal aquaporin (AQP2) expression in Alb+/− mice was significantly higher than that of WT mice. These revealed hypoalbuminemia contributed to the occurrence of ascites in liver cirrhosis through sodium and water retention.

Assessment of the levels of vasopressin and androgen in the sample of Iraqi children with Autism spectrum disorder

Assessment of the levels of vasopressin and androgen in the sample of Iraqi children with Autism spectrum disorder

#2119 Long-term efficacy of tolvaptan therapy in patients with ADPKD

Abstract Background and Aims Currently, the only available therapy to ameliorate disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) is tolvaptan, a vasopressin V2 receptor antagonist. Real-life data on tolvaptan treatment effect is sparce, with several limitations including restricted follow-up, relatively small patient groups, no control groups, or only data reported on kidney function without total kidney volume. We studied, therefore, the long-term effect of tolvaptan on kidney function as well as kidney growth in a relatively large number of real-life ADPKD patients and controls. Moreover, we investigated the effect of salt and protein intake on long-term treatment efficacy. Method Data from two national ADPKD cohorts were pooled. Kidney function (creatinine-based eGFR) was measured at least yearly and total kidney volume (TKV, measured by MRI or CT) at least 3-yearly. Salt and protein intake were measured by 24 h urine excretion. To investigate the long-term effects of tolvaptan we assessed change in eGFR and TKV before as well as after start of tolvaptan using linear mixed effects models. For this purpose, we excluded the acute treatment effect from start to 6 months after initiation of tolvaptan. As a control group, we included all patients who were not treated with tolvaptan, assessing change in eGFR and TKV before and after the theoretical start of treatment (based on the average time of tolvaptan initiation observed in the tolvaptan-treated group) as well as a matched control group. Subgroup analyses of salt and protein intake were based on the median urinary excretion of sodium or urea. Results 697 patients (47 ± 12 years, 59.1% female) were included, of which 104 patients used tolvaptan. Mean duration of tolvaptan use was 6.0 ± 4.5 years (range: 0.8 to 15.6). Tolvaptan use reduced yearly eGFR decline by 17.4% (−4.43 to −3.66 mL/min/1.73 m2/year, p = 0.03, number of measurements: n = 817), whereas in the non-tolvaptan control group after the theoretical start of treatment, eGFR decline increased by 13.3% (−1.95 to −2.21 mL/min/1.73 m2/year, p = 0.2, n = 2804). Long-term TKV growth did not change after start of tolvaptan treatment (4.90 to 5.53%/year, p = 0.5, n = 316). Similar results were obtained in the matched control group. A more substantial treatment effect of tolvaptan on eGFR slope was noted in patients with high compared to low salt intake (assessed as ≥ versus &amp;lt; median urinary sodium excretion of 146 mmol/24 h (difference 1.62 (0.22 to 3.02) mL/min/1.73 m2/year, p = 0.02). Subgroup analysis according to median protein intake did not show a significant difference in tolvaptan treatment effect. Conclusion In this study, with real-life patient data, long-term follow-up, and a control group, we found that tolvaptan attenuated long-term kidney function decline but, notably, did not influence kidney growth. Higher daily salt intake was associated with a more substantial tolvaptan treatment effect, perhaps due to higher vasopressin levels before treatment, and consequently more vasopressin antagonism by tolvaptan.

Fraxinus excelsior L. for Prevention of Capecitabine-induced Enterocolitis in Rat: An Integrated Biochemical, Molecular, and Histopathological Study

Background Chemotherapy drugs damage intestinal cells, weakening the intestinal barrier. This damage results in higher permeability, which enables bacteria and toxins to enter the intestinal tissue. Purpose This study aimed to explore the protective effects of Fraxinus excelsior L. (F. excelsior) extract against Capecitabine (CT)-induced enterocolitis. Materials and Methods Fifty Wistar rats were divided into five groups: sham, F. excelsior (750 mg/kg orally), CT (500 mg/kg orally), and two co-treatment groups receiving CT with F. excelsior (500 and 750 mg/kg orally). After 50 days, rats were sacrificed, and blood samples were collected for various analyses. Biochemical assessments included measurements of serum nitric oxide, catalase, glutathione peroxidase, and superoxide mutase enzymes. Tissue oxidative stress was evaluated through FRAP, thiol, and TBARS levels. Pro-inflammatory cytokines were quantified using ELISA, and apoptosis was assessed through the evalution of p53/Bax/Bcl-2 pathway. Histopathological examination affirmed the preservation of tissue structure in groups treated with F. excelsior extract. Results F. excelsior extract reduced intestinal cell apoptosis and elevated the expression of intestinal aquaporin (AQP) genes/proteins by enhancing antioxidant enzymes and diminishing free radicals. Additionally, the extract modulated inflammatory cytokine levels, regulated antidiuretic hormone (ADH) and arginine vasopressin (AVP) levels, maintaining serum and intestinal osmotic balance. The study also revealed decreased expression of pro-inflammatory cytokines and a positive impact on water homeostasis-related genes (AQP3, AQP8, AQP10). Conclusion The study concludes that F. excelsior extract exhibits potential benefits in treating enterocolitis in individuals undergoing chemotherapy, emphasizing its ability to mitigate oxidative stress, inflammation, apoptosis, and maintain osmotic balance.

Brain-Derived Extracellular Vesicles from Dahl Salt-Sensitive Rats with High Salt Diet Increase PVN and SON Vasopressin Levels in Sprague Dawley rats

Extracellular vesicles (EVs), naturally secreted by almost all cell types, encapsulate a broad spectrum of biological molecules, and ferry these contents to the local and distal recipient cells. Under disease conditions, EV-to-cell communication can lead to diverse cell responses and changes. Previously we have demonstrated that brain-derived EVs from hypertensive rats increased inflammation and oxidative stress in primary neurons and hypothalamic paraventricular nucleus (PVN) of the brain, however, the long-term effects of EVs are unclear. PVN is a key hub to mediate blood pressure via its endocrine and autonomic control. Increased vasopressin (AVP) levels have been found in Dahl salt sensitive hypertensive rats, which are produced by PVN and supraoptic nucleus (SON). In this study, we hypothesized that brain-derived EVs from hypertensive rats regulate blood pressure via AVP system. To test this hypothesis, we first labeled brain-derived EVs with Rhodamine dye (Rho-EVs) and studied their bio-distribution via intracerebroventricular (i.c.v.) injection into the normal Sprague Dawley (SD) rats. Rats were euthanized 24 hours after injection, and brain sections containing the PVN and SON regions were stained to test the colocalization of Rho-EVs with neurons (NeuN), astrocytes (GFAP) and microglia (Iba1). Then we injected brain-derived EVs obtained from hypertensive Dahl salt sensitive rats (DSS-EVs) and normotensive Sprague Dawley rats (SD-EVs) into the lateral ventricle (8 μg/rat) in the SD male rats, and the injection was repeated 2 weeks later. Blood pressure and heart rates of each rat were monitored each week using telemetry transducers. 4 weeks post first EVs injections, rats were euthanized, their blood were tested for plasma AVP and norepinephrine (NE) levels, and their brains were tested for AVP and Fos-related antigen 1 (Fra1) mRNA levels. Besides, we also performed biweekly PVN (800 ng/rat) and SON (800ng/rat) injections of DSS-EVs and SD-EVs and measured the AVP and/or Fra1 protein levels with immunostaining. Lastly, we determined the colocalization of Rho-EVs with AVP-containing cells in the PVN and SON. Results show that Rho-EVs are dominantly taken up by neurons in both PVN and SON regions. Biweekly i.c.v. injections of DSS-EVs do not increase blood pressure and heart rate. However, DSS-EVs significantly upregulate mRNA levels of AVP (2.4-fold) and Fra1 (2.5-fold) in the PVN compared to SD-EVs. There is an increasing trend of plasma AVP levels in DSS-EV-treated rats compared to control. Biweekly PVN injections of DSS-EVs significantly increase AVP (1.5-fold) protein levels relative to SD-EVs, and biweekly SON injections of DSS-EVs significantly increase AVP (1.5-fold) and Fra1 (2.6-fold) protein levels relative to SD-EVs. Lastly, we found that Rho-EVs are mainly colocalized with vasopressin-containing cells in the SON. These results suggest that brain-derived EVs cause SON and PVN neuron activation, which in turn may regulate AVP system during hypertensive development. R01HL163159 (Shan); R15HL150703 (Shan); AHA 1807047 (Bi). 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.

Central Inhibition of Antidiuretic Hormone by the Kappa Opioid Receptor Agonist Nalfurafine Prevents and Reverses Loop Diuretic Resistance

PURPOSE: Diuretic resistance is a failure to achieve a therapeutically desired increase in the renal excretion of sodium and water and reduction in edema despite a full dose of a loop diuretic. High levels of antidiuretic hormone (ADH) have been associated with reduced urine output in heart failure patients. However, ADH’s contribution to the development of diuretic resistance is not known. Assuming that ADH may be released in response to the diuresis produced by loop diuretics, we tested the premise that co-treatment of rats with nalfurafine, a centrally acting kappa opioid (KOR) agonist that inhibits the release of ADH would prevent and/or reverse diuretic resistance to the loop diuretic furosemide. METHODS: Changes in 5-hr urine output (metabolic cages; no water access during collection), urinary Na/K excretion, and osmolality were measured in male Sprague-Dawley rats administered twice-daily i.p. injections (9:00am, 2:00pm; n=6/group) for 11 days with 1) furosemide only (F, 10mg/kg, i.p.; days 1-11), 2) furosemide + nalfurafine (F+N, 10ug/kg, i.p.; days 1-11) or 3) F (days 1-5) followed by F+N (days 6-11). 5-hr urine collection was measured in between the morning and afternoon drug injections and rats were returned to home cages. Control 5-hr urine samples (saline, i.p.) were collected 2 days prior to beginning drug treatments. SUMMARY: Initial treatment (day 1) of rats with F alone and F+N markedly increased urine output. However, over days 6-10, urine output was significantly reduced (diuretic resistance) in rats that continued to receive F alone. Daily co-treatment of F+N beginning day 1 maintained a marked 5-hrdiuresis for all 11 days. Further, delaying addition of nalfurafine co-administration with F until day 6 reversed established diuretic resistance as noted by a marked increase in diuresis over days 6-10 with F+N cotreatment. Initial treatment (day 1) of rats with furosemide also produced a marked natriuresis and kaliuresis. However, on subsequent days (2-11) there was a significant decrease in the renal excretion of sodium and potassium that remained lower in all 3 treatment groups. In contrast, nalfurafine co-treatment beginning either day 1 (Group 2) or day 6 (Group 3) increased free-water clearance as compared to furosemide alone (Group 1). CONCLUSIONS: These results demonstrate that co-administration of the KOR agonist nalfurafine prevented and reversed diuretic resistance to furosemide without worsening electrolyte excretion. Further, these findings support the premise that in response to fluid loss caused by repeated loop diuretic administration, a compensatory release and renal action of ADH plays an important role in mediating loop diuretic resistance. NIH P30GM106392 (DK) LSUHSC REP243 (DK). 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.

Elevated blood pressure follows physiological body-water conservation

Background: Pre-clinical evidence suggests that blood pressure (BP) increase is part of an adaptive physiological body response designed to prevent under-hydration. This idea challenges established thinking that hypertension is caused by initial salt-driven over-hydration. We tested the hypothesis that this alternative view also holds true in humans. Methods: In a mechanistic study, we investigated the interrelation between daily Na+ and water intake, renal solute and water excretion, renal water conservation, and body Na+ balance with BP in 6 healthy men living in a controlled environment for 205 days. In an additional daily-life observational study we investigated the interrelation between BP and adaptive-physiological water and Na+ conservation in 108 Singaporeans. Results: In participants living under controlled conditions, BP increased when urine osmolality was high, and fluid intake or urine volume was low. This BP-increasing water conservation response was not caused by body Na+ retention. Similarly, participants living under daily-life conditions showed a BP-elevating adaptive body water conservation response with increased plasma solute concentration, increased plasma vasopressin levels, and reduced urine volume production due to reduced renal free-water excretion. Participants with higher BP relied on more urea and glucose solutes, but on less Na+ solutes, to maintain their hydration status. Participants with essential hypertension showed more pronounced adaptive-physiological water conservation. None of these hypertension-specific water conservation responses were accompanied by differences in 24-h Na+ excretion. Conclusions: BP increase in humans is part of a systemic body water conservation response that occurs largely independent of body Na+ balance. The Mars500 Salt and Water Homeostasis Project was realized by grant support from the German Federal Ministry for Economics and Technology/DLR Forschung unter Weltraumbedingungen (50WB1624-50WB2024) and the Interdisciplinary Centre for Clinical Research (IZKF Junior Research Group 2), Friedrich-Alexander-University of Erlangen-Nuremberg to JT. The food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever. The Sodium Storage in Singaporeans Project was realized with grant support from Duke NUS Medical School (Duke-NUS-KBrFA/2019/0026) to JT. 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.

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.

Congenital nephrogenic diabetes insipidus with a novel variant of AVPR2 gene mutation: A case report

ABSTRACT Congenital nephrogenic diabetes insipidus (CNDI) is a rare genetic disorder characterized by impaired water reabsorption despite normal or elevated levels of antidiuretic hormone. We report a 6-month-old male with classical symptoms of CNDI, such as fever, excessive thirst, polyuria, and failure to thrive. Laboratory investigations revealed hypernatremia, low urine osmolality, and a lack of response to a vasopressin challenge, confirming the diagnosis. Genetic testing identified a hemizygous base pair deletion in the AVPR2 gene, leading to a frameshift mutation and premature protein truncation. Treatment strategies, including hydrochlorothiazide and amiloride therapy, aim to manage symptoms and improve quality of life. Long-term management involves monitoring growth, hydration status, and genetic counseling for affected families. This case highlights the importance of early recognition and management of CNDI to prevent long-term sequelae. Further research into genetic variations and novel therapeutic approaches is warranted to improve outcomes for these children.

Isotonic hydroxyethyl starch is ineffective in restoring blood pressure during experimental septic shock: Implications for fluid resuscitation strategies

Objectives: The objectives of the study were to evaluate the effect of isotonic or hypertonic hydroxyethyl starch (HES) solutions on blood pressure and to assess the influence of the neurohypophyseal system on this response during experimental septic shock. Male Wistar rats were randomly allocated to undergo either cecal and ligation puncture (CLP) or a simulated surgical procedure (sham). Materials and Methods: Of 6 h post-surgery, either isotonic saline (0.9% sodium chloride, 4 mL/kg), isotonic (HES; at doses of 4, 8 or 16 mL/kg), or hypertonic saline-HES (HS-HES; 4 mL/kg) was administered through the endovenous route, followed by the recording of blood pressure and heart rate. In addition, the levels of sodium, vasopressin, and oxytocin were evaluated after the fluid infusion. Results: The administration of HES did not have a significant effect on blood pressure in our study. However, the HS-HES solution increased plasma osmolality, sodium, vasopressin, and oxytocin levels. Furthermore, the HS-HES induced a transient elevation in blood pressure immediately after infusion, which could be completely blunted by the pre-administration of a V1-vasopressin antagonist. Conclusion: Our results demonstrate that the infusion of an isotonic blood volume expander during experimental septic shock is ineffective in restoring blood pressure due to blood vessel compliance. In contrast, the infusion of a hypertonic solution stimulates vasopressin secretion and can transiently restore blood pressure.