Action Of Vasopressin Research Articles

Evidence for a Prehypertensive Water Dysregulation Affecting the Development of Hypertension: Results of Very Early Treatment of Vasopressin V1 and V2 Antagonism in Spontaneously Hypertensive Rats.

In addition to long-term regulation of blood pressure (BP), in the kidney resides the initial trigger for hypertension development due to an altered capacity to excrete sodium and water. Betaine is one of the major organic osmolytes, and its betaine/gamma-aminobutyric acid transporter (BGT-1) expression in the renal medulla relates to interstitial tonicity and urinary osmolality and volume. This study investigated altered water and sodium balance as well as changes in antidiuretic hormone (ADH) activity in female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats from their 3–5 weeks of age (prehypertensive phase) to SHR’s 28–30 weeks of age (established hypertension-organ damage). Young prehypertensive SHRs showed a reduced daily urine output, an elevated urine osmolarity, and higher immunostaining of tubule BGT-1, alpha-1-Na-K ATPase in the outer medulla vs. age-matched WKY. ADH circulating levels were not different between young prehypertensive SHR and WKY, but the urine aquaporin2 (AQP2)/creatinine ratio and labeling of AQP2 in the collecting duct were increased. At 28–30 weeks, hypertensive SHR with moderate renal failure did not show any difference in urinary osmolarity, urine AQP2/creatinine ratio, tubule BGT-1, and alpha-1-Na-K ATPase as compared with WKY. These results suggest an increased sensitivity to ADH in prehypertensive female SHR. On this basis, a second series of experiments were set to study the role of ADH V1 and V2 receptors in the development of hypertension, and a group of female prehypertensive SHRs were treated from the 25th to 49th day of age with either V1 (OPC21268) or V2 (OPC 41061) receptor antagonists to evaluate the BP time course. OPC 41061-treated SHRs had a delayed development of hypertension for 5 weeks without effect in OPC 21268-treated SHRs. In prehypertensive female SHR, an increased renal ADH sensitivity is crucial for the development of hypertension by favoring a positive water balance. Early treatment with selective V2 antagonism delays future hypertension development in young SHRs.

MODERN SURGICAL METHODS OF TREATMENT OF PATIENTS WITH CENTRAL DIABETES INSIPIDUS

Annotation: Diabetes insipidus is a disease characterized by the inability of the kidneys to reabsorb water and concentrate urine. According to the classification, there are three main types of diabetes insipidus: central, nephrogenic, primary polydipsia. Other rarer types of diabetes insipidus should also be remembered: gestational, functional (pediatric), iatrogenic. The pathogenesis of central diabetes insipidus is associated with impaired secretion or action of vasopressin on V2 receptors.

Early Biomarkers of Altered Renal Function and Orthostatic Intolerance During 10-day Bedrest.

Exposure to actual or simulated microgravity results in alterations of renal function, fluid redistribution, and bone loss, which is coupled to a rise of urinary calcium excretion. We provided evidence that high calcium delivery to the collecting duct reduces local Aquaporin 2 (AQP2)-mediated water reabsorption under vasopressin action, thus limiting the maximal urinary concentration to reduce calcium saturation. To investigate early renal adaptation into simulated microgravity, we investigated the effects of 10 days of strict bedrest in 10 healthy volunteers. We report here that 10 days of inactivity are associated with a transient, significant decrease (day 5) in vasopressin (copeptin) paralleled by a decrease in AQP2 excretion, consistent with an increased central volume to the heart, resulting in reduced water reabsorption. Moreover, bedrest caused a significant increase in calciuria secondary to bone demineralization paralleled by a decrease in PTH. Urinary osteopontin, a glycoprotein exerting a protective effect on stone formation, was significantly reduced during bedrest. Moreover, a significant increase in adrenomedullin (day 5), a peptide with vasodepressor properties, was observed at day 5, which may contribute to the known reduced orthostatic capacity post-bedrest. We conclude that renal function is altered in simulated microgravity and is associated with an early increase in the risk of stone formation and reduced orthostatic capacity post-bedrest within a few days of inactivity.

A Novel Form of Familial Vasopressin Deficient Diabetes Insipidus Transmitted in an X-linked Recessive Manner.

Familial pituitary diabetes insipidus has been described only in an autosomal dominant or recessive mode of inheritance. This work aims to determine the cause of a novel form of familial diabetes insipidus (DI) that is controlled by desmopressin therapy but segregates in an X-linked recessive manner. Thirteen members from 3 generations of the kindred with familial DI were studied. Water intake, urine volume, urine osmolality, plasma osmolality, and plasma vasopressin were measured under basal conditions, during fluid deprivation, 3% saline infusion, and water loading. Magnetic resonance images of the posterior pituitary also were obtained. In affected males, the effects of desmopressin therapy and linkage of the DI to markers for chromosome Xq28 were determined. In addition, the genes encoding vasopressin, aquaporin-2, the AVPR2 receptor, and its flanking regions were sequenced. This study showed that 4 males from 3 generations of the kindred have DI that is due to a deficiency of vasopressin, is corrected by standard doses of desmopressin, and segregates with markers for the AVPR2 gene in Xq28. However, no mutations were found in AVPR2 or its highly conserved flanking regions. Exome sequencing confirmed these findings and also revealed no deleterious variants in the provasopressin and aquaporin-2 genes. The 4 obligate female carriers osmo-regulated vasopressin in the low normal range. X-linked recessive transmission of DI can be due to a defect in either the secretion or the action of vasopressin. Other criteria are necessary to differentiate and manage the 2 disorders correctly.

Multiple Aspects of Inappropriate Action of Renin-Angiotensin, Vasopressin, and Oxytocin Systems in Neuropsychiatric and Neurodegenerative Diseases.

The cardiovascular system and the central nervous system (CNS) closely cooperate in the regulation of primary vital functions. The autonomic nervous system and several compounds known as cardiovascular factors, especially those targeting the renin–angiotensin system (RAS), the vasopressin system (VPS), and the oxytocin system (OTS), are also efficient modulators of several other processes in the CNS. The components of the RAS, VPS, and OTS, regulating pain, emotions, learning, memory, and other cognitive processes, are present in the neurons, glial cells, and blood vessels of the CNS. Increasing evidence shows that the combined function of the RAS, VPS, and OTS is altered in neuropsychiatric/neurodegenerative diseases, and in particular in patients with depression, Alzheimer’s disease, Parkinson’s disease, autism, and schizophrenia. The altered function of the RAS may also contribute to CNS disorders in COVID-19. In this review, we present evidence that there are multiple causes for altered combined function of the RAS, VPS, and OTS in psychiatric and neurodegenerative disorders, such as genetic predispositions and the engagement of the RAS, VAS, and OTS in the processes underlying emotions, memory, and cognition. The neuroactive pharmaceuticals interfering with the synthesis or the action of angiotensins, vasopressin, and oxytocin can improve or worsen the effectiveness of treatment for neuropsychiatric/neurodegenerative diseases. Better knowledge of the multiple actions of the RAS, VPS, and OTS may facilitate programming the most efficient treatment for patients suffering from the comorbidity of neuropsychiatric/neurodegenerative and cardiovascular diseases.

Study on the Etiology of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Among the Hospital Admitted Patient

Background: The syndrome of inappropriate antidiuretic hormone (SIADH) is a clinical illness that increases antidiuretic hormone (ADH) production or activity due to different disease processes. Normal release of ADH, or arginine vasopressin (AVP), occurs in the posterior lobe of the pituitary gland. SIADH, a hemodynamic disturbance, does not cause secretion of ADH. It is mediated through no osmotic receptors, resulting in water retention and dilutional hyponatremia. Materials methods: This was a cross-sectional observational study carried out by the Department of Medicine, Shaheed Ziaur Rahman Medical College Hospital, Bogura. Total 100 consecutive patients had hyponatremia due to SIADH. All patients were interviewed using standardized questionnaires. Data were analyzed using the statistical packages for social sciences (SPSS) for windows version 16. Results: Most of the patients (42%) in the study were older people >60 years. The average age was 60.69 years. The male-female ratio was 1.43.1. The symptoms of hyponatremia were fever (32%), headache (34%), weakness (40%). confusion (48%), convulsion (19%) and coma (52%). Of them, 34% were hypertensive, and 51% of patients had a Glasgow coma scale of 3/15. It was observed that the most common etiology of SIADH was hemorrhagic stroke (46%) then ischemic (41%). Among the hemorrhagic strokes, 40% were intracerebral, 4% were subarachnoid hemorrhage, and 2% were brain stem hemorrhage. Another etiology was meningitis (4%). Encephalitis (4%). Pneumonia (3%) and pulmonary tuberculosis (2%). Serum Na+ <120 mmol/L was seen in 38% patients. Total plasma osmolality was 260.40±8.51 (mmol/Kg), urinary Na+ was 13465±55.81 mmol/L, urinary osmolality was 408.05±157.02 mmol/L. S. creatinine was 1.06±1.02 m/dl, and S. uric acid was 3.35±0.75 mg/dl. Conclusions: The most common symptoms were Coma, confusion, weakness, headache, fever, and convulsion by hemorrhagic stroke and ischemic stroke. Meningitis, encephalitis, pneumonia, and pulmon

Aggressive but not reproductive boldness in male green anole lizards correlates with baseline vasopressin activity

Across species, individuals within a population differ in their level of boldness in social encounters with conspecifics. This boldness phenotype is often stable across both time and social context (e.g., reproductive versus agonistic encounters). Various neural and hormonal mechanisms have been suggested as underlying these stable phenotypic differences, which are often also described as syndromes, personalities, and coping styles. Most studies examining the neuroendocrine mechanisms associated with boldness examine subjects after they have engaged in a social interaction, whereas baseline neural activity that may predispose behavioral variation is understudied. The present study tests the hypotheses that physical characteristics, steroid hormone levels, and baseline variation in Ile3-vasopressin (VP, a.k.a., Arg8-vasotocin) signaling predispose boldness during social encounters. Boldness in agonistic and reproductive contexts was extensively quantified in male green anole lizards (Anolis carolinensis), an established research organism for social behavior research that provides a crucial comparison group to investigations of birds and mammals. We found high stability of boldness across time, and between agonistic and reproductive contexts. Next, immunofluorescence was used to colocalize VP neurons with phosphorylated ribosomal protein S6 (pS6), a proxy marker of neural activity. Vasopressin-pS6 colocalization within the paraventricular and supraoptic nuclei of the hypothalamus was inversely correlated with boldness of aggressive behaviors, but not of reproductive behaviors. Our findings suggest that baseline vasopressin release, rather than solely context-dependent release, plays a role in predisposing individuals toward stable levels of displayed aggression toward conspecifics by inhibiting behavioral output in these contexts.

Suprachiasmatic nucleus-mediated glucose entry into the arcuate nucleus determines the daily rhythm in blood glycemia

Glycemia is maintained within very narrow boundaries with less than 5% variation at a given time of the day. However, over the circadian cycle, glycemia changes with almost 50% difference. How the suprachiasmatic nucleus, the biological clock, maintains these day-night variations with such tiny disparities remains obscure. We show that via vasopressin release at the beginning of the sleep phase, the suprachiasmatic nucleus increases the glucose transporter GLUT1 in tanycytes. Hereby GLUT1 promotes glucose entrance into the arcuate nucleus, thereby lowering peripheral glycemia. Conversely, blocking vasopressin activity or the GLUT1 transporter at the daily trough of glycemia increases circulating glucose levels usually seen at thepeak of the rhythm. Thus, biological clock-controlled mechanisms promoting glucose entry into the arcuate nucleus explain why peripheral blood glucose is low before sleep onset.

Renin, antidiuretic hormone (ADH), and ADH receptor levels in cerebral salt wasting associated with tuberculous meningitis.

To evaluate serum antidiuretic hormone (ADH), its receptors, and renin levels in cerebral salt wasting (CSW) in tuberculous meningitis (TBM). Patients diagnosed with definite (n = 30) or probable TBM (n = 47) who developed hyponatremia (CSW, SIADH, or miscellaneous causes) were included. Sequential measurement of serum ADH, ADH-R, and renin activity by enzyme-linked immunosorbent assay was done and correlated with serum sodium level, urinary output, and fluid balance. Out of 79 TBM patients, CSW was observed in 36, SIADH in four, and miscellaneous hyponatremia in eight patients. CSW patients had a longer hospital stay (P < 0.001), lower GCS score (P < 0.007), higher MRC grade (P < 0.007), and a lower serum Na (P < 0.001) compared to non-CSW TBM patients. In severe CSW patients, serum ADH and ADH-R were correlated with hyponatremia and returned to baseline on correction; however, serum renin levels remained elevated. Serum ADH was related to hyponatremia but ADH-R and renin were not. ADH-R and renin levels did not significantly differ in CSW and SIADH. CSW is the commonest cause of hyponatremia in TBM and correlates with disease severity. ADH is related to hyponatremia, but ADH receptor and renin are not.

Serum sodium level is inversely correlated with body temperature in children.

Several studies have demonstrated that non-osmotic antidiuretic hormone activity contributes to the development of hyponatremia in children with common febrile diseases. However, the relationship between hyponatremia and body temperature has remained unclear. We therefore examined this relationship in children with common diseases. In this retrospective case study based on a chart review, 1,973 children presenting with acute illnesses at Hirakata City Hospital between November 2008 and October 2009, and for whom blood test data were available, were enrolled. The median age of this cohort was 2.7 years and the mean serum sodium concentration was 136.4 mEq/L; 454 patients showed hyponatremia (<135 mEq/L). The patients were classified into four groups on the basis of body temperature, <37 °C, 37 °C (37.0-37.9 °C), 38 °C (38.0-38.9 °C) and ≥39 °C, and their serum sodium concentration was compared. The mean sodium level was significantly lower in febrile (135.9 mEq/L) than in non-febrile (138.5 mEq/L) patients. The mean serum sodium levels in the four temperature groups were, in ascending order, 138.5 mEq/L (95% CI, 138.3-138.8 mEq/L), 137.3 mEq/L (137.1-137.5 mEq/L), 136.1 mEq/L (135.8-136.3 mEq/L) and 134.6 mEq/L (134.4-134.9 mEq/L), respectively. The serum sodium level in each individual temperature range became significantly lower as body temperature increased (P < 0.001). There is a clear inverse correlation between serum sodium level and body temperature in children with common febrile diseases, and fever may play an important role in this relationship.

Environmental Enrichment Protects Against Sepsis-Associated Encephalopathy-Induced Learning and Memory Deficits by Enhancing the Synthesis and Release of Vasopressin in the Supraoptic Nucleus.

BackgroundAs a severe complication of sepsis, sepsis-associated encephalopathy (SAE) usually manifests as impaired learning and memory ability in survivors. Previous studies have reported that environmental enrichment (EE) can increase the learning and memory ability in different brain injury models. However, there has been no research on the possible positive effect of EE on SAE.AimThe present study aimed to test the effect of EE on SAE-induced impairment of learning and memory and its related mechanisms.MethodsA Morris water maze test (MWM) was used to evaluate the learning and memory ability of SAE rats that received EE housing or not. The expression of vasopressin (VP) was assessed using immunofluorescence microscopy and enzyme-linked immunosorbent assays (ELISAs). The synthesis of VP in the supraoptic nucleus (SON) was determined using quantitative real-time reverse transcription-PCR analysis. Moreover, inflammatory markers and brain-derived neurotrophic factor (BDNF) were detected using ELISA.ResultsThe results showed that SAE induced a decreased learning and memory ability, while EE reversed this impairment. EE also enhanced the synthesis and secretion of VP in the SON. Blocking the action of VP in the hippocampus interrupted the EE-induced amelioration of learning and memory impairment. Moreover, EE induced changes to the levels of BDNF and cytokines in the hippocampus and these effects were mediated by VP binding to the VP receptor 1a.ConclusionOur findings demonstrated that the enhanced synthesis and secretion of VP in the SON are a key determinant responsible for EE-induced alleviation of learning and memory deficits caused by SAE.

OR30. Effect of hyponatremia in heart failure patients at discharge on 30-day readmission rate: a single-centre study

Abstract Background and Aims Hyponatremia is often observed in patients with heart failure. The proposed pathophysiology of hyponatremia in heart failure is due to increase of arginine vasopressin activity that elevates renal water reabsorption, thereby diluting sodium content in plasma. Hyponatremia has been identified as a factor that worsens heart failure patients' prognosis, including cardiovascular morbidity and mortality. Thus, this study was conducted to investigate the impact of hyponatremia in heart failure patients on rehospitalisation within thirty days. Methods and Results This is a single-centre prospective cohort study. A total of 205 acute decompensated heart failure patients admitted to National Cardiovascular Center Harapan Kita from July 2018 to March 2019 were included into the study. The study population was then divided into two groups based on predischarge sodium level. In this study, hyponatremia was defined as serum sodium level less than 135 mEq/l. Among the study population, 58 patients (28.3%) had hyponatremia at discharge. The data was analyzed using chi-square test. There were 19 patients who were readmitted within 30 days and 52.9% of them had hyponatremia at discharge. The effect of hyponatremic status at discharge to 30-day readmission rate was statistically significant (p = 0.03, OR = 3.19 95%CI 1.22-8.33). Conclusion Hyponatremia in heart failure patients at discharge is associated with increased risk of 30-day readmission.

Chemogenetic activation of endogenous arginine vasopressin exerts anorexigenic effects via central nesfatin-1/NucB2 pathway

We examined whether the chemogenetic activation of endogenous arginine vasopressin (AVP) affects central nesfatin-1/NucB2 neurons, using a transgenic rat line that was previously generated. Saline (1 mL/kg) or clozapine-N-oxide (CNO, 1 mg/mL/kg), an agonist for hM3Dq, was subcutaneously administered in adult male AVP-hM3Dq-mCherry transgenic rats (300–370 g). Food and water intake were significantly suppressed after subcutaneous (s.c.) injection of CNO, with aberrant circadian rhythmicity. The percentages of Fos expression in nesfatin-1/NucB2-immunoreactive neurons were significantly increased in the hypothalamus and brainstem at 120 min after s.c. injection of CNO. Suppressed food intake that was induced by chemogenetic activation of endogenous AVP was ablated after intracerebroventricularly administered nesfatin-1/NucB2-neutralizing antibody in comparison with vehicle, without any alteration of water intake nor circadian rhythmicity. These results suggest that chemogenetic activation of endogenous AVP affects, at least in part, central nesfatin-1/NucB2 neurons and may exert anorexigenic effects in the transgenic rats.

Hypomagnesemia and Hypokalemia: The Possible Role of Vasopressinase in This Rare Presentation of Gestational Diabetes Insipidus

Background: Gestational diabetes insipidus (GDI) is a rare but recognized complication of pregnancy. We are reporting the case of a 33-year-old patient who presented in her 3rd trimester with GDI, severe asymptomatic hypokalemia & hypomagnesemia. This presentation of GDI has not been reported yet to our knowledge. Clinical Case: A 33-year-old G2P1 patient who presented to the hospital due to the discovery of new onset severe asymptomatic hypokalemia on routine labs. Further evaluation revealed K of 2.8 mEq/L, Mg of 1.4 mg/dL & Na of 142mEq/L. She endorsed polyuria & polydipsia and a 24-hour urine collection of 9.35L confirmed diabetes insipidus. Labs also revealed a serum osmolality of 286mOsm/kg & urine K of 15mEq/L. Her urine osmolality was inappropriately low at 138mOsm/kg. She received K & Mg supplementation. In pregnant patients suspected of having GDI who have normal serum Na, water restriction test can be done for further evaluation. It must performed with close monitoring because dehydration can lead to uteroplacental insufficiency. Given her history of previous fetal demise & report of headaches with attempts of water restriction, we opted not to do the test. She was given subcutaneous 1 mcg of desmopressin overnight with her thirst & polyuria improving only briefly. Due to her suboptimal response, we began her on 10 mcg of intranasal spray of desmopressin once in the evening. Her symptoms resolved on this regimen after a few days of observation. Her Mg & eventually K levels reached and remained at normal levels after repletion. The rest of her pregnancy went on without complications and she delivered a healthy male infant via scheduled cesarean section at 36 weeks gestation. She discontinued intranasal desmopressin after 2 weeks and has remained asymptomatic. Labs at follow up 4 weeks later remained normal. It is known that vasopressinase which is made by placental trophoblasts during pregnancy degrade endogenous ADH1. We are hypothesizing that since ADH has been shown to be effective in conserving magnesium in rats by stimulating its uptake in the distal convoluted tubule cells2, a similar mechanism could be present in humans. We believe that the loss of endogenous ADH, leads to the depletion of Mg and consequently hypokalemia in susceptible patients. Conclusion: To our knowledge this is the first case presenting the possible role of vasopressinase in the development of hypomagnesemia & hypokalemia in a patient with GDI. Reference: 1. Gordge MP, Williams DJ, Huggett NJ, Payne NN, and Neild GH. Loss of biological activity of arginine vasopressin during its degradation by vasopressinase from pregnancy serum. Clinical Endocrinology, vol. 42, no. 1, pp. 51- 58, 1995. 2. Dai LJ, Bapty B, Ritchie G, Quamme GA. Glucagon and arginine vasopressin stimulate Mg2+ uptake in mouse distal convoluted tubule cells. Am J Physiol. 1998 Feb;274(2):F328-35. doi: 10.1152/ajprenal.1998.274.2.F328. PMID: 9486227.

Diuretic Action of Apelin-13 Mediated by Inhibiting cAMP/PKA/sPRR Pathway.

Emerging evidence is showing that apelin plays an important role in regulating salt and water balance by counteracting the antidiuretic action of vasopressin (AVP). However, the underlying mechanism remains unknown. Here, we hypothesized that (pro) renin receptor (PRR)/soluble prorenin receptor (sPRR) might mediate the diuretic action of apelin in the distal nephron. During water deprivation (WD), the urine concentrating capability was impaired by an apelin peptide, apelin-13, accompanied by the suppression of the protein expression of aquaporin 2 (AQP2), NKCC2, PRR/sPRR, renin and nuclear β-catenin levels in the kidney. The upregulated expression of AQP2 or PRR/sPRR both induced by AVP and 8-Br-cAMP was blocked by apelin-13, PKA inhibitor (H89), or β-catenin inhibitor (ICG001). Interestingly, the blockage of apelin-13 on AVP-induced AQP2 protein expression was reversed by exogenous sPRR. Together, the present study has defined the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/sPRR pathway in the CD as the molecular target of the diuretic action of apelin.

Mechanism, spectrum, consequences and management of hyponatremia in tuberculous meningitis.

Hyponatremia is the commonest electrolyte abnormality in hospitalized patients and is associated with poor outcome. Hyponatremia is categorized on the basis of serum sodium into severe (< 120 mEq/L), moderate (120-129 mEq/L) and mild (130-134mEq/L) groups. Serum sodium has an important role in maintaining serum osmolality, which is maintained by the action of antidiuretic hormone (ADH) secreted from the posterior pituitary, and natriuretic peptides such as atrial natriuretic peptide and brain natriuretic peptide. These peptides act on kidney tubules via the renin angiotensin aldosterone system. Hyponatremia <120mEq/L or a rapid decline in serum sodium can result in neurological manifestations, ranging from confusion to coma and seizure. Cerebral salt wasting (CSW) and syndrome of inappropriate secretion of ADH (SIADH) are important causes of hyponatremia in tuberculosis meningitis (TBM). CSW is more common than SIADH. The differentiation between CSW and SIADH is important because treatment of one may be detrimental for the other; evidence of hypovolemia in CSW and euvolemia or hypervolemia in SIADH is used for differentiation. In addition, evidence of dehydration, polyuria, negative fluid balance as assessed by intake output chart, weight loss, laboratory evidence and sometimes central venous pressure are helpful in the diagnosis of these disorders. Volume contraction in CSW may be more protracted than hyponatremia and may contribute to border zone infarctions in TBM. Hyponatremia should be promptly and carefully treated by saline and oral salt, while 3% saline should be used in severe hyponatremia with coma and seizure. In refractory patients with hyponatremia, fludrocortisone helps in early normalization of serum sodium without affecting polyuria or functional outcome. In SIADH, V2 receptor antagonist conivaptan or tolvaptan may be used if the patient is not responding to fluid restriction. Fluid restriction in SIADH has not been found to be beneficial in TBM and should be avoided.

Olive Leaf Extract (OLE) impaired vasopressin-induced aquaporin-2 trafficking through the activation of the calcium-sensing receptor

Vasopressin (AVP) increases water permeability in the renal collecting duct through the regulation of aquaporin-2 (AQP2) trafficking. Several disorders, including hypertension and inappropriate antidiuretic hormone secretion (SIADH), are associated with abnormalities in water homeostasis. It has been shown that certain phytocompounds are beneficial to human health. Here, the effects of the Olive Leaf Extract (OLE) have been evaluated using in vitro and in vivo models. Confocal studies showed that OLE prevents the vasopressin induced AQP2 translocation to the plasma membrane in MCD4 cells and rat kidneys. Incubation with OLE decreases the AVP-dependent increase of the osmotic water permeability coefficient (Pf). To elucidate the possible effectors of OLE, intracellular calcium was evaluated. OLE increases the intracellular calcium through the activation of the Calcium Sensing Receptor (CaSR). NPS2143, a selective CaSR inhibitor, abolished the inhibitory effect of OLE on AVP-dependent water permeability. In vivo experiments revealed that treatment with OLE increases the expression of the CaSR mRNA and decreases AQP2 mRNA paralleled by an increase of the AQP2-targeting miRNA-137. Together, these findings suggest that OLE antagonizes vasopressin action through stimulation of the CaSR indicating that this extract may be beneficial to attenuate disorders characterized by abnormal CaSR signaling and affecting renal water reabsorption.

Diabetes Insipidus: A Pragmatic Approach to Management.

Diabetes insipidus (DI) is a disorder of water balance characterized by polyuria and polydipsia. It can occur due to genetic and acquired causes that affect the secretion or action of arginine vasopressin (AVP) or antidiuretic hormone (ADH).Markedly increased thirst and urination are not only quite distressing but also increases the risk of volume depletion and hypernatremia in severe situations. A careful diagnosis of the type of DI and its etiology is based on careful clinical evaluation, measurement of urine and serum osmolality, and water deprivation test. Management includes the correction of any water deficit and the use of specific pharmacological agents, including desmopressin, thiazides, and amiloride.

Ifosfamide-induced nephrogenic diabetes insipidus responsive to supraphysiologic doses of intravenous desmopressin

Nephrogenic diabetes insipidus (DI) refers to the reduction in the ability of the kidney to concentrate urine, which can be caused by partial or complete resistance at the site of action of anti-diuretic hormone (ADH) in the collecting tubules. Ifosfamide-induced nephrogenic DI typically occurs concomitantly in patients who have other signs of tubular toxicity consistent with Fanconi syndrome including glucosuria, aminoaciduria, and hypophosphatemia. We present a case of a 36-year-old female with recurrent synovial cell sarcoma of the pleural membranes, treated with ifosfamide-based chemotherapy, who was admitted to the hospital for the management of polyuria, hypotension, as well as electrolyte derangements including hypokalemia, hypophosphatemia and non-anion gap metabolic acidosis, 1 week after receiving a cumulative ifosfamide dose of 7.5 g/m2. Nephrogenic DI was indicated by polyuria as well as a urine osmolality to plasma osmolality ratio of less than 1.5 following a trial of intravenous desmopressin, but the patient’s acute kidney injury on presentation precluded the early employment of thiazides and non-steroidal anti-inflammatory drugs (NSAIDs). Instead, the patient’s polyuria and urine osmolality improved only after the administration of repetitive supraphysiologic doses of intravenous desmopressin. Our case reiterates that patients with non-hereditary nephrogenic DI may have partial rather than complete resistance to ADH and highlights that desmopressin may be considered in patients with ifosfamide-induced nephrogenic DI to prevent severe volume depletion, especially in patients who have persistent symptomatic polyuria despite maintaining a careful fluid balance and pharmacological therapy with NSAIDs and diuretics, or if the patient’s clinical condition precludes the use of these strategies.

Chapter 18 - The vasopressin–aquaporin-2 pathway syndromes

Vasopressin is the key hormone involved in water conservation and regulation of water balance, essential for life. In the renal collecting duct, vasopressin binds to the V2 receptor, increasing water permeability through activation of aquaporin-2 redistribution to the luminal membrane. This mechanism promotes rapid water reabsorption, important for immediate survival; however, only recently it has become clear that long-term adverse effects are associated with alterations of the vasopressin-aquaporin-2 pathway, leading to several syndromes associated with water balance disorders. The kidney resistance to the vasopressin action may cause severe dehydration for patients and, conversely, nonosmotic release of vasopressin is associated with water retention and increasing the circulatory blood volume. This chapter discusses the relevance of the altered vasopressin-aquaporin-2 pathway in some diseases associated with water balance disorders, including congenital nephrogenic diabetes insipidus, syndrome of inappropriate secretion of antidiuretic hormone, nephrogenic syndrome of inappropriate antidiuresis, and autosomal dominant polycystic kidney disease. The emerging picture suggests that targeting the vasopressin-AQP2 axis can provide therapeutic benefits in those patients.