The Emerging Role of Copeptin

Direct measurement of the nonapeptide vasopressin has been limited by analyte instability ex vivo and in vivo rapid degradation, low serum concentrations requiring a sensitive assay and inherent secretory pulsatility. Copeptin is a 39 amino acid glycopeptide cleavage product of vasopressin synthesis with high stability, providing a marker of vasopressin secretion. Copeptin measurement has applications in diagnosis of diabetes insipidus and other diseases with altered vasopressin secretion. This review summarises our current understanding of serum copeptin measurement in diabetes insipidus and possible future applications of copeptin assays. As vasopressin is a stress hormone, there is emerging evidence on the use of copeptin for diagnosis and prognostication of disorders such as syndrome of inappropriate anti-diuretic hormone secretion, diabetes mellitus, critical illness, stroke, cardiovascular disease, respiratory disease, renal disease and thermal stress. Copeptin concentration measurement is likely to improve the diagnostic reliability of diabetes insipidus and, as a marker of stress, may have diagnostic or prognostic utility in specific clinical circumstances. Further studies are needed to determine if goal-directed therapy using plasma copeptin concentrations may improve patient outcomes.     

Postoperative Copeptin as a Biomarker for Development of Diabetes Insipidus Following Hypothalamic-Pituitary Surgery

ObjectiveCopeptin is a surrogate marker of arginine vasopressin release with better stability and simplicity of measurement. Postoperative copeptin levels may guide clinicians in stratifying patients who need close monitoring of fluid balance. The objective is to determine whether copeptin is a predictive marker of postoperative diabetes insipidus (DI).MethodsThis is a prospective diagnostic study. Patients who underwent neurosurgical intervention of the sellar-suprasellar regions were recruited. Serum copeptin levels were measured before and after surgery, within 24 hours. Logistic regression analysis and diagnostic performance measures were calculated to determine the relationship between postoperative copeptin levels and DI.ResultsOf 82 patients, 26 (31.7%) developed postoperative DI, with 7 patients (8.5%) having permanent DI. The samples for copeptin measurement were taken at 13 ± 2.1 hours postoperatively. From the receiver operating characteristic analysis, low postoperative copeptin levels (<2.5 pmol/L) demonstrated an acceptable ability to predict DI (area under the curve, 0.72; 95% CI, 0.60-0.84). Discriminative power was stronger in the permanent DI group (area under the curve, 0.82; 95% CI, 0.64-1.00). Postoperative copeptin levels <2.5 pmol/L were associated with DI (specificity > 91%). However, postoperative copeptin levels >20 pmol/L were rarely associated with DI, with a negative predictive value of 100%.ConclusionsIn patients undergoing sellar-suprasellar interventions, low postoperative copeptin levels within the first postoperative day predict postoperative DI, whereas high levels exclude it. Copeptin measurement should be applied in the clinical practice of postoperative care in patients following hypothalamic-pituitary surgery. This study may expand the potential use of copeptin, including in the Asian population.     

Maintained serum sodium in male ultra-marathoners--the role of fluid intake, vasopressin, and aldosterone in fluid and electrolyte regulation

Exercise-associated hyponatremia (EAH) is a well know electrolyte disorder in endurance athletes. Although fluid overload is the most like etiology, recent studies, however, argued whether EAH is a disorder of vasopressin secretion. The aims of the present study were to investigate (i) the prevalence of EAH in male ultra-marathoners and (ii) whether fluid intake, aldosterone or vasopressin, as measured by copeptin, were associated with post-race serum sodium concentration ([Na+]). In 50 male ultra-marathoners in a 100?km ultra-marathon, serum [Na+], aldosterone, copeptin, serum and urine osmolality, and body mass were measured pre- and post-race. Fluid intake, renal function parameters and urine excretion were measured. No athlete developed EAH. Copeptin and aldosterone increased; a significant correlation was found between the change in copeptin and the change in serum [Na+], no correlation was found between aldosterone and serum [Na+]. Serum [Na+] increased by 1.6%; body mass decreased by 1.9?kg. The change in serum [Na+] and body mass correlated significantly and negatively. The fluid intake of ~?0.58?l/h was positively related to the change in body mass and negatively to both post-race serum [Na+] and the change in serum [Na+]. We conclude that serum [Na+] was maintained by both the mechanisms of fluid intake and the hormonal regulation of vasopressin.     

Copeptin as an Indicator of Hemodynamic Derangement and Prognosis in Liver Cirrhosis

Background

Advanced liver cirrhosis is associated with systemic hemodynamic derangement leading to the development of severe complications associated with increased mortality. Copeptin is a stable cleavage product of the precursor of arginine vasopressin, a key-regulator in hemodynamic homeostasis. Copeptin is currently considered a reliable prognostic marker in a wide variety of diseases other than cirrhosis. The present study aimed to assess copeptin, both experimentally and clinically, as a potential biomarker of hemodynamic derangement and to evaluate its prognostic significance in cirrhosis.

Materials and Methods

Two studies were executed: 1) in 18 thioacetamide-induced cirrhotic rats and 5 control rats, plasma copeptin and hemodynamic measurements were performed, 2) in 61 cirrhotic patients, serum copeptin concentration was measured in samples collected at time of registration at the waiting list for liver transplantation. In 46 patients, also a second copeptin measurement was performed during follow-up while registered at the waiting list for liver transplantation. To determine the association of serum copeptin and clinical data with outcome, Cox proportional hazard regression analysis and Kaplan Meier analysis were performed.

Results

Plasma copeptin concentration was significantly higher in cirrhotic rats than in controls (1.6 ± 0.5 vs. 0.9 ± 0.1 pmol/L, p< 0.01) and was negatively correlated to the mean arterial blood pressure (r = -0.574, p = 0.013). In cirrhotic patients, serum copeptin concentration was high [11.0 (5.2–24.0) pmol/L] and increased significantly during the time of registration at the waiting list for liver transplantation. MELD and MELD-sodium score were significantly correlated to serum copeptin [MELD: (r = 0.33, p = 0.01), MELD-sodium: (r = 0.29, p = 0.02)], also at time of the second copeptin measurement [MELD and MELD-sodium: r = 0.39, p< 0.01]. In cirrhotic humans, serum copeptin concentration was significantly associated with outcome, independently of the MELD and MELD-sodium score. Patients with a low serum copeptin concentration at time of registration at the liver transplant waiting list had significantly better transplant-free survival rates at 3, 6 and 12 months of follow-up as compared to those with a high serum copeptin concentration (Log-rank: p< 0.01, p< 0.01 and p = 0.02 respectively).

Conclusions

Circulating copeptin levels are elevated in rats and humans with cirrhosis. Copeptin is independently associated with outcome in cirrhotic patients awaiting liver transplantation.     

Structure, processing and evolution of the neurohypophysial hormone-neurophysin precursors

Neurohypophysial hormones and neurophysins are derived from common precursors processed during the axonal transport from the hypothalamus to the neurohypophysis. Two neurohormones, an oxytocin-like and a vasopressin-like, on one hand, two neurophysins, termed VLDV-and MSEL-neurophysins according to residues in positions 2, 3, 6 and 7, on the other, are usually found in vertebrate species. In contrast to placental mammals that have oxytocin and arginine vasopressin, marsupials have undergone a peculiar evolution. Two pressor peptides, lysipressin and vasopressin for American species, lysipressin and phenylpressin for Australian macropods, have been identified in individual glands and it is assumed that the primordial vasopressin gene has been duplicated in these lineages. On the other hand, the reptilian mesotocin is still present in Australian species instead of the mammalian oxytocin, while the North American opossum has both hormones and South American opossums have only oxytocin. The neurophysin domain of each precursor is encoded by 3 exons and different evolutionary rates have been found for the 3 corresponding parts of the protein. The central parts, encoded by the central exons, are evolutionarily very stable and nearly identical in the 2 neurophysins of a given species. Recurrent gene conversions have apparently linked the evolutions of the 2 precursor lineages. In mammals, the 3-domain precursor of vasopressin is processed in 2 stages: a first cleavage splitting off vasopressin and a second cleavage separating MSEL-neurophysin from copeptin. Two distinct enzymatic systems seem to be involved in these cleavages. Processing is usually complete at the level of the neurohypophysis, but an intermediate precursor encompassing MSEL -neurophysin and copeptin linked by an arginine residue has been characterized in guinea pig. In vitro processing of this intermediate through trypsin--Sepharose reveals cleavages only in the interdomain region. In non-mammalian tetrapods, such as birds and amphibians, mesotocin and vasotocin are associated with neurophysins in precursors similar to those found in mammals. However, processing of the vasotocin precursor seems to be different from the processing of the vasopressin precursor, with a single cleavage leading to the hormone release.     

Guinea pig copeptin. The glycopeptide domain of the vasopressin precursor

The vasopressin precursor is composed of 3 domains in line, namely vasopressin, MSEL-neurophysin and a glycopeptide referred to as copeptin, which are separated during the processing. In guinea pig neurohypophysis, the precursor is partially processed so that a two-domain fragment, MSEL-neurophysin--copeptin, can be found along with free MSEL-neurophysin adn copeptin. Guinea pig copeptin has been sequenced. It is a glycopeptide composed of 38 amino acid residues rather than the 39 found in other mammalian copeptins. Compared with other copeptins, that from guinea pig shows a few substitutions and the deletion of one acidic residue, probably in position 32. This deletion might be responsible for incomplete cleavage by the trypsin-like processing enzyme.     

One-step processing of the amphibian vasotocin precursor: structure of a frog (Rana esculenta) "big" neurophysin

Vasotocin-associated neurophysin (MSEL-neurophysin) from the frog Rana esculenta has been isolated and sequenced through tryptic and staphylococcal proteinase peptides and cyanogen bromide fragments. This protein appears homologous to the mammalian vasopressin-associated neurophysin with a C-terminal glycopeptide extension homologous to the mammalian copeptin. In contrast to the two-step processing of mammalian vasopressin/MSEL-neurophysin/copeptin precursor, a single cleavage is therefore involved in the processing of the amphibian vasotocin/neurophysin precursor. It appears that the physiological release of the vasopressin-like hormone from the N-terminal end of the protein precursor is not dependent upon a previous trimming of the C-terminal copeptin-like moiety.     

Plasma copeptin in the assessment of febrile neutropenia

Copeptin, the surrogate marker of arginine vasopressin (AVP), has been suggested to be a useful biomarker in monitoring sepsis reflecting hemodynamic imbalance and stress state. This prospective study conducted at a hematology ward in a Finnish University Hospital aimed to investigate whether plasma copeptin predicts the development of complicated course of neutropenic fever (bacteremia or need for treatment at intensive care unit) in 100 hematological patients experiencing their first neutropenic fever episode after intensive chemotherapy for hematological malignancy. Contrary to study presumptions, not elevated copeptin but the lack of a proper initial increase of plasma copeptin (<0.02 ng/mL from day 0 to day 1) predicted blood culture positive sepsis (p=0.023) and gram-negative bacteremia (p=0.045). No correlation was observed with plasma sodium, blood pressure or evaluated osmolality. Plasma copeptin correlated inversely with the same day pentraxin 3 on day 0-day 2 (all p-values <0.001) and with C-reactive protein on day 1 (p=0.015). In conclusion, copeptin did not correlate with disease severity, but the lack of a proper initial increase was associated with bacteremic complications of febrile neutropenia in hematological patients. The findings suggest the possibility of central dysregulation of AVP release and do not support the use of copeptin as a biomarker of septic complications in this patient group.     

Properties of human vasopressin precursor constructs: inefficient monomer folding in the absence of copeptin as a potential contributor to diabetes insipidus

These studies were aimed at an initial characterization of the human vasopressin precursor and the evaluation of factors leading to misfolding by the pathological 87STOP mutation. This mutation deletes the precursor's glycosylated copeptin segment, which has been considered unnecessary for folding, and the last seven neurophysin residues. We investigated the role in folding of the last seven neurophysin residues by comparing the properties of the 87STOP precursor and its derivative neurophysin with those of the corresponding wild-type proteins from which copeptin had been deleted, leading to the following conclusions. First, despite modulating effects on several protein properties, the last seven neurophysin residues do not make a significant net thermodynamic contribution to precursor folding; stabilities of the mutant and wild-type precursors to both guanidine denaturation and redox buffer unfolding are similar, as are in vitro folding rates. Second, the monomeric forms of both precursors are unstable and predicted to fold inefficiently at physiological pH and temperature, as evidenced by precursor behavior in redox buffers and by thermodynamic calculations. Third, both precursors are significantly less stable than the bovine oxytocin precursor. These results, together with earlier studies elsewhere of vasopressin precursor behavior within rat neurons, are shown to represent a self-consistent argument for a role for glycosylated copeptin in vasopressin precursor folding in vivo, copeptin most probably assisting refolding by facilitating interaction of misfolded monomers with the calnexin/calreticulin system. This hypothesis provides an explanation for the absence of copeptin in the more stable oxytocin precursor and suggests that the loss of copeptin contributes to 87STOP pathogenicity. Reported cell culture studies of rat precursor folding are also discussed in this context. Most generally, the results emphasize the significance of monomer stability in the folding pathways of oligomeric proteins.     

Changes in Plasma Copeptin Levels during Hemodialysis: Are the Physiological Stimuli Active in Hemodialysis Patients?

ObjectivesPlasma levels of copeptin, a surrogate marker for the vasoconstrictor hormone arginine vasopressin (AVP), are increased in hemodialysis patients. Presently, it is unknown what drives copeptin levels in hemodialysis patients. We investigated whether the established physiological stimuli for copeptin release, i.e. plasma osmolality, blood volume and mean arterial pressure (MAP), are operational in hemodialysis patients.MethodsOne hundred and eight prevalent, stable hemodialysis patients on a thrice-weekly dialysis schedule were studied during hemodialysis with constant ultrafiltration rate and dialysate conductivity in this observational study. Plasma levels of copeptin, sodium, MAP, and blood volume were measured before, during and after hemodialysis. Multivariate analysis was used to determine the association between copeptin (dependent variable) and the physiological stimuli plasma sodium, MAP, excess weight as well as NT-pro-BNP immediately prior to dialysis and between copeptin and changes of plasma sodium, MAP and blood volume with correction for age, sex and diabetes during dialysis treatment.ResultsPatients were 63±15.6 years old and 65% were male. Median dialysis vintage was 1.6 years (IQR 0.7–4.0). Twenty-three percent of the patients had diabetes and 82% had hypertension. Median predialysis copeptin levels were 141.5 pmol/L (IQR 91.0–244.8 pmol/L). Neither predialysis plasma sodium levels, nor NT-proBNP levels, nor MAP were associated with predialysis copeptin levels. During hemodialysis, copeptin levels rose significantly (p<0.01) to 163.0 pmol/L (96.0–296.0 pmol/L). Decreases in blood volume and MAP were associated with increases in copeptin levels during dialysis, whereas there was no significant association between the change in plasma sodium levels and the change in copeptin levels.ConclusionsPlasma copeptin levels are elevated predialysis and increase further during hemodialysis. Volume stimuli, i.e. decreases in MAP and blood volume, rather than osmotic stimuli, are associated with change in copeptin levels during hemodialysis.     

Copeptin as a diagnostic biomarker for sepsis-related deaths

Copeptin has been shown to increase in patients with sepsis, severe sepsis and septic shock. In the study herein described, copeptin was measured in a series of sepsis-related fatalities and control cases that underwent medico-legal investigations. No age-dependent differences in copeptin levels in either sepsis or control cases were observed. No correlation between copeptin concentrations and postmortem interval was identified in either group. Copeptin levels were significantly higher in sepsis cases. Moreover, copeptin concentrations in septic cases correlated with procalcitonin, C-reactive protein and interleukin 6 values. These preliminary findings seem to indicate that copeptin can be reliably measured in biological samples collected during postmortem investigations. These results also suggest that hemodynamic instability associated with sepsis and septic shock can be characterized by copeptin measurement also in the forensic casework.     

Diagnostic Accuracy of Copeptin in the Differential Diagnosis of Patients With Diabetes Insipidus: A Systematic Review and Meta-analysis

ObjectiveAccurate diagnosis of diabetes insipidus (DI) is of significant importance for correct management. We aimed to evaluate the diagnostic accuracy of copeptin level measurements in the differential diagnosis between DI and primary polydipsia (PP).MethodsA literature search of electronic databases from January 1, 2005, to July 13, 2022, was performed. Primary studies that evaluated the diagnostic accuracy of copeptin concentration in patients with DI and PP were considered eligible. Two reviewers independently screened relevant articles and extracted data. The Quality Assessment of Diagnostic Accuracy Studies 2 tool was used to assess the quality of the included studies. The hierarchical summary receiver operating characteristic model and bivariate method were used.ResultsSeven studies including 422 patients with polydipsia-polyuria syndrome were included; of the 422 patients, 189 (44.79%) presented with arginine vasopressin deficiency (AVP-D, cranial DI) and 212 (50.24%) with PP. The summary estimates of the diagnostic performance of stimulated copeptin to differentiate between PP and AVP-D were 0.93 (95% CI, 0.89-0.97) for sensitivity and 0.96 (95% CI, 0.88-1.00) for specificity. Baseline copeptin level showed high performance in identifying AVP resistance (nephrogenic DI), with a pooled sensitivity of 1.00 (95% CI, 0.82-1.00) and specificity of 1.00 (95% CI, 0.98-1.00); however, it showed little value in the differentiation between PP and AVP-D.ConclusionCopeptin level measurement is a useful tool for the differential diagnosis of patients with DI and PP. Stimulation before copeptin measurement is necessary in the diagnosis of AVP-D.     

Alteration of serum and cardiac tissue adropin,copeptin, irisin and TRPM2 expressions in DOX treated male rats

Abstract

Doxorubicin (DOX) cardiotoxicity is a significant side effect in cancer survivors. DOX and its metabolites alter cardiac gene expression and affect metabolic energy-related peptides. Adropin, copeptin, irisin and TRPM2 are produced locally in the heart and play a role in energy homeostasis. We investigated the fates of adropin, copeptin, irisin and TRPM2 in serum and cardiac tissues of DOX treated rats. Animals were divided into three groups of six: 1) untreated controls, 2) DOX treated and 3) saline treated. The rats were fed a standard diet ad libitum for 14 days then were sacrificed and heart and serum samples were taken. Adropin, copeptin, irisin levels in tissue homogenates and serum were measured using ELISA. Immunoreactivity of heart tissue adropin, copeptin, irisin and TRPM2 also were investigated. The peptides increased in both serum and cardiac tissue homogenates in animals treated with DOX compared to the other groups. DOX increased adropin in endocardial and myocardial cells, but it decreased expression of copeptin. DOX did not affect endocardial irisin and TRPM2 expressions, but myocardial irisin and TRPM2 expressions were increased. Serum adropin, irisin and copeptin were increased in DOX treated rats. Cardiac adropin, copeptin, irisin and TRPM2 are affected by DOX and may play a role in DOX cardiotoxicity.     

beta-Endorphin controls vasopressin release during foot shock-induced stress in the rat

This study tested the possibility that beta-endorphin is involved in the regulation of vasopressin release during stress induced by inescapable electric foot shock. To this end, a specific anti-beta-endorphin antiserum or a control serum lacking the specific anti-beta-endorphin antibodies was administered to male rats. Plasma vasopressin concentrations, measured by radioimmunoassay, were not affected by brief foot shock stress in control rats, but were raised significantly by the stress in animals which had received an intracerebroventricular (i.c.v.) injection of the anti-beta-endorphin antiserum. In contrast, when the same volume of the anti-beta-endorphin antiserum was injected into a tail vein, foot shock stress produced only a slight effect on vasopressin release. I.c.v. injection of the antiserum changed neither basal nociceptive threshold nor stress-induced analgesia as revealed by the tail-flick latency. Vasopressin release induced by an osmotic stimulus was not influenced by the anti-beta-endorphin antiserum given i.c.v. The opiate antagonist naloxone or the glucocorticoid dexamethasone raised plasma vasopressin concentration in stressed rats which had received the control serum (i.c.v.); however, after i.c.v. injection of the anti-beta-endorphin antiserum neither naloxone nor dexamethasone elevated the plasma vasopressin concentration beyond the level reached by the anti-beta-endorphin antiserum (i.c.v.) alone. These results suggest that beta-endorphin inhibits the release of vasopressin during foot shock-induced stress in the rat.     

Blood concentrations of vasopressin, neuropeptide FF and prolactin are increased by high-dose right unilateral ECT.

Electroconvulsive therapy (ECT) is known to stimulate subcortical brain regions and release hormones from the anterior and the posterior pituitary. To enhance the subcortical effect of ECT and the neuroendocrinological response we used high dose right unilateral ECT (RUL-ECT) in 11 depressive patients and studied its effect on the release of vasopressin, prolactin and neuropeptide FF. The RUL ECT stimulus for all studied patients was 5 times the individual seizure threshold and it led to immediate release of vasopressin in all studied patients. The release of prolactin was less uniform however in accordance with results from earlier studies. The ECT also stimulated a NPFF secretion peak that came approximately 5 min after ECT stimulus and preceded the prolactin peak. The maximal elevations in circulating vasopressin and prolactin concentrations were 680% and 950%, respectively. The neuropeptide FF concentration increased by 100% after ECT. There was a second rise in NPFF concentration at 25 min after the ECT treatment. The increases in all peptide concentrations were significant, but were not correlated with each other. The neuropeptide FF concentration returned to baseline level at 10 min and the vasopressin concentration at 25 min after ECT. The prolactin concentration remained increased during the 30 min follow up period. Our results complete earlier finding on ECT stimulated vasopressin and prolactin release and show that high intensity RUL-ECT releases neuropeptide FF into human blood. The modest rise of circulating NFFF most likely represents leakage from the CNS.     

Copeptin as a Serum Biomarker of Febrile Seizures

Background and Objectives

Accurate diagnosis of febrile seizures in children presenting after paroxysmal episodes associated with fever, is hampered by the lack of objective postictal biomarkers. The aim of our study was to investigate whether FS are associated with increased levels of serum copeptin, a robust marker of arginine vasopressin secretion.

Methods

This was a prospective emergency-setting cross-sectional study of 161 children between six months and five years of age. Of these, 83 were diagnosed with febrile seizures, 69 had a febrile infection without seizures and nine had epileptic seizures not triggered by infection. Serum copeptin and prolactin levels were measured in addition to standard clinical, neurophysiological, and laboratory assessment. Clinical Trial Registration: NCT01884766.

Results

Circulating copeptin was significantly higher in children with febrile seizures (median [interquartile range] 18.9 pmol/L [8.5-36.6]) compared to febrile controls (5.6 pmol/L [4.1-9.4]; p <0.001), with no differences between febrile and epileptic seizures (21.4 pmol/L [16.1-46.6]; p = 0.728). In a multivariable regression model, seizures were the major determinant of serum copeptin (beta 0.509; p <0.001), independently of clinical and baseline laboratory indices. The area under the receiver operating curve for copeptin was 0.824 (95% CI 0.753-0.881), significantly higher compared to prolactin (0.667 [0.585-0.742]; p <0.001). The diagnostic accuracy of copeptin increased with decreasing time elapsed since the convulsive event (at 120 min: 0.879 [0.806-0.932] and at <60 min: 0.975 [0.913-0.997]).

Conclusions

Circulating copeptin has high diagnostic accuracy in febrile seizures and may be a useful adjunct for accurately diagnosing postictal states in the emergency setting.     

Vasotocin genes of the teleost fish Catostomus commersoni: gene structure, exon-intron boundary, and hormone precursor organization

cDNA clones encoding two members of the vasotocin hormone precursor gene family have been isolated from the white sucker Catostomus commersoni. The hormone is encoded by at least two distinct genes, both of which are expressed, as indicated by Northern blot analysis. Genomic DNA amplified by the polymerase chain reaction has been used to define exon-intron boundaries. Both vasotocin genes contain introns in positions corresponding to those found in the gene of their mammalian counterpart vasopressin. The predicted vasotocin precursors show a surprising degree of sequence divergence, amounting to 45% at the amino acid level, of which only approximately half can be accounted for by conservative amino acid changes. The precursors include a hormone moiety followed by a putative neurophysin sequence that is longer at the C-terminus by a tract of some 30 amino acids by comparison to their mammalian counterpart. Each of these sequences contains a leucine-rich core segment resembling that found in copeptin, a glycopeptide moiety present in mammalian vasopressin precursors.     

Ontogeny of the bovine neurohypophysial hormone precursors. III. Identification of neurohormones, neurophysins and copeptin in the early bovine fetus

Neurohypophysial hormone precursors are small proteins processed into several fragments during axonal transport from hypothalamus to neurohypophysis. From 3-month-old fetal bovine pituitaries the three fragments of vasopressin precursor, arginine vasopressin, MSEL-neurophysin and copeptin, and the two fragments of oxytocin precursor, oxytocin and VLDV-neurophysin, have been isolated and characterized. These polypeptides are identical to those previously identified in the late fetus (7-9 months old) and in the adult. It is concluded that the same genes are expressed during fetal and adult lives, the vasopressin gene appearing roughly four times more active than the oxytocin gene in the early fetus. Vasotocin, mesotocin and additional neurophysin have not been detected in the early fetus.     

Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle

In adipose and muscle cells, insulin stimulates the exocytic translocation of vesicles containing GLUT4, a glucose transporter, and insulin-regulated aminopeptidase (IRAP), a transmembrane aminopeptidase. A substrate of IRAP is vasopressin, which controls water homeostasis. The physiological importance of IRAP translocation to inactivate vasopressin remains uncertain. We previously showed that in skeletal muscle, insulin stimulates proteolytic processing of the GLUT4 retention protein, TUG, to promote GLUT4 translocation and glucose uptake. Here we show that TUG proteolysis also controls IRAP targeting and regulates vasopressin action in vivo. Transgenic mice with constitutive TUG proteolysis in muscle consumed much more water than wild-type control mice. The transgenic mice lost more body weight during water restriction, and the abundance of renal AQP2 water channels was reduced, implying that vasopressin activity is decreased. To compensate for accelerated vasopressin degradation, vasopressin secretion was increased, as assessed by the cosecreted protein copeptin. IRAP abundance was increased in T-tubule fractions of fasting transgenic mice, when compared with controls. Recombinant IRAP bound to TUG, and this interaction was mapped to a short peptide in IRAP that was previously shown to be critical for GLUT4 intracellular retention. In cultured 3T3-L1 adipocytes, IRAP was present in TUG-bound membranes and was released by insulin stimulation. Together with previous results, these data support a model in which TUG controls vesicle translocation by interacting with IRAP as well as GLUT4. Furthermore, the effect of IRAP to reduce vasopressin activity is a physiologically important consequence of vesicle translocation, which is coordinated with the stimulation of glucose uptake.     

Interrelations between vasopressin and the renin-angiotensin system.

The interrelationships between vasopressin and the renin-angiotensin system are reviewed. Vasopressin can inhibit the release of renin by the kidney. This effect can occur at physiological plasma concentrations of vasopressin. Centrally administered angiotensin II can stimulate the release of vasopressin, a response that may be partially mediated by brain prostaglandins. The significance of this action of angiotensin II depends on whether there is an effective brain renin-angiotensin system and on whether peripherally generated or administered angiotensin can reach sites in the brain where it can act on vasopressin release. Peripherally administered angiotensin II can under certain, but not all, conditions stimulate vasopressin release. Peripheral angiotensin II can also potentiate the vasopressin response to an osmotic stimulus and to dehydration, but has little effect the release of vasopressin and renin, there is a failure to demonstrate any correlation between the two. Blockade of the renin-angiotensin system fails to modify the vasopressin response to a reduction in blood volume. In conclusion, the physiological significance of the interactions between the vasopressin and the renin-angiotensin system is not as yet clearly established.