Pancreatic neuroendocrine tumor producing vasopressin: A case report.

RATIONALE: Functional pancreatic neuroendocrine tumors (pNETs) rarely produce vasopressin. Here, we reported a case of pNET producing vasopressin in a 78-year-old man with hyponatremia. PATIENT CONCERNS: The patient presented with anorexia approximately 4 years ago, and the laboratory test results indicated hyponatremia. He was hospitalized 3 times subsequently due to anorexia in the past 4 years, during which laboratory tests consistently indicated severe hyponatremia. DIAGNOSIS: Upon admission, his serum osmolarity, urine osmolarity, urine sodium level, and 24-hour urine sodium level was 277 mOsm/kg H2O, 465 mOsm/kg H2O, 82.5 mmol/L, and 140.25 mmol, respectively. Gallium-68-labeled tetraazacyclododecanetetraacetic acid-Dphel-Tyr3-octreotate positron emission tomography-computed tomography showed a high uptake lesion measuring approximately 1 cm in diameter in the pancreatic body, and the possibility of pNET was considered. Besides, laboratory tests showed that adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone released by the pituitary was insufficient in the case of low levels of cortisol, estradiol, progesterone, and testosterone. Thus, the diagnosis of the syndrome of inappropriate antidiuresis (SIAD) was considered along with hypopituitarism. INTERVENTIONS: The patient underwent surgery, and pNET was confirmed by pathology examination. The immunohistochemical study showed that the tumor cells were positive for somatostatin receptors 2 and vasopressin. OUTCOMES: In the last follow-up 17 months after surgery, the patient was in good condition, taking methylprednisolone 4 mg every other day, and had been free of anorexia or hyponatremia episodes. LESSONS: This case illustrated the potential ectopic production of vasopressin resulting in SIAD in pNETs, highlighting the adoption of gallium-68-labeled tetraazacyclododecanetetraacetic acid-Dphel-Tyr3-octreotate positron emission tomography-computed tomography and vasopressin immunohistochemical staining in the evaluation of the etiology of SIAD.

Vasopressin mediates fructose-induced metabolic syndrome by activating the V1b receptor.

Subjects with obesity frequently have elevated serum vasopressin levels, noted by measuring the stable analog, copeptin. Vasopressin acts primarily to reabsorb water via urinary concentration. However, fat is also a source of metabolic water, raising the possibility that vasopressin might have a role in fat accumulation. Fructose has also been reported to stimulate vasopressin. Here, we tested the hypothesis that fructose-induced metabolic syndrome is mediated by vasopressin. Orally administered fructose, glucose, or high-fructose corn syrup increased vasopressin (copeptin) concentrations and was mediated by fructokinase, an enzyme specific for fructose metabolism. Suppressing vasopressin with hydration both prevented and ameliorated fructose-induced metabolic syndrome. The vasopressin effects were mediated by the vasopressin 1b receptor (V1bR), as V1bR-KO mice were completely protected, whereas V1a-KO mice paradoxically showed worse metabolic syndrome. The mechanism is likely mediated in part by de novo expression of V1bR in the liver that amplifies fructokinase expression in response to fructose. Thus, our studies document a role for vasopressin in water conservation via the accumulation of fat as a source of metabolic water. Clinically, they also suggest that increased water intake may be a beneficial way to both prevent or treat metabolic syndrome.

Angiotensin AT1A receptors expressed in vasopressin-producing cells of the supraoptic nucleus contribute to osmotic control of vasopressin.

Angiotensin II (ANG) stimulates the release of arginine vasopressin (AVP) from the neurohypophysis through activation of the AT1 receptor within the brain, although it remains unclear whether AT1 receptors expressed on AVP-expressing neurons directly mediate this control. We explored the hypothesis that ANG acts through AT1A receptors expressed directly on AVP-producing cells to regulate AVP secretion. In situ hybridization and transgenic mice demonstrated localization of AVP and AT1A mRNA in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN), but coexpression of both AVP and AT1A mRNA was only observed in the SON. Mice harboring a conditional allele for the gene encoding the AT1A receptor (AT1Aflox) were then crossed with AVP-Cre mice to generate mice that lack AT1A in all cells that express the AVP gene (AT1AAVP-KO). AT1AAVP-KO mice exhibited spontaneously increased plasma and serum osmolality but no changes in fluid or salt-intake behaviors, hematocrit, or total body water. AT1AAVP-KO mice exhibited reduced AVP secretion (estimated by measurement of copeptin) in response to osmotic stimuli such as acute hypertonic saline loading and in response to chronic intracerebroventricular ANG infusion. However, the effects of these receptors on AVP release were masked by complex stimuli such as overnight dehydration and DOCA-salt treatment, which simultaneously induce osmotic, volemic, and pressor stresses. Collectively, these data support the expression of AT1A in AVP-producing cells of the SON but not the PVN, and a role for AT1A receptors in these cells in the osmotic regulation of AVP secretion.

Pancreatic Neuroendocrine Tumor Producing Insulin and Vasopressin.

The objective of the study is to report a rare case of pancreatic neuroendocrine tumor (pNET) producing insulin and vasopressin. We describe the clinical presentation and management of a metastatic pNET with refractory hypoglycemia and progressive severe hyponatremia. A 52-year-old patient had abdominal pain leading to the diagnosis of a tumor that was initially presumed to be splenic in origin. Investigations ultimately identified a pancreatic mass that on biopsy proved to be a pNET. Eventually, he developed extensive liver metastases, and with tumor progression, he manifested hypoglycemia and severe hyponatremia. He was managed with multiple therapies including somatostatin analogue, peptide-receptor-radionuclide-therapy (PRRT), diazoxide, and everolimus; none of these therapeutic modalities was successful in controlling functional and structural progression of the tumor. Ultimately, the pNET proved fatal and autopsy confirmed widely metastatic disease that stained strongly and diffusely for vasopressin, a feature not seen in the previous liver biopsy. This case illustrates the challenges of diagnosis and management of aggressive insulin-producing pNETs and highlights the potential concomitant ectopic production of vasopressin leading to refractory hyponatremia.

Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock?

Severe systemic inflammatory response to infection results in severe sepsis and septic shock, which are the leading causes of death in critically ill patients. Septic shock is characterised by refractory hypotension and is typically managed by fluid resuscitation and administration of catecholamine vasopressors such as norepinephrine. Vasopressin can also be administered to raise mean arterial pressure or decrease the norepinephrine dose. Endogenous norepinephrine and vasopressin are synthesised by the copper-containing enzymes dopamine ß-hydroxylase and peptidylglycine α-amidating monooxygenase, respectively. Both of these enzymes require ascorbate as a cofactor for optimal activity. Patients with severe sepsis present with hypovitaminosis C, and pre-clinical and clinical studies have indicated that administration of high-dose ascorbate decreases the levels of pro-inflammatory biomarkers, attenuates organ dysfunction and improves haemodynamic parameters. It is conceivable that administration of ascorbate to septic patients with hypovitaminosis C could improve endogenous vasopressor synthesis and thus ameliorate the requirement for exogenously administered vasopressors. Ascorbate-dependent vasopressor synthesis represents a currently underexplored biochemical mechanism by which ascorbate could act as an adjuvant therapy for severe sepsis and septic shock.

The circadian gene Clock oscillates in the suprachiasmatic nuclei of the diurnal rodent Barbary striped grass mouse, Lemniscomys barbarus: a general feature of diurnality?

A major challenge in the field of circadian rhythms is to understand the neural mechanisms controlling the oppositely phased temporal organization of physiology and behaviour between night- and day-active animals. Most identified components of the master clock in the suprachiasmatic nuclei (SCN), called circadian genes, display similar oscillations according to the time of day, independent of the temporal niche. This has led to the predominant view that the switch between night- and day-active animals occurs downstream of the master clock, likely also involving differential feedback of behavioral cues onto the SCN. The Barbary striped grass mouse, Lemniscomys barbarus is known as a day-active Muridae. Here we show that this rodent, when housed in constant darkness, displays a temporal rhythmicity of metabolism matching its diurnal behaviour (i.e., high levels of plasma leptin and hepatic glycogen during subjective midday and dusk, respectively). Regarding clockwork in their SCN, these mice show peaks in the mRNA profiles of the circadian gene Period1 (Per1) and the clock-controlled gene Vasopressin (Avp), which occur during the middle and late subjective day, respectively, in accordance with many observations in both diurnal and nocturnal species. Strikingly, expression of the circadian gene Clock in the SCN of the Barbary striped grass mouse was not constitutive as in nocturnal rodents, but it was rhythmic. As this is also the case for the other diurnal species investigated in the literature (sheep, marmoset, and quail), a hypothesis is that the transcriptional control of Clock within the SCN participates in the mechanisms underlying diurnality and nocturnality.

[STRESS-INDUCED PATTERNS OF THE HYPOTHALAMIC CRH AND VASOPRESSIN EXPRESSION IN FEMALE RATS IN A MODEL OF POSTTRAUMATIC STRESS DISORDER].

The neuroendocrine mechanisms underlying anxiety-like state development in cycling female rats with different plasma estradiol levels have been studied in a stress-restress paradigm, an animal model of posttraumatic stress disorder (PTSD). The effect of stress-restress on the hypothalamic expression of corticotropin-releasing hormone (CRH) and vasopressin was analyzed by quantitative immunocytochemistry. Stress-restress was found to increase CRH expression in the hypothalamic paraventricular nucleus (PVN) on the 10th post-restress day, but the level of CRH expression in the PVN restored to the basal values on the 30th post-restress day in all experimental groups. It was shown an increase in vasopressin immunoreactivity in the PVN from the 10th to the 30th post-restress days in female rats exposed to stress during the estrus phase (low plasma estradiol level). In summary, female rats with low plasma estradiol level exhibited the most significant changes in the hypothalamic neuroendocrine system following stress-restress exposure. It might be hypothesized that hyperactivity of the hypothalamic circuit of the central vasopressinergic system is one of the possible mechanisms underlying PTSD-like state development in female rats in a stress-restress paradigm.

Ultrastructural correlates of antidiuretic response of rat kidney.

We studied ultrastructural features of epithelial cells of the inner medullary collecting tubules in Brattleboro and Wistar under the action of desmopressin (dDAVP, 5 µg/100 g body weight for 2 days). Intracellular reorganization of transepithelial barrier for osmotic water transport depended on the capacity of rats to the synthesis of endogenous vasopressin.

Hypothalamic neurosecretory and circadian vasopressinergic neuronal systems in the blind cone-rod homeobox knockout mouse (Crx-/-) and the 129sv wild-type mouse.

Vasopressin (AVP) is both a neuroendocrine hormone located in magnocellular neurosecretory neurons of the hypothalamus of mammals but also a neurotransmitter/neuromodulator in the parvocellular suprachiasmatic nucleus (SCN). The SCN is the endogenous clock of the brain and exhibits a prominent circadian AVP rhythm. We have in this study of the brown 129sv mouse and the visual blind cone-rod homeobox gene knock out mouse (Crx(-/-) ) with degeneration of the retinal rods and cones, but a preserved non-image forming optic system, studied the temporal Avp expression in both the neurosecretory magnocellular and parvocellular vasopressinergic systems in both genotypes. We here present a detailed mapping of all classical hypothalamopituitary and accessory magnocellular nuclei and neurons in the hypothalamus by use of immunohistochemistry and in situ hybridization in both genotypes. Semiquantitative in situ hybridization revealed a very high expression of Avp mRNA in all the magnocellular nuclei compared with a much lower level in the parvocellular suprachiasmatic nucleus. In a series of mice killed every 4 hours, the Avp mRNA expression in the SCN showed a significant daily rhythm with a zenith at late day time and nadir during the dark in both the Crx(-/-) and the wild type mouse. None of the magnocellular neurosecretory neurons exhibited a diurnal vasopressin expression. Light stimulation of both genotypes during the dark period did not change the Avp expression in the SCN. This shows that Avp expression in the mouse SCN is independent of Crx-regulated photoreceptor systems.

[Expression of the RT1A molecule of the class I major histocompatibility complex in a Walker 256 tumor after transplantation into Brattleboro rats with a genetic defect of arginine-vasopressin synthesis].

The dynamics of expression of the RT1A antigen of the class I major histocompatibility complex (MHC) in a Walker 256 tumor after its transplantation into Brattleboro rats with a genetic defect of Arginine-Vasopressin synthesis in the hypothalamus was studied. Expression of the RT1A antigen was detected by means of Western-blotting and flow cytometry in the tumor cells on the 14th-17th days after transplantation. In addition, a simultaneous increase in the portion of cells that express the RT1A antigen and in the level of its expression per cell was observed. It is presupposed that at a deficiency of Arginine-Vasopressin, a renewal of expression of the class I MHC antigens, which results in an increase of immunogenicity of this tumor and regression, occurs in the Walker 256 tumor in the Brattleboro rats.

[Role of Bcl-2 in the regulation of creb activity and vasopressin expression in the hypothalamic neurons of rats].

The antiapoptotic protein Bcl-2 has various functions besides its role in protecting cells from apoptosis. Previous studies have demonstrated that Bcl-2 recruits ERK1/2 and/or CREB to initiate different transcription program in the regulation of various neuronal activities as well as axonal growth. Recently we reported that Bcl-2 can participate in the regulation of synthesis and secretion of vasopressin of rat hypothalamic magnocellular nuclei. In thise study we have investigated the inhibition of Bcl-2 on vasopressin expression in magnocellular neurons of hypothalamic supraoptic nuclei. The experiments were done on short-term incubated rat hypothalamic slices containing supraoptic nuclei. Our data demonstrated that in vitro inhibition of Bcl-2 by HA14-1 prevented CREB translocation into the cell nuclei and significantly decreased vasopressin mRNA level and enhanced contents of vasopressin protein in magnocellular neurons in supraoptic nucleus. Our results indicate that CREB-dependent vasopressin gene transcription in the hypothalamic magnocellular neurons can be regulated by Bcl-2.

Cutting edge: neuronal recognition by CD8 T cells elicits central diabetes insipidus.

An increasing number of neurologic diseases is associated with autoimmunity. The immune effectors contributing to the pathogenesis of such diseases are often unclear. To explore whether self-reactive CD8 T cells could attack CNS neurons in vivo, we generated a mouse model in which the influenza virus hemagglutinin (HA) is expressed specifically in CNS neurons. Transfer of cytotoxic anti-HA CD8 T cells induced an acute but reversible encephalomyelitis in HA-expressing recipient mice. Unexpectedly, diabetes insipidus developed in surviving animals. This robust phenotype was associated with preferential accumulation of cytotoxic CD8 T cells in the hypothalamus, upregulation of MHC class I molecules, and destruction of vasopressin-expressing neurons. IFN-γ production by the pathogenic CD8 T cells was necessary for MHC class I upregulation by hypothalamic neurons and their destruction. This novel mouse model, in combination with related human data, supports the concept that autoreactive CD8 T cells can trigger central diabetes insipidus.

Structural and neurochemical plasticity in both supraoptic and paraventricular nuclei of hypothalamus of a desert rodent Meriones shawi after a severe dehydration versus opposite treatment by rehydration: GFAP and vasopressin immunohistochemical study.

Various lines of evidence indicate that astrocytes can undergo morphological changes that modify their relationship to adjacent neurons in response to physiological stimulation such as dehydration. Supraoptic (SON) and paraventricular (PVN) nuclei of hypothalamus represent obvious examples of activity-dependent neuro-astrocytic plasticity. In the present study, Meriones shawi is used as an animal model. Moreover, GFAP and vasopressin expressions are used as indicators successively of astrocytes and neuronal activations. In order to evaluate the reversibility of the neuro-astrocytic plasticity in SON and PVN, prolonged episode of water deprivation followed by episode of rehydration were examined. Hence, we studied the immunoreactivity in various hydration states: water ad libitum, dehydration, and rehydration of animals. Our results showed that dehydration of Meriones induced a significant decrease of GFAP immunoreactivity accompanied by a significant increase of AVP immunoreactivity, the latter concerns both cell bodies and fibers in the same hypothalamic nuclei SON and PVN. Conversely, rehydration of animals shows a reversible phenomenon leading a return of vasopressin and GFAP immunoreactivities to the control level. These results show that both astrocytes and vasopressin neurons display a remarkable structural and physiological plasticity, allowing to M. shawi, a great ability to support the hostile conditions in dry environment.

The molecular physiology of CRH neurons.

Corticotropin releasing hormone (CRH) is essential for stress adaptation by mediating hypothalamic-pituitary-adrenal (HPA) axis, behavioral and autonomic responses to stress. Activation of CRH neurons depends on neural afferents from the brain stem and limbic system, leading to sequential CRH release and synthesis. CRH transcription is required to restore mRNA and peptide levels, but termination of the response is essential to prevent pathology associated with chronic elevations of CRH and HPA axis activity. Inhibitory feedback mediated by glucocorticoids and intracellular production of the repressor, Inducible Cyclic AMP Early Repressor (ICER), limit the magnitude and duration of CRH neuronal activation. Induction of CRH transcription is mediated by the cyclic AMP/protein kinase A/cyclic AMP responsive element binding protein (CREB)-dependent pathways, and requires cyclic AMP-dependent nuclear translocation of the CREB co-activator, Transducer of Regulated CREB activity (TORC). This article reviews current knowledge on the mechanisms regulating CRH neuron activity.

Effects of A-CREB, a dominant negative inhibitor of CREB, on the expression of c-fos and other immediate early genes in the rat SON during hyperosmotic stimulation in vivo.

Intraperitoneal administration of hypertonic saline to the rat supraoptic nucleus (SON) increases the expression of several immediate early genes (IEG) and the vasopressin gene. These increases have usually been attributed to action of the cyclic-AMP Response Element Binding Protein (CREB). In this paper, we study the role of CREB in these events in vivo by delivering a potent dominant-negative form of CREB, known as A-CREB, to the rat SON through the use of an adeno-associated viral (AAV) vector. Preliminary experiments on HEK 293 cells in vitro showed that the A-CREB vector that we used completely eliminated CREB-induced c-fos expression. We stereotaxically injected this AAV-A-CREB into one SON and a control AAV into the contralateral SON of the same rat. Two weeks following these injections we injected hypertonic saline intraperitoneally into the rat. Using this paradigm, we could measure the relative effects of inhibiting CREB on the induced expression of c-fos, ngfi-a, ngfi-b, and vasopressin genes in the A-CREB AAV injected SON versus the control AAV injected SON in the same rat. We found only a small (20%) decrease of c-fos expression and a 30% decrease of ngfi-b expression in the presence of the A-CREB. There were no significant changes in expression found in the other IEGs nor in vasopressin that were produced by the A-CREB. This suggests that CREB may play only a minor role in the expression of IEGs and vasopressin in the osmotically activated SON in vivo.

Oxytocin, vasopressin and estrogen receptor gene expression in relation to social recognition in female mice.

Inter- and intra-species differences in social behavior and recognition-related hormones and receptors suggest that different distribution and/or expression patterns may relate to social recognition. We used qRT-PCR to investigate naturally occurring differences in expression of estrogen receptor-alpha (ERα), ER-beta (ERß), progesterone receptor (PR), oxytocin (OT) and receptor, and vasopressin (AVP) and receptors in proestrous female mice. Following four 5 min exposures to the same two conspecifics, one was replaced with a novel mouse in the final trial (T5). Gene expression was examined in mice showing high (85-100%) and low (40-60%) social recognition scores (i.e., preferential novel mouse investigation in T5) in eight socially-relevant brain regions. Results supported OT and AVP involvement in social recognition, and suggest that in the medial preoptic area, increased OT and AVP mRNA, together with ERα and ERß gene activation, relate to improved social recognition. Initial social investigation correlated with ERs, PR and OTR in the dorsolateral septum, suggesting that these receptors may modulate social interest without affecting social recognition. Finally, increased lateral amygdala gene activation in the LR mice may be associated with general learning impairments, while decreased lateral amygdala activity may indicate more efficient cognitive mechanisms in the HR mice.

Effect of chronic central endothelin-1 on hemodynamics and plasma vasopressin in conscious rats.

OBJECTIVES: These studies were designed to test whether chronic central administration of endothelin-1 induces changes in systemic hemodynamics and plasma vasopressin similar to those observed with acute microinjections of endothelin-1. METHODS: Sprague Dawley rats underwent sham denervation or sinoaortic denervation. Three days later, baseline mean arterial blood pressure, heart rate, and vasopressin were assessed in conscious rats. Then, a cannula was stereotaxically inserted into the lateral ventricle and attached to an osmotic minipump that delivered one of the following: (i) artificial cerebrospinal fluid; (ii) endothelin-1, 10 pmol/hour; (iii) BQ-123, 400 pmol/hour; or (iv) endothelin-1+BQ-123. Mean arterial blood pressure and heart rate were monitored daily and blood was obtained for plasma vasopressin on days 3 and 9. On day 10, the rats were euthanized, the hypothalami were removed, and vasopressin messenger ribonucleic acid content was assessed. RESULTS: The pressor effect of intracerebroventricular endothelin-1 was similar in intact and sinoaortic denervation rats and was prevented by endothelin receptor A antagonism with BQ-123. Administration of BQ-123 alone resulted in a depressor and bradycardia in sinoaortically denervated rats. Chronic endothelin-1 administration did not change plasma vasopressin but resulted in a significant decrease in hypothalamic vasopressin messenger ribonucleic acid levels, which was reversed by endothelin receptor A inhibition. DISCUSSION: Although the pressor effect of chronic central endothelin-1 is similar to that reported with acute endothelin-1, plasma vasopressin levels do not increase, at least in part, due to downregulation of hypothalamic vasopressin gene expression. Sinoaortic denervation increases endogenous central endothelin receptor A tone. Furthermore, these observations confirm that the pressor effect of central endothelin-1 is not mediated by plasma vasopressin.

Differential involvement of noradrenaline and nitric oxide in the regulation of vasopressin and oxytocin expression in rat supraoptic nucleus.

The hydroosmotic balance of the body is controlled by supraoptic nuclei and paraventricular nuclei of the hypothalamo-posthypophyseal complex. In response to a physiological stimulation such as an osmotic stress, the supraoptic nuclei (SON) and the paraventricular nuclei undergo remarkable neurochemical and morphological changes. Therefore, the neuroendocrine hypothalamus is a particularly relevant model for studying the molecular and cellular mechanisms that govern these plasticity phenomena. Slices of rat hypothalamus maintained ex vivo by perfusion were used to study the short-term involvement of noradrenaline (NA) and nitric oxide (NO) in the mechanisms of chemical plasticity of the SON. NA is involved early in the regulation of the expression of neuropeptides, including vasopressin (AVP) and oxytocin (OT). NO appears to be a key molecule in noradrenergic control of the chemical plasticity of the endocrine neurons: in the SON, NO is involved in the signaling pathway regulating the expression of AVP but not that of OT.