Increased Vasopressin Secretion Research Articles

Fluid homeostatic action of dapagliflozin in patients with chronic kidney disease: the DAPA-BODY Trial.

Sodium glucose cotransporter 2 (SGLT2) inhibitors have both glucose-lowering and diuretic effects. We recently reported that the SGLT2 inhibitor dapagliflozin exerts short-term fluid homeostatic action in patients with chronic kidney disease (CKD). However, the long-term effects of SGLT2 inhibitors on body fluid status in patients with CKD remain unclear. This was a prospective, non-randomized, open-label study that included a dapagliflozin treatment group (n = 73) and a control group (n = 24) who were followed for 6 months. Body fluid volume was measured using a bioimpedance analysis device. The extracellular water-to-total body water ratio (ECW/TBW), a predictor of renal outcomes, was used as a parameter for body fluid status (fluid retention, 0.400 ≤ ECW/TBW). Six-month treatment with dapagliflozin significantly decreased ECW/TBW compared with the control group (-0.65% ± 2.03% vs. 0.97% ± 2.49%, p = 0.0018). Furthermore, dapagliflozin decreased the ECW/TBW in patients with baseline fluid retention, but not in patients without baseline fluid retention (-1.47% ± 1.93% vs. -0.01% ± 1.88%, p = 0.0017). Vasopressin surrogate marker copeptin levels were similar between the control and dapagliflozin groups at 6 months (32.3 ± 33.4 vs. 30.6 ± 30.1 pmol/L, p = 0.8227). However, dapagliflozin significantly increased the change in copeptin levels at 1 week (39.0% ± 41.6%, p = 0.0010), suggesting a compensatory increase in vasopressin secretion to prevent hypovolemia. Renin and aldosterone levels were similar between the control and dapagliflozin groups at 6 months, while epinephrine and norepinephrine (markers of sympathetic nervous system activity) were significantly lower in the dapagliflozin group than in the control group. In conclusion, the SGLT2 inhibitor dapagliflozin ameliorated fluid retention and maintained euvolemic fluid status in patients with CKD, suggesting that SGLT2 inhibitors exert sustained fluid homeostatic actions in patients with various fluid backgrounds. Clinical trial registration: https://www.umin.ac.jp/ctr/, identifier [UMIN000048568].

Involvement of Vasopressin in Tissue Hypoperfusion during Cardiogenic Shock Complicating Acute Myocardial Infarction in Rats

Acute heart failure (AHF) due to acute myocardial infarction (AMI) is likely to involve cardiogenic shock (CS), with neuro-hormonal activation. A relationship between AHF, CS and vasopressin response is suspected. This study aimed to investigate the implication of vasopressin on hemodynamic parameters and tissue perfusion at the early phase of CS complicating AMI. Experiments were performed on male Wistar rats submitted or not to left coronary artery ligation (AMI and Sham). Six groups were studied Sham and AMI treated or not with either a vasopressin antagonist SR-49059 (Sham-SR, AMI-SR) or agonist terlipressin (Sham-TLP, AMI-TLP). Animals were sacrificed one day after surgery (D1) and after hemodynamic parameters determination. Vascular responses to vasopressin were evaluated, ex vivo, on aorta. AHF was defined by a left ventricular ejection fraction below 40%. CS was defined by AHF plus tissue hypoperfusion evidenced by elevated serum lactate level or low mesenteric oxygen saturation (SmO2) at D1. Mortality rates were 40% in AMI, 0% in AMI-SR and 33% in AMI-TLP. Immediately after surgery, a sharp decrease in SmO2 was observed in all groups. At D1, SmO2 recovered in Sham and in SR-treated animals while it remained low in AMI and further decreased in TLP-treated groups. The incidence of CS among AHF animals was 72% in AMI or AMI-TLP while it was reduced to 25% in AMI-SR. Plasma copeptin level was increased by AMI. Maximal contractile response to vasopressin was decreased in AMI (32%) as in TLP- and SR- treated groups regardless of ligation. Increased vasopressin secretion occurring in the early phase of AMI may be responsible of mesenteric hypoperfusion resulting in tissue hypoxia. Treatment with a vasopressin antagonist enhanced mesenteric perfusion and improve survival. This could be an interesting therapeutic strategy to prevent progression to cardiogenic shock.

Signaling of Phoenixin via GPR173 and the Paradox of Increased Vasopressin Secretion in Preeclampsia

Preterm birth affects over 15 million pregnancies annually worldwide, and is associated with severe health risks for both mother and child. The leading cause of clinically indicated, non-spontaneous preterm delivery is preeclampsia, which can lead to maternal and fetal morbidity and mortality if not appropriately and promptly managed. At this time, the only “cure” for preeclampsia is delivery of the fetus and associated products of conception, which presents the clinical challenge of weighing the risks versus benefits of delivery if the pregnancy is preterm. The etiology of preeclampsia is multifactorial and incompletely understood. However, several carefully conducted studies have implicated the paradoxical secretion of the posterior pituitary hormone, arginine vasopressin (AVP) as a potential causative factor. Women with preeclampsia exhibit elevated plasma levels of AVP even in the face of the ongoing hypertension and hyponatremia, and infusion of AVP into pregnant rodents recapitulated multiple features of preeclampsia. The reason for the inappropriately elevated AVP in preeclampsia is unknown. Using a bioinformatic algorithm, our group identified a novel peptide that is conserved across multiple species, and named it phoenixin (PNX) (PMID 22963497). Our published data demonstrate a reproductive role of the peptide, and indicate that hypothalamic and pituitary PNX expression is modulated by sex hormones (PMID 27440717). Likewise, we recently have demonstrated that cerebroventrcular administration of PNX elevated plasma AVP levels in rats (PMID 29364701). Using the RNAscope approach we have now demonstrated that the receptor for PNX, identified by our group as GPR173 (PMID 27440717), is expressed by AVP neurons. Importantly expression of GPR173 increased across pregnancy in the rat hypothalamus coincident with increased AVP production and release (PMID 27330717). These data strongly suggest that PNX, acting through GPR173, could act as a molecular link between sex hormones and AVP secretion. In addition, we now demonstrate that central injection of PNX increases blood pressure, likely through PNX-induced elevation in AVP secretion. We hypothesize that the paradox of increased AVP secretion in the hyponatremic and hypervolemic state of preeclampsia is due to exaggerated PNX signaling in hypothalamus via GPR173 on AVP neurons and possibly on GPR173 expressing neurons in autonomic centers in hindbrain.

The Effects of Pregnancy on the Sympathoexcitatory and Pressor Responses to Nanoinjection of Angiotensin II into the Arcuate Nucleus

Pregnancy induces profound increases in sympathetic nerve activity (SNA). Angiotensin II (AngII) may contribute, since systemic or central blockade of AngII production or receptors (AT1aR) decreases SNA in pregnant animals. However, the brain sites involved are unknown. One possibility is the arcuate nucleus (ArcN), since AngII binds to ArcN AT1aR to increase SNA, and the ArcN is a well‐established reproductive integrating center. To begin to test this hypothesis, we measured the changes in SNA and mean arterial pressure (MAP) in response to bilateral nanoinjections of AngII (30 pmol in 30 nL) into the ArcN of α‐chloralose anesthetized pregnant rats and virgin rats throughout the estrus cycle. ArcN AngII slowly increased (P<0.05) lumbar SNA (LSNA) in pregnant rats (by 50±10 % after 90 min; n=6), and the rise was larger than in proestrus rats (‐1±8 %; n=5; P<0.05), similar to diestrus rats (40±9 %; n=4), but less than estrus rats (72±12 %; n=6; P<0.05). ArcN AngII rapidly increased (P<0.05) MAP by ~10 mmHg (after 10 min) in all groups, but after 90 min the increase was sustained (P<0.05) only in pregnant (13±2 mmHg) and estrus (11±4 mmHg) rats. A cohort of ArcN neurons projects to and stimulates vasopressinergic neurons in the hypothalamic paraventricular and supraoptic nuclei. Therefore, to test if the initial or sustained increases in MAP were mediated by vasopressin, another set of estrus and pregnant rats were pretreated with the Manning Compound (V1x; 5 μg iv) 15 min before ArcN AngII. In estrus rats (n=4), V1x had no effects on baseline LSNA or MAP, but completely blocked the initial rise in MAP induced by ArcN AngII (2±3 mmHg). Nevertheless, the increase in MAP at 90 min was unchanged (13±3 mmHg; P<0.05). The LSNA response to ArcN AngII (83±9 %) was also not altered. In pregnant rats pretreated with V1x (n=4), baseline MAP decreased (P<0.05) by 10±1 mmHg, and again ArcN AngII failed to increase MAP initially (2±1 mmHg). However, the increase in MAP 90 min after ArcN AngII (7±2 mmHg) was the same as the increase 90 min after injection of artificial cerebrospinal fluid into the ArcN of V1x‐treated pregnant rats (5±2 mmHg). Again, the increase in LSNA to ArcN AngII was unchanged (30±6 %). Finally, RNAScope was used to assay AT1aR mRNA expression in the ArcN in diestrus, proestrus, and pregnant rats. ArcN AT1aR were undetectable in proestrus rats and were expressed at low but detectable levels in diestrus rats. In contrast, pregnancy markedly increased the expression of AT1aR in the ArcN. In summary, during pregnancy, ArcN AngII produces substantial increases in LSNA in association with elevated AT1aR expression. Moreover, the increase in MAP in response to ArcN AngII was reduced or eliminated in estrus and pregnant rats pretreated with a vasopressin V1 receptor blocker. In conclusion, these data highlight the ArcN as a potential site at which AngII increases SNA during normal pregnancy. The data also suggest that AngII can elicit an increase in vasopressin secretion via an action in the ArcN and that vasopressin contributes to the pressor responses induced by ArcN AngII in both estrus and pregnant rats.Support or Funding InformationHL128181

Increased vasopressin secretion during preeclampsia despite normal plasma osmolality

Preeclampsia (PE) is a cardiovascular disorder that affects 4–7% of pregnancies and typically involves new onset hypertension, proteinuria, and edema. Diagnosis of the disorder is formally performed in the second half of gestation based upon clinical signs, but we and others have discovered that maternal plasma levels of copeptin (CPP, the stable C‐terminal fragment of arginine vasopressin, AVP) are elevated already in the first trimester and are highly predictive of the development of PE. Further, chronic low‐dose AVP infusion is sufficient to model almost all the clinical features of PE in pregnant mice. Our objective is therefore to understand the cause of elevated AVP secretion in human PE. Previous studies indicate that blood volume is reduced during PE, but no change in osmolality has been noted. We therefore hypothesized (i) that plasma AVP levels are elevated in early gestation of pregnancies that later develop PE, and (ii) that elevated AVP and CPP secretion during PE is secondary to altered volume regulation. Blood samples (1st and 2nd trimester) from women who later developed PE or represent clinically‐matched case controls were obtained from the Maternal Fetal Tissue Bank (IRB#200910784) at the University of Iowa. Consistent with our first hypothesis, plasma levels of AVP, assessed by ELISA after Sep‐Pak C18 reversed solid phase extraction, were increased in 1st and 2nd trimester from women who later developed PE (25.5±3.6, n=63 vs 52.1±22.2, n=5 pg/mL, mean±SEM, p=0.01) despite no change in osmolality (279.6±0.7, n=46 vs 277.5±1.2, n=4 mOsm/kg H2O). Plasma sodium was increased in 1st and 2nd trimesters before the onset of PE (133.9±0.6, n=91 vs 138.5±0.6, n=6 mmol/L, p<0.05), but potassium was unchanged (4.13±0.05 vs 4.38±0.14 mmol/L). These findings support the conclusions that (i) AVP levels are indeed increased in early pregnancy before the onset of clinical symptoms of PE, as was suspected based upon previous studies of CPP; that (ii) the defended osmolality set‐point is similar between control and PE pregnancies, and therefore chronically elevated osmolality is unlikely to be the major cause of elevated AVP secretion during PE, and that (iii) offsetting changes in concentrations of individual osmolytes may be present during PE.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

P1862Preeclampsia induces the acquired salt-sensitivity characteristics via the increased vasopressin secretion in postpartum

P1862Preeclampsia induces the acquired salt-sensitivity characteristics via the increased vasopressin secretion in postpartum

Preeclampsia induces the acquired salt‐sensitivity characteristics via increased vasopressin secretion in the postpartum stage

BackgroundWomen with a history of preeclampsia exhibit increased salt‐sensitivity in the postpartum stage, which might account for their increased risk of future cardiovascular disease. However, it is unclear whether the increased salt‐sensitivity is a cause or effect of preeclampsia. Various factors, such as kidney injury and renin‐angiotensin system, are associated with salt‐sensitive hypertension. Vasopressin may also play a role in the pathogenesis of both preeclampsia and salt‐sensitive hypertension.PurposeThe aim of the present study was to investigate whether the onset of preeclampsia in subjects with originally normal salt‐sensitivity induces increased salt‐sensitivity in the postpartum stage, and to elucidate the possible mechanisms.Methods and ResultsWe used the reduced uterine perfusion pressure (RUPP) rat model, which is widely used as an acquired model of preeclampsia. Pregnant Sprague‐Dawley rats at day 14 of gestation were divided into two groups: RUPP‐operated (n=7) and sham‐operated (SHAM) controls (n=8). At 3 weeks postpartum, a high‐salt diet was initiated for 1 week. The high‐salt diet‐induced changes in mean arterial pressure (MAP) and the sodium sensitive index (SSI=ΔMAP/Δurine sodium) were significantly greater in the RUPP group than in the SHAM group (ΔMAP: 19.8±2.7 vs. 9.3±1.7 mmHg, SSI: 801±140 vs. 421±95.3 mmHg/mmol, both p<0.05). Creatinine clearance was not significantly different between groups, and histological studies revealed that both groups had normal kidney structures. Plasma renin activity and plasma aldosterone levels did not differ between groups. Levels of plasma copeptin, a substitute for plasma vasopressin, were significantly increased in the RUPP group compared with the SHAM group (150±20.3 vs. 98±18.6 pg/ml, p<0.05). Double immunofluorescence staining also revealed that expression of c‐Fos, a marker of neural activity, in vasopressin‐producing neurons was significantly increased in the hypothalamic paraventricular nucleus in the RUPP group compared with the SHAM group (% of c‐Fos positive neurons in vasopressin neurons: 45.8±7.1% vs. 23.1±2.0%, p<0.05). Gavage administration of the dual V1a/V2 vasopressin receptor antagonist conivaptan (1.0 mg/kg/day) while on the high‐salt diet attenuated the increase in MAP and decreased SSI in the RUPP rats (ΔMAP: 9.5±2.1 mmHg, SSI: 437±76.9 mmHg/mmol, n=4), but not in the SHAM rats (ΔMAP: 14.5±2.8 mmHg, SSI: 574±106 mmHg/mmol, n=5).ConclusionPreeclampsia caused salt‐sensitivity of blood pressure in the postpartum stage, probably due to increased vasopressin secretion.Support or Funding InformationKanae Foundation for the Promotion of Medical ScienceThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Interleukin-1 receptor antagonist decreases cerebrospinal fluid nitric oxide levels and increases vasopressin secretion in the late phase of sepsis in rats.

The aim of this study was to analyze the effect of IL-1ra (an Interleukin-1 receptor antagonist) on sepsis-induced alterations in vasopressin (AVP) and nitric oxide (NO) levels. In addition, IL-1ra effect on the hypothalamic nitric oxide synthase (NOS) activities and survival rate was also analyzed. After Wistar rats were intracerebroventricular injected with IL-1ra (9 pmol) or vehicle (PBS 0.01 M), sepsis was induced by cecal-ligation and puncture (CLP). Blood, CSF, and hypothalamic samples were collected from different groups of rats (n = 8/group) after 4, 6, and 24 h. AVP and NO levels were greatly increased in CLP. Both total NOS and inducible NOS (iNOS) activities were also greatly increased in CLP rats. These changes in AVP, NO, and NOS were not observed in sham-operated control rats. IL-1ra administration did not alter plasma AVP levels after 4 and 6 h as compared to vehicle in CLP animals but after 24 h were significantly (P < 0.01) higher in IL-1ra-treated animals. IL-1ra administration significantly (P < 0.01) decreased NO concentration in CSF but not in plasma. Both total NOS and iNOS activities were also significantly decreased by IL-1ra at 24 h in CLP animals. Moreover, the 24 h survival rate of IL-1ra-treated rats increased by 38 % in comparison to vehicle administered animals. The central administration of IL-1ra increased AVP secretion in the late phase of sepsis which was beneficial for survival. We believe that one of the mechanisms for this effect of IL-1ra is through reduction of NO concentration in CSF and hence lower hypothalamic iNOS activities in the septic rats.

Kidney injury in cirrhosis: pathophysiological and therapeutic aspects of hepatorenal syndromes

Acute kidney injury (AKI) is frequent in patients with cirrhosis. AKI and hyponatraemia are major determinants of the poor prognosis in advanced cirrhosis. The hepatorenal syndrome (HRS) denotes a functional and potential reversible impairment of renal function. Type 1 HRS, a special type of AKI, is a rapidly progressive AKI, whereas the renal function in type 2 HRS decreases more slowly. HRS is precipitated by factors such as sepsis that aggravate the effective hypovolaemia in decompensated cirrhosis, by lowering arterial pressure and cardiac output and enhanced sympathetic nervous activity. Therefore, attempts to prevent and treat HRS should seek to improve liver function and to ameliorate arterial hypotension, central hypovolaemia and cardiac output, and to reduce renal vasoconstriction. Ample treatment of HRS is important to prevent further progression and death, but as medical treatment only modestly improves long-term survival, these patients should always be considered for liver transplantation. Hyponatraemia, defined as serum sodium <130 mmol/L, is common in patients with decompensated cirrhosis. From a pathophysiological point of view, hyponatraemia is related to an impairment of renal solute-free water excretion most likely caused by an increased vasopressin secretion. Patients with cirrhosis mainly develop hypervolaemic hyponatraemia. Current evidence does not support routine use of vaptans in the management of hyponatraemia in cirrhosis.

Central administration of IL‐1 receptor antagonist increases vasopressin secretion in late phase of sepsis in rats (876.7)

Clinical and experimental studies have reported that the initial phase of sepsis is characterized by elevated plasma vasopressin (AVP) concentrations. However, in the late phase, despite of the significant decrease in the arterial pressure, the AVP secretion decrease and the plasma concentrations remain unusually low, contributing to the hypotension, vasodilator shock, and death. Considering the role of AVP in the vasopressor response, the elucidation of the mechanisms of this deficient hormone secretion may contribute to therapy during sepsis.The aim of this study was to analyze the effect of IL‐1ra (an Interleukin‐1 receptor antagonist) on sepsis‐induced alterations in plasma AVP and NO, and cerebrospinal fluid (CSF) NO levels. After Wistar rats were intracerebroventricullary injected with 2 ul of IL‐1ra (9 nmol/ or vehicle (PBS 0.01M) sepsis was induced by cecal ligation and puncture (CLP). Blood samples were collected from different groups of rats (n=6‐8/group) by decapitation after 4‐, 6‐ and 24‐h. Specific ELISA and Chemiluminescence assays were used for measurement of AVP and NO concentrations, respectively. All experiments were carried out according to an institutional ethical committee approved protocol.IL‐1ra administration did not alter plasma vasopressin after 4‐ and 6‐h as compared to vehicle in CLP animals. In contrast, after 24‐h AVP levels were significantly (P&lt;0.01) higher in IL‐1ra treated animals as compared to vehicle treated animals. IL‐1ra administration significantly (P&lt;0.01) decreased NO concentration in CSF but not in plasma. Moreover, the survival rate of IL‐1ra treated rats increased by 38% in comparison to vehicle administered animals.In conclusion, the central administration of IL‐1ra increases AVP secretion in the late phase of sepsis which was beneficial for survival. We believe that one of the mechanisms for this effect of IL‐1ra is through reduction of NO concentration in CSF of the septic rats.

GABAergic inhibition through synergistic astrocytic neuronal interaction transiently decreases vasopressin neuronal activity during hypoosmotic challenge

The neuropeptide vasopressin is crucial to mammalian osmotic regulation. Local hypoosmotic challenge transiently decreases and then increases vasopressin secretion. To investigate mechanisms underlying this transient response, we examined the effects of hypoosmotic challenge on the electrical activity of rat hypothalamic supraoptic nucleus (SON) vasopressin neurons using patch-clamp recordings. We found that 5 min exposure of hypothalamic slices to hypoosmotic solution transiently increased inhibitory postsynaptic current (IPSC) frequency and reduced the firing rate of vasopressin neurons. Recovery occurred by 10 min of exposure, even though the osmolality remained low. The γ-aminobutyric acid (GABA)A receptor blocker, gabazine, blocked the IPSCs and the hypoosmotic suppression of firing. The gliotoxin l-aminoadipic acid blocked the increase in IPSC frequency at 5 min and the recovery of firing at 10 min, indicating astrocytic involvement in hypoosmotic modulation of vasopressin neuronal activity. Moreover, β-alanine, an osmolyte of astrocytes and GABA transporter (GAT) inhibitor, blocked the increase in IPSC frequency at 5 min of hypoosmotic challenge. Confocal microscopy of immunostained SON sections revealed that astrocytes and magnocellular neurons both showed positive staining of vesicular GATs (VGAT). Hypoosmotic stimulation in vivo reduced the number of VGAT-expressing neurons, and increased co-localisation and molecular association of VGAT with glial fibrillary acidic protein that increased significantly by 10 min. By 30 min, neuronal VGAT labelling was partially restored, and astrocytic VGAT was relocated to the ventral portion while it decreased in the somatic zone of the SON. Thus, synergistic astrocytic and neuronal GABAergic inhibition could ensure that vasopressin neuron firing is only transiently suppressed under hypoosmotic conditions.

Rapid stimulation of human renal ENaC by cAMP in Xenopus laevis oocytes

Among the compensatory mechanisms restoring circulating blood volume after severe haemorrhage, increased vasopressin secretion enhances water permeability of distal nephron segments and stimulates Na(+) reabsorption in cortical collecting tubules via epithelial sodium channels (ENaC). The ability of vasopressin to upregulate ENaC via a cAMP-dependent mechanism in the medium to long term is well established. This study addressed the acute regulatory effect of cAMP on human ENaC (hENaC) and thus the potential role of vasopressin in the initial compensatory responses to haemorrhagic shock. The effects of raising intracellular cAMP (using 5 mmol/L isobutylmethylxanthine (IBMX) and 50 μmol/L forskolin) on wild-type and Liddle-mutated hENaC activity expressed in Xenopus oocytes and hENaC localisation in oocyte membranes were evaluated by dual-electrode voltage clamping and immunohistochemistry, respectively. After 30 min, IBMX + forskolin had stimulated amiloride-sensitive Na(+) current by 52% and increased the membrane density of Na(+) channels in oocytes expressing wild-type hENaC. These responses were prevented by 5 μmol/L brefeldin A, which blocks antegrade vesicular transport. By contrast, IBMX + forskolin had no effects in oocytes expressing Liddle-mutated hENaC. cAMP stimulated rapid, exocytotic recruitment of wild-type hENaC into Xenopus oocyte membranes, but had no effect on constitutively over-expressed Liddle-mutated hENaC. Extrapolating these findings to the early cAMP-mediated effect of vasopressin on cortical collecting tubule cells, they suggest that vasopressin rapidly mobilises ENaC to the apical membrane of cortical collecting tubule cells, but does not enhance ENaC activity once inserted into the membrane. We speculate that this stimulatory effect on Na(+) reabsorption (and hence water absorption) may contribute to the early restoration of extracellular fluid volume following severe haemorrhage.

Abstract 126: Transgenic Hyperactivity of the Brain Renin-Angiotensin System Causes Vasopressin-Dependent Hypertension

Hypertension in many animal models is sensitive to inhibition of the brain renin-angiotensin system (RAS). We examined mice with transgenic hyperactivity of the brain RAS (sRA mice) to determine whether this manipulation is sufficient to cause hypertension, and to identify the causative mechanism. sRA mice exhibit brain-specific increases in angiotensin (ANG) peptide production through neuron-specific expression of human renin (synapsin promoter) and expression of human angiotensinogen through its own promoter. We determined both through tail-cuff and radiotelemetric methods that sRA mice are hypertensive (SBP; control 112±2 vs sRA 127±5 mmHg, P=0.02). Despite normal plasma osmolality and moderate hyponatremia, sRA mice exhibit double the number of vasopressin-expressing neurons in the supraoptic nucleus (P=0.002), as detected by immunohistochemistry. Plasma levels of the vasopressin pro-segment, copeptin, were reduced in sRA mice (140±19 vs 68±21 pg/mL, P=0.02), which correlated with severe polyuria (1.8±0.3 vs 12.3±1.6 mL/day, P&lt;0.001). Indeed, total daily copeptin loss in the urine was significantly increased almost twenty-fold in sRA mice (7.9±4.3 vs 154.4±62.4 pg/day, P=0.03), highlighting an increase in vasopressin secretion per unit time. The baseline hypertension of sRA mice was completely reversed by chronic infusion of the dual V 1A / V 2 receptor antagonist, conivaptan (22 ng/hr, 10 days, s.c.; 113±5 mmHg, P=0.02). Preliminary experiments demonstrate that infusion of the selective V 2 receptor antagonist, tolvaptan (22 ng/hr, 10 days, s.c.), has similar effects. Further, while abdominal aorta and mesenteric arteries demonstrate selective desensitization to vasopressin and down-regulation of the V 1A receptor (38% of control, P&lt;0.05), renal V 2 receptor expression remained normal in sRA mice. Together, these data demonstrate major roles for vasopressin and its V 2 receptor in the hypertension caused by elevated brain RAS activity.

Oestradiol Potentiates Hormone Secretion and Neuronal Activation in Response to Hypertonic Extracellular Volume Expansion in Ovariectomised Rats

Secretion of vasopressin (VP), oxytocin (OT) and atrial natriuretic peptide (ANP) is an essential mechanism for the maintenance of hydromineral homeostasis. Secretion of these hormones is modulated by several circulating factors, including oestradiol. However, it remains unclear how oestradiol exerts this modulation. In the present study we investigated the participation of oestradiol in the secretion of VP, OT and ANP and in activation of vasopressinergic and oxytocinergic neurones of the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus in response to extracellular volume expansion (EVE). For this purpose, ovariectomised (OVX) rats treated for 7 days with vehicle (corn oil, 0.1 ml/rat, OVX+O group) or oestradiol (oestradiol cypionate, 10 μg/kg, OVX+E group) were subjected to either isotonic (0.15 m NaCl, 2 ml/100 g b.w., i.v.) or hypertonic (0.30 m NaCl, 2 ml/100 g b.w., i.v.) EVE. Blood samples were collected for plasma VP, OT and ANP determination. Another group of rats was subjected to cerebral perfusion, and brain sections were processed for c-Fos-VP and c-Fos-OT double-labelling immunohistochemistry. In OVX+O rats, we observed that both isotonic and hypertonic EVE increased plasma OT and ANP concentrations, although no changes were observed in VP secretion. Oestradiol replacement did not alter hormonal secretion in response to isotonic EVE, but it increased VP secretion and potentiated plasma OT and ANP concentrations in response to hypertonic EVE. Immunohistochemical data showed that, in the OVX+O group, hypertonic EVE increased the number of c-Fos-OT and c-Fos-VP double-labelled neurones in the PVN and SON. Oestradiol replacement did not alter neuronal activation in response to isotonic EVE, but it potentiated vasopressinergic and oxytocinergic neuronal activation in the medial magnocellular PVN (PaMM) and SON. Taken together, these results suggest that oestradiol increases the responsiveness of vasopressinergic and oxytocinergic magnocellular neurones in the PVN and SON in response to osmotic stimulation.

Neuronostatin acts in brain to biphasically increase mean arterial pressure through sympatho-activation followed by vasopressin secretion: the role of melanocortin receptors

Neuronostatin is a recently described neuropeptide that is derived from the somatostatin preprohormone. We have shown previously that neuronostatin led to a biphasic, dose-related increase in mean arterial pressure when injected into the lateral cerebroventricle of adult, male rats. Because neuronostatin depolarized both magnocellular and parvocellular, paraventricular nucleus neurons in hypothalamic slice preparations, we hypothesized that neuronostatin elevated mean arterial pressure first by stimulating sympathetic nervous system activity followed by the release of a pressor hormone, specifically vasopressin. We found that the first phase of neuronostatin-induced increase in mean arterial pressure was reversed by pretreatment with phentolamine, indicating that phase 1 was, indeed, due to an increase in sympathetic activity. We also found that centrally injected neuronostatin led to a dose-related increase in vasopressin secretion in a time course consistent with the peak of the second phase. Furthermore, the second phase of arterial pressure elevation was reversed by pretreatment with a vasopressin 1 receptor antagonist, indicating that phase 2 was likely due to an increase in vasopressin secretion. We previously have shown that the anorexigenic and antidipsogenic effects of neuronostatin were reversed by pretreatment with the melanocortin 3/4 receptor antagonist, SHU9119, so we evaluated the ability of SHU9119 to reverse the effects of neuronostatin on MAP and vasopressin secretion. We found that SHU9119 abrogated the second phase of neuronostatin-induced increase in MAP and neuronostatin-induced vasopressin secretion, indicating that neuronostatin acts through the central melanocortin system to increase vasopressin release, ultimately leading to an elevation in MAP.

State‐Dependent Plasticity in Vasopressin Neurones: Dehydration‐Induced Changes in Activity Patterning

Moderate dehydration impairs concentration and co-ordination, whereas severe dehydration can cause seizures, brain damage or death. To slow the progression of dehydration until body fluids can be replenished by drinking, the increased body fluid osmolality associated with dehydration increases vasopressin (antidiuretic hormone) secretion from the posterior pituitary gland. Increased vasopressin secretion reduces water loss in the urine by promoting water reabsorption in the collecting ducts of the kidney. Vasopressin secretion is largely determined by action potential discharge in vasopressin neurones, and depends on both the rate and pattern of discharge. Vasopressin neurone activity depends on intrinsic and extrinsic mechanisms. We review recent advances in our understanding of the physiological regulation of vasopressin neurone activity patterning and the mechanisms by which this is altered to cope with the increased secretory demands of dehydration.

Diagnosis and management of hyponatremia in acute illness

Hyponatremia is the most common electrolyte disorder present in hospitalized patients. Acute and severe hyponatremia can cause significant morbidity and mortality. The present review discusses the epidemiology, causes, and a practical approach to the diagnosis and management of acute and chronic hyponatremia, including the appropriate use of hypertonic saline and potential future use of the new V2 vasopressin receptor antagonists in critically ill patients. The increasing knowledge of aquaporin water channels and the role of vasopressin in water homeostasis have enhanced our understanding of hyponatremic disorders. Increased vasopressin secretion due to nonosmotic stimuli leads to decreased electrolyte-free water excretion with resulting water retention and hyponatremia. Vasopressin receptor antagonists induce electrolyte-free water diuresis without natriuresis and kaliuresis. Phase three trials indicate that these agents predictably reduce urine osmolality, increase electrolyte-free water excretion, and raise serum sodium concentration. They are likely to become a mainstay of treatment of euvolemic and hypervolemic hyponatremia. The correct diagnosis and management of hyponatremia is complex and requires a systematic approach. Vasopressin receptor antagonists are potential tools in the management of hyponatremia. Further studies are needed to determine their role in the treatment of acute, severe, life-threatening hyponatremia as well as chronic hyponatremia.

Vasopressinergic neurons in rats in ontogenesis: Responses to salt loading and their modulation by noradrenergic afferents

Salt loading in adult mammals leads to increased vasopressin secretion by vasopressinergic neurons in the supraoptic nucleus, which is mediated by the actions of a number of hormones and neurotransmitters, including noradrenaline. The present study addressed identification of the stage of ontogenesis at which vasopressinergic neurons start to respond to salt loading and when the noradrenalinergic regulation of this process begins. Studies were performed on rats at embryonic day 21 (E21), postnatal day 3 (P3), and postnatal day 13 (P13) using immunocytochemical and in situ hybridization. Animals were subjected to salt loading, in some cases on the background of the alpha1-adrenoceptor inhibitor prazosin. Salt loading in rats of all age groups induced increases in the synthesis of vasopressin mRNA, probably accompanied by increased synthesis of vasopressin peptide. At E21 and P3, intraneuronal vasopressin levels were increased; there was no change at P13. In salt loading on the background of prazosin administration, vasopressin mRNA and vasopressin contents at E21 showed no change, while at P3 they were increased, which is evidence of the inhibitory effect of noradrenaline on vasopressin expression in the early postnatal period. Thus, vasopressinergic neurons start to respond to salt loading at the end of the prenatal period with increases in vasopressin expression; noradrenergic afferents have inhibitory influences on vasopressin expression in the early postnatal period.

Vasopressin administration facilitates fluid removal during hemodialysis

Inadequate secretion of vasopressin during fluid removal by hemodialysis may contribute to the cardiovascular instability that complicates this therapy and administration of exogenous hormone, by supporting arterial pressure, may facilitate volume removal. To test this, we measured plasma vasopressin in patients with end-stage renal disease (ESRD) during hemodialysis and found that despite significant fluid removal, plasma vasopressin concentration did not increase. We further found that ESRD did not alter the endogenous removal rate of plasma vasopressin and that plasma hormone is not dialyzed. Finally, in a randomized, double-blinded, placebo-controlled trial in 22 hypertensive patients, we examined the effect of a constant infusion of a non-pressor dose of vasopressin on the arterial pressure response during a hemodialysis in which the target fluid loss was increased by 0.5 kg over the baseline prescription. We found that arterial pressure was more stable in the patients receiving vasopressin and that while only one patient (9%) in the vasopressin group had a symptomatic hypotensive episode, 64% of the patients receiving placebo had such an episode (P=0.024). Moreover, increased fluid removal was achieved only in the vasopressin group (520+/-90 ml vs 64+/-130 ml, P=0.01). Thus, administration of non-pressor doses of vasopressin to hypertensive subjects improves cardiovascular stability during hemodialysis and allows increased removal of excess extracellular fluid. Inadequate vasopressin secretion during hemodialysis-induced fluid removal is a likely contributor to the intradialytic hypotension that limits fluid removal.

Validation of a test model of induced dysmenorrhea

The myometrial hyperactivity and reduced uterine blood flow of primary dysmenorrhea is to a large extent caused by increased vasopressin secretion. A new therapeutic approach for this condition is to develop antagonists of uterine vasopressin V1a receptors. We studied a test model of vasopressin-induced dysmenorrhea in healthy, sterilized women and compared responses against those in dysmenorrheic subjects. Eight women with primary dysmenorrhea and eight sterilized, healthy women participated in recordings of intrauterine pressure and experienced pain on days 1-2 of two menstruations. We tried to identify biochemical markers in plasma of uterine ischemia. Furthermore, the effects of repeated bolus injections of 10 pmol/kg b w of vasopressin or placebo on these parameters were assessed. The vasopressin injections caused statistically significant increases in the area under the intrauterine pressure curve (AUC) in both healthy volunteers and patients with dysmenorrhea, the overall responses being greater in healthy volunteers. The experienced pain measured by visual analog scale in individual dysmenorrheic subjects tended to show higher maximal post-dose scores for the vasopressin injections than for placebo. Maximum visual analog scale scores and maximum AUCs in individual subjects tended to be related. Mean creatine kinase MB levels were higher in women with dysmenorrhea than in healthy subjects both before and after vasopressin administration, the converse being observed for C-reactive protein levels. The present model appears to be useful for evaluating new drugs for the treatment of primary dysmenorrhea.