Characterization of a functional V1B vasopressin receptor in the male rat kidney: evidence for cross talk between V1B and V2 receptor signaling pathways.

Although vasopressin V1B receptor (V1BR) mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using the selective V1B agonist d[Leu4, Lys8]VP, either fluorescent or radioactive, we showed that V1BR is mainly present in principal cells of the inner medullary collecting duct (IMCD) in the male rat kidney. Protein and mRNA expression of V1BR were very low compared with the V2 receptor (V2R). On the microdissected IMCD, d[Leu4, Lys8]VP had no effect on cAMP production but induced a dose-dependent and saturable intracellular Ca2+ concentration increase mobilization with an EC50 value in the nanomolar range. This effect involved both intracellular Ca2+ mobilization and extracellular Ca2+ influx. The selective V1B antagonist SSR149415 strongly reduced the ability of vasopressin to increase intracellular Ca2+ concentration but also cAMP, suggesting a cooperation between V1BR and V2R in IMCD cells expressing both receptors. This cooperation arises from a cross talk between second messenger cascade involving PKC rather than receptor heterodimerization, as supported by potentiation of arginine vasopressin-stimulated cAMP production in human embryonic kidney-293 cells coexpressing the two receptor isoforms and negative results obtained by bioluminescence resonance energy transfer experiments. In vivo, only acute administration of high doses of V1B agonist triggered significant diuretic effects, in contrast with injection of selective V2 agonist. This study brings new data on the localization and signaling pathways of V1BR in the kidney, highlights a cross talk between V1BR and V2R in the IMCD, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.NEW & NOTEWORTHY Although V1BR mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using original pharmaceutical tools, this study brings new data on the localization and signaling pathways of V1BR, highlights a cross talk between V1BR and V2 receptor (V2R) in the inner medullary collecting duct, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.

Perinatal exposure to octabromodiphenyl ether mixture, DE-79, alters the vasopressinergic system in adult rats.

Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants considered as neurotoxicants and endocrine disruptors with important biological effects ranging from alterations in growth, reproduction, and effects on the hypothalamus-pituitary-adrenal axis. The vasopressinergic (AVPergic) system is a known target for pentaBDEs mixture (DE-71) and the structurally similar chemicals, polychlorinated biphenyls. However, the potential adverse effects of mixtures containing octaBDE compounds, like DE-79, on the AVPergic system are still unknown. The present study aims to examine the effects of perinatal DE-79 exposure on the AVPergic system. Dams were dosed from gestational day 6 to postnatal day 21 at doses of 0 (control), 1.7 (low) or 10.2 (high) mg/kg/day, and male offspring from all doses at 3-months-old were subjected to normosmotic and hyperosmotic challenge. Male offspring where later assessed for alterations in osmoregulation (i.e. serum osmolality and systemic vasopressin release), and both vasopressin immunoreactivity (AVP-IR) and gene expression in the hypothalamic paraventricular and supraoptic nuclei. Additionally, to elucidate a possible mechanism for the effects of DE-79 on the AVPergic system, both neuronal nitric oxide synthase immunoreactivity (nNOS-IR) and mRNA expression were investigated in the same hypothalamic nuclei. The results showed that perinatal DE-79 exposure AVP-IR, mRNA expression and systemic release in adulthood under normosmotic conditions and more evidently under hyperosmotic stimulation. nNOS-IR and mRNA expression were also affected in the same nuclei. Since NO is an AVP regulator, we propose that disturbances in NO could be a mechanism underlying the AVPergic system disruption following perinatal DE-79 exposure leading to osmoregulation deficits.

The spiking and secretory activity of oxytocin neurones in response to osmotic stimulation: a computational model.

KEY POINTS: A quantitative model of oxytocin neurones that combines a spiking model, a model of stimulus-secretion coupling and a model of plasma clearance of oxytocin was tested. To test the model, a variety of sources of published data were used that relate either the electrical activity of oxytocin cells or the secretion of oxytocin to experimentally induced changes in plasma osmotic pressure. To use these data to test the model, the experimental challenges involved were computationally simulated. The model predictions closely matched the reported outcomes of the different experiments. ABSTRACT: Magnocellular vasopressin and oxytocin neurones in the rat hypothalamus project to the posterior pituitary, where they secrete their products into the bloodstream. In rodents, both vasopressin and oxytocin magnocellular neurones are osmoresponsive, and their increased spiking activity is mainly a consequence of an increased synaptic input from osmoresponsive neurons in regions adjacent to the anterior wall of the third ventricle. Osmotically stimulated vasopressin secretion promotes antidiuresis while oxytocin secretion promotes natriuresis. In this work we tested a previously published computational model of the spiking and secretion activity of oxytocin cells against published evidence of changes in spiking activity and plasma oxytocin concentration in response to different osmotic challenges. We show that integrating this oxytocin model with a simple model of the osmoresponsive inputs to oxytocin cells achieves a strikingly close match to diverse sources of data. Comparing model predictions with published data using bicuculline to block inhibitory GABA inputs supports the conclusion that inhibitory inputs and excitatory inputs are co-activated by osmotic stimuli. Finally, we studied how the gain of osmotically stimulated oxytocin release changes in the presence of a hypovolaemic stimulus, showing that this is best explained by an inhibition of an osmotically regulated inhibitory drive to the magnocellular neurones.

Social isolation rearing-induced anxiety and response to agomelatine in male and female rats: Role of corticosterone, oxytocin, and vasopressin.

BACKGROUND: The chronobiotic antidepressant, agomelatine, acts via re-entrainment of circadian rhythms. Earlier work has demonstrated late-life anxiety and reduced corticosterone in post-weaning social isolation reared (SIR) rats. Agomelatine was anxiolytic in this model but did not reverse hypocortisolemia. Reduced corticosterone or cortisol (in humans) is well-described in anxiety states, although the anxiolytic-like actions of agomelatine may involve targeting another mechanism. Central oxytocin and vasopressin exert anxiolytic and anxiogenic effects, respectively, and are subject to circadian fluctuation, while also showing sex-dependent differences in response to various challenges. AIMS AND METHODS: If corticosterone is less involved in the anxiolytic-like actions of agomelatine in SIR rats, we wondered whether effects on vasopressin and oxytocin may mediate these actions, and whether sex-dependent effects are evident. Anxiety as assessed in the elevated plus maze, as well as plasma vasopressin, oxytocin, and corticosterone were analyzed in social vs SIR animals receiving sub-chronic treatment with vehicle or agomelatine (40 mg/kg/day intraperitoneally at 16:00) for 16 days. RESULTS: Social isolation rearing induced significant anxiety together with increased plasma vasopressin levels, but decreased corticosterone and oxytocin. While corticosterone displayed sex-dependent changes, vasopressin, and oxytocin changes were independent of sex. Agomelatine suppressed anxiety as well as reversed elevated vasopressin in both male and female rats and partially reversed reduced oxytocin in female but not male rats. CONCLUSION: SIR-associated anxiety later in life involves reduced corticosterone and oxytocin, and elevated vasopressin. The anxiolytic-like effects of agomelatine in SIR rats predominantly involve targeting of elevated vasopressin.

Testosterone enhancement during pregnancy influences social coping and gene expression of oxytocin and vasopressin in the brain of adult rats.

Steroid hormones are important mediators of prenatal maternal effects and play an important role in fetal programming. The aim of our study was to investigate how testosterone enhancement during pregnancy influences neurobehavioral aspects of social coping of rat offspring in adulthood. Pregnant rat dams were exposed to depot form of testosterone during the last third of pregnancy (i.e., beginning on the 14th day of pregnancy). Their adult offspring were later tested in a social interaction test and expression of oxytocin and arginine-vasopressin mRNA in the hypothalamic nuclei was evaluated. Our research showed that prenatal exposure to higher levels of testosterone activated socio­cohesive and socio­aversive interactions, but only in males. The testosterone­exposed group also showed decreased oxytocin mRNA expression in the supraoptic and paraventricular nuclei of the hypothalamus, and increased arginine-vasopressin mRNA expression in the supraoptic and suprachiasmatic nuclei as compared to controls. However, we did not observe any sex differences in the expression of oxytocin and arginine­vasopressin mRNA in these regions. Our findings show that testosterone enhancement in pregnancy could have long­lasting effects on oxytocin and arginine-vasopressin levels in the brain of adult animals, but lead to changes in behavioral aspects of coping strategies only in males.

Involvement of dopamine, but not norepinephrine, in the sex-specific regulation of juvenile socially rewarding behavior by vasopressin.

Social play is a highly rewarding behavior displayed mostly during the juvenile period. We recently showed that vasopressin V1a receptor (V1aR) blockade in the lateral septum (LS) enhances social play in male juvenile rats, but reduces it in females. Here, we determined whether the LS-AVP system modulates dopamine (DA) and/or norepinephrine (NE) neurotransmission in the LS to regulate social play behavior in sex-specific ways. Using microdialysis combined with retrodialysis, we demonstrated that both LS-AVP administration and social play exposure increased extracellular LS-DA release in females, but not in males. Pharmacological blockade of LS-DA receptors reduced social play in both sexes, but required a higher dose in females. This suggests that baseline LS-DA release is sufficient for social play in males, while increased LS-DA release is necessary for social play in females. Administration of a V1aR antagonist into the LS inhibited the social play-induced increase in extracellular LS-DA release in females. Furthermore, co-administration of the DA agonist apomorphine prevented the LS-V1aR blockade-induced decrease in social play in females. This suggests that LS-V1aR blockade reduces social play in females by dampening the rise in LS-DA release. Extracellular LS-NE release was enhanced in response to pharmacological manipulations of the LS-AVP system and to social play in males and/or females, but pharmacological blockade or stimulation of LS-NE receptors did not alter social play in either sex. Overall, we define a mechanism by which the LS-AVP system alters LS-DA neurotransmission differently in males than females resulting in the sex-specific regulation of juvenile social play behavior.

High salt intake enhances swim stress-induced PVN vasopressin cell activation and active stress coping.

PURPOSE: Stress contributes to many psychiatric disorders; however, responsivity to stressors can vary depending on previous or current stress exposure. Relatively innocuous heterotypic (differing in type) stressors can summate to result in exaggerated neuronal and behavioral responses. Here we investigated the ability of prior high dietary sodium chloride (salt) intake, a dehydrating osmotic stressor, to enhance neuronal and behavioral responses of mice to an acute psychogenic swim stress (SS). Further, we evaluated the contribution of the osmo-regulatory stress-related neuropeptide arginine vasopressin (VP) in the hypothalamic paraventricular nucleus (PVN), one of only a few brain regions that synthesize VP. The purpose of this study was to determine the impact of high dietary salt intake on responsivity to heterotypic stress and the potential contribution of VPergic-mediated neuronal activity on high salt-induced stress modulation, thereby providing insight into how dietary (homeostatic) and environmental (psychogenic) stressors might interact to facilitate psychiatric disorder vulnerability. APPROACH: Salt loading (SL) with 4% saline for 7 days was used to dehydrate and osmotically stress mice prior to exposure to an acute SS. Fluid intake and hematological measurements were taken to quantify osmotic dehydration, and serum corticosterone levels were measured to index stress axis activation. Immunohistochemistry (IHC) was used to stain for the immediate early gene product c-Fos to quantify effects of SL on SS-induced activation of neurons in the PVN and extended amygdala - brain regions that are synaptically connected and implicated in responding to osmotic stress and in modulation of SS behavior, respectively. Lastly, the role of VPergic PVN neurons and VP type 1 receptor (V1R) activity in the amygdala in mediating effects of SL on SS behavior was evaluated by quantifying c-Fos activation of VPergic PVN neurons and, in functional experiments, by nano-injecting the V1R selective antagonist dGly[Phaa1,d-tyr(et), Lys, Arg]-VP bilaterally into the amygdala prior to the SS. FINDINGS: SL increased serum osmolality (P < 0.01), which positively correlated with time spent mobile during, and time spent grooming after a SS (P < 0.01, P < 0.01), and SL increased serum corticosterone levels (P < 0.01). SL alone increased c-Fos immunoreactivity among PVN neurons (P = .02), including VP positive neurons (P < 0.01). SL increased SS-induced c-Fos activation of PVN neurons as well (P < 0.01). In addition, SL and SS each increased the total number of PVN neurons that were immunoreactive for VP (P < 0.01). An enhancing effect of SL and SS was observed on c-Fos positive cell counts in the central (P = .02) and basolateral (P < 0.01) nuclei of the amygdala and bilateral nano-injections of V1R antagonist into the amygdala reduced time spent mobile both in salt loaded and control mice during SS (P < 0.05, P < 0.05). SUMMARY: Taken together, these data indicate that neuronal and behavioral responsivity to an acute psychogenic stressor is potentiated by prior exposure to high salt intake. This synergistic effect was associated with activation of PVN VP neurons and depended, in part, on activity of V1 receptors in the amygdala. Findings provide novel insight into neural mechanisms whereby prior exposure to a homeostatic stressor such as osmotic dehydration by excessive salt intake increases responsivity to a perceived stress. These experiments show that high dietary salt can influence stress responsivity and raise the possibility that excessive salt intake could be a contributing factor in the development of stress-related psychiatric disorders.

Terlipressin, a vasoactive prodrug recommended in hepatorenal syndrome, is an agonist of human V1, V2 and V1B receptors: Implications for its safety profile.

Terlipressin is recommended as a gold standard to treat hepatorenal syndrome complicating liver cirrhosis. It is presented as a specific V1A receptor agonist, beyond its enzymatic conversion into lysine8-Vasopressin (LVP), able to counteract the splanchnic vasodilation. However, the complete pharmacological characterization of this drug with respect to the different vasopressin receptor subtypes is missing. We studied terlipressin intrinsic properties, focusing not only on V1A, but also on other vasopressin receptor subtypes. The experimental studies were conducted on rat and human cellular models. Binding experiments were performed on rat liver membranes and CHO cells transfected with the different human vasopressin receptor subtypes. Agonist status was assessed from inositol phosphate or cyclic AMP assays, and measurement of intracellular calcium variations, performed on cultured vascular smooth muscle cells from rat aorta and human uterine artery and CHO cells. Terlipressin binds to the rat and human V1A receptors with an affinity in the micromolar range, a value 120 fold lower than that of LVP. It induces a rapid and transient intracellular calcium increase, a robust stimulation of phospholipase C but with reduced maximal efficiencies as compared to LVP, indicating a partial V1A agonist property. In addition, terlipressin is also a full agonist of human V2 and V1B receptors, with also a micromomolar affinity. CONCLUSIONS: Terlipressin is a non-selective vasopressin analogue, exhibiting intrinsic agonist properties. Its full V2 receptor agonism may result in renal effects potentially aggravating water retention and hyponatremia of cirrhosis.

Control of Stress-Induced ACTH Secretion by Vasopressin and CRH: Additional Evidence.

Vasopressin and CRH have complementary roles in the secretion of ACTH following different stress modalities. The concomitant use of V1b and CRF1 receptor antagonists completely inhibits ACTH secretion in response to different stress modalities. The combination of the CRF1 antagonist SSR125543 with the V1b antagonist SSR149415 effectively suppressed plasma ACTH 1.30 h after injection in rats stressed by ether vapor inhalation for 1 min, restraint stress for 1 h or forced swimming for 5 min. The duration of the effect was also studied. The CRF1 antagonist effectively suppressed ACTH secretion in restraint stress, while the V1b antagonist was effective against ether inhalation. Both antagonists were necessary to block the forced swimming stress response. SSR125543 induced a prolonged effect and can be used in a model of prolonged HPA axis blockade.

Effects of hydrogen sulfide (H2S) on water intake and vasopressin and oxytocin secretion induced by fluid deprivation.

During dehydration, responses of endocrine and autonomic control systems are triggered by central and peripheral osmoreceptors and peripheral baroreceptors to stimulate thirst and sodium appetite. Specifically, it is already clear that endocrine system acts by secreting vasopressin (AVP), oxytocin (OT) and angiotensin II (ANG II), and that gaseous molecules, such as nitric oxide (NO) and carbon monoxide (CO), play an important role in modulating the neurohypophyseal secretion as well as ANG II production and thirst. More recently, another gas-hydrogen sulfide (H2S)-has been studied as a neuronal modulator, which is involved in hypothalamic control of blood pressure, heart frequency and temperature. In this study, we aimed to investigate whether H2S and its interaction with NO system could participate in the modulatory responses of thirst and hormonal secretion induced by fluid deprivation. For this purpose, Wistar male rats were deprived of water for 12 and 24h, and the activity of sulfide-generating enzymes was measured. Surprisingly, 24-h water deprivation increased the activity of sulfide-generating enzymes in the medial basal hypothalamus (MBH). Furthermore, the icv injection of sodium sulfide (Na2S, 260nmol), a H2S donor, reduced water intake, increased AVP, OT and CORT plasma concentrations and decreased MBH nitrate/nitrite (NOX) content of 24-h water-deprived animals compared to controls. We thus suggest that H2S system has an important role in the modulation of hormonal and behavioral responses induced by 24-h fluid deprivation.

Cardiovascular effects of the intracerebroventricular injection of adrenomedullin: roles of the peripheral vasopressin and central cholinergic systems

Our objective was to investigate in conscious Sprague-Dawley (6-8 weeks, 250-300 g) female rats (N = 7 in each group) the effects of intracerebroventricularly (icv) injected adrenomedullin (ADM) on blood pressure and heart rate (HR), and to determine if ADM and calcitonin gene-related peptide (CGRP) receptors, peripheral V1 receptors or the central cholinergic system play roles in these cardiovascular effects. Blood pressure and HR were observed before and for 30 min following drug injections. The following results were obtained: 1) icv ADM (750 ng/10 µL) caused an increase in both blood pressure and HR (DMAP = 11.8 ± 2.3 mmHg and ΔHR = 39.7 ± 4.8 bpm). 2) Pretreatment with a CGRP receptor antagonist (CGRP8-37) and ADM receptor antagonist (ADM22-52) blocked the effect of central ADM on blood pressure and HR. 3) The nicotinic receptor antagonist mecamylamine (25 µg/10 µL, icv) and the muscarinic receptor antagonist atropine (5 µg/10 µL, icv) prevented the stimulating effect of ADM on blood pressure. The effect of ADM on HR was blocked only by atropine (5 µg/10 µL, icv). 4) The V1 receptor antagonist [β-mercapto-β-β-cyclopentamethylenepropionyl¹, O-me-Tyr²,Arg8]-vasopressin (V2255; 10 µg/kg), that was applied intravenously, prevented the effect of ADM on blood pressure and HR. This is the first study reporting the role of specific ADM and CGRP receptors, especially the role of nicotinic and muscarinic central cholinergic receptors and the role of peripheral V1 receptors in the increasing effects of icv ADM on blood pressure and HR.

Cardiovascular effects of the intracerebroventricular injection of adrenomedullin: roles of the peripheral vasopressin and central cholinergic systems.

Our objective was to investigate in conscious Sprague-Dawley (6-8 weeks, 250-300 g) female rats (N = 7 in each group) the effects of intracerebroventricularly (icv) injected adrenomedullin (ADM) on blood pressure and heart rate (HR), and to determine if ADM and calcitonin gene-related peptide (CGRP) receptors, peripheral V1 receptors or the central cholinergic system play roles in these cardiovascular effects. Blood pressure and HR were observed before and for 30 min following drug injections. The following results were obtained: 1) icv ADM (750 ng/10 µL) caused an increase in both blood pressure and HR (DMAP = 11.8 ± 2.3 mmHg and ΔHR = 39.7 ± 4.8 bpm). 2) Pretreatment with a CGRP receptor antagonist (CGRP8-37) and ADM receptor antagonist (ADM22-52) blocked the effect of central ADM on blood pressure and HR. 3) The nicotinic receptor antagonist mecamylamine (25 µg/10 µL, icv) and the muscarinic receptor antagonist atropine (5 µg/10 µL, icv) prevented the stimulating effect of ADM on blood pressure. The effect of ADM on HR was blocked only by atropine (5 µg/10 µL, icv). 4) The V1 receptor antagonist [ß-mercapto-ß-ß-cyclopentamethylenepropionyl¹, O-me-Tyr²,Arg8]-vasopressin (V2255; 10 µg/kg), that was applied intravenously, prevented the effect of ADM on blood pressure and HR. This is the first study reporting the role of specific ADM and CGRP receptors, especially the role of nicotinic and muscarinic central cholinergic receptors and the role of peripheral V1 receptors in the increasing effects of icv ADM on blood pressure and HR.

A multicenter, randomized, double-blind, placebo-controlled study of tolvaptan monotherapy compared to furosemide and the combination of tolvaptan and furosemide in patients with heart failure and systolic dysfunction.

BACKGROUND: Increased vasopressin levels may be present in patient with chronic heart failure (HF) and contribute to pathophysiology through effects on the vasopressin V2 receptor. The presence of background diuretic therapy may confound evaluations of vasopressin receptor antagonists (VRA). METHODS AND RESULTS: Eligible patients had HF (New York Heart Association Class II-III), systolic dysfunction (left ventricular ejection fraction ≤0.40) and signs of congestion (eg, edema, rales). At screening, patients were removed from baseline diuretic therapy and placed on a low-sodium diet (2 g/day). After a 2-day run-in period, 83 patients were randomized to placebo (n = 21), monotherapy with the vasopressin V2 receptor antagonist tolvaptan (TLV) 30 mg (n = 20), monotherapy with furosemide 80 mg (FURO, n = 22) or both TLV 30 mg and FURO 80 mg (n = 20) once daily for 7 days. Patients were on standard background therapy and not fluid-restricted throughout the study. A decrease in body weight of -1.37 ± 1.61, -0.54 ± 1.59, and -1.13 ± 1.49 kg was observed versus baseline for TLV, FURO, and TLV+FURO, respectively, at day 8. At the same point, the placebo group showed a body weight increase of +0.72 ± 2.42 kg versus baseline (P = .0006 for TLV versus placebo). Increases in urine volume from baseline were greater with TLV alone (2646 ± 1503 mL/24 hours) than with FURO (894 ± 853 mL/24 hours, P < .001), or PLC (423 ± 786 mL/24 hours, P < .001), and similar to TLV+FURO (2585 ± 2119 mL/24 hours). An increase in serum sodium within the normal range was also observed in TLV-treated patients (P < .02 versus placebo; P < .01 versus FURO). No changes in serum potassium, other laboratory values, or blood pressure were observed. TLV therapy was well tolerated. CONCLUSIONS: In patients with HF and signs of volume overload, TLV monotherapy without concomitant loop diuretic therapy reduced body weight when compared to placebo without adverse changes in serum electrolytes, during a sodium restricted diet while on background medications including angiotensin-converting enzyme inhibitors and ß-blockers.

Carbon dioxide-induced anesthesia results in a rapid increase in plasma levels of vasopressin.

Brief anesthesia, such as after exposure to high levels of carbon dioxide, prior to decapitation is considered a more humane alternative for the euthanasia of rodents, compared with use of decapitation alone. Studies of the levels of certain stress hormones in plasma such as corticosterone and ACTH have supported the use of this method of euthanasia in endocrinological and molecular studies. In the current study, rats were briefly exposed to a chamber filled with carbon dioxide until recumbent (20-25 sec), immediately killed via decapitation, and trunk blood collected; findings were compared with rats killed via decapitation with no exposure to carbon dioxide. RIAs were used to measure arginine vasopressin (AVP) and ACTH immunoreactivity (ir) in plasma. Whereas ACTH-ir levels remained steady after brief exposure to carbon dioxide (in accordance with results of other investigators), AVP-ir levels were increased by more than an order of magnitude. These results were confirmed by quantitative capillary-liquid chromatography-mass spectrometry, indicating this observation of rapid increase in plasma AVP-ir levels is not due to nonspecific recognition by the antibody used in the RIA. Likewise, using capillary-liquid chromatography-mass spectrometry, we observed a rapid increase in plasma oxytocin levels after carbon dioxide exposure. These surprising findings have important implications for the design and interpretation of studies involving brief carbon dioxide exposure prior to decapitation as well as those with euthanasia resulting from carbon dioxide-induced asphyxiation.

Efficacy and safety of the vasopressin V1A/V2-receptor antagonist conivaptan in acute decompensated heart failure: a dose-ranging pilot study.

BACKGROUND: Hospitalization for acute decompensated heart failure (ADHF) involves substantial morbidity and mortality. Current management strategies have major limitations, and there has been little progress in the development of newer therapies. Arginine vasopressin-receptor antagonists may have promise in the treatment of ADHF in view of their ability to facilitate diuresis. This pilot study was designed to evaluate the efficacy and safety of intravenous conivaptan, a dual arginine vasopressin V(1A)/V(2)-receptor antagonist, in treating ADHF. METHODS AND RESULTS: In a double-blind, multicenter trial, 170 patients hospitalized for worsening heart failure and given standard therapy were randomly assigned to treatment with conivaptan (20-mg loading dose followed by 2 successive 24-hour continuous infusions of 40, 80, or 120 mg/d) or placebo. The conivaptan and placebo groups did not differ significantly in patient or clinician assessments of global and respiratory status at 48 hours. There was no evidence of worsening heart failure in any group. Conivaptan at each dosage increased urine output significantly more than placebo at 24 hours (P

The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat.

It is becoming increasingly apparent that probiotics are important to the health of the host. The absence of probiotic bacteria in the gut can have adverse effects not only locally in the gut, but has also been shown to affect central HPA and monoaminergic activity, features that have been implicated in the aetiology of depression. To evaluate the potential antidepressant properties of probiotics, we tested rats chronically treated with Bifidobacteria infantis in the forced swim test, and also assessed the effects on immune, neuroendocrine and central monoaminergic activity. Sprague-Dawley rats were treated for 14 days with B. infantis. Probiotic administration in naive rats had no effect on swim behaviours on day 3 or day 14 following the commencement of treatment. However, there was a significant attenuation of IFN-gamma, TNF-alpha and IL-6 cytokines following mitogen stimulation (p<0.05) in probiotic-treated rats relative to controls. Furthermore, there was a marked increase in plasma concentrations of tryptophan (p<0.005) and kynurenic acid (p<0.05) in the bifidobacteria-treated rats when compared to controls. Bifidobacteria treatment also resulted in a reduced 5-HIAA concentration in the frontal cortex and a decrease in DOPAC in the amygdaloid cortex. The attenuation of pro-inflammatory immune responses, and the elevation of the serotonergic precursor, tryptophan by bifidobacteria treatment, provides encouraging evidence in support of the proposition that this probiotic may possess antidepressant properties. However, these findings are preliminary and further investigation into the precise mechanisms involved, is warranted.

Cardiovascular effects of activation of central alpha7 and alpha4beta2 nAChRs: a role for vasopressin in anaesthetized rats.

BACKGROUND AND PURPOSE: Central application of nicotine causes the release of vasopressin and affects blood pressure. Involvement of the 5 neuronal nicotinic receptor groups, alpha2(*)-alpha7(*) in these effects is unknown. The availability of selective agonists for alpha7 (PSAB-OFP) and alpha4beta2 (TC-2559) nACh receptors allowed their role to be investigated. EXPERIMENTAL APPROACH: Recordings were made of arterial blood pressure, heart rate and renal sympathetic nerve activity in anaesthetized male rats with neuromuscular blockade and artificial respiration. Effects of the agonists, PSAB-OFP (1-10 micromol kg(-1)) and TC-2559 (1-10 micromol kg(-1)) on these variables given intracerebroventricularly (i.c.v.) and intracisternally (i.c.) in the presence or absence of the antagonists, DhbetaE (10 micromol kg(-1)) and MLA (0.5 micromol kg(-1)), for the appropriate nicotinic receptor subtypes, respectively, and a V(1) receptor antagonist, given i.v. or centrally, were investigated. KEY RESULTS: Both agonists given i.c.v. caused a delayed rise in blood pressure and renal nerve activity which could be blocked only with the appropriate antagonist. The agonists had an earlier onset of action when given i.c., favouring the brainstem as the major site of action. The effects of these agonists were also attenuated by the V(1) receptor antagonist given i.v. and blocked when this antagonist was given centrally. Antagonists had no effect on baseline variables. CONCLUSIONS AND IMPLICATIONS: Activation of alpha4beta2 and alpha7 receptors in the brainstem is mainly responsible for the cardiovascular effects of activating these receptors, which have a similar profile of action. These actions, although independent, are mediated by the central release of vasopressin.