pituitrin and relcovaptan

Embryo transfer, the final stage of IVF/embryo transfer (IVF/ET) treatment, independently influences treatment outcome.Successful embryo implantation following embryo transfer, among other factors, is also dependant on uterine receptivity.Uterine contractile activity may adversely affect the implantation. Although increased contractions have been found in approximately 30% of patients undergoing embryo transfer, to date it has not been a subject to any diagnosis or therapy. Pharmacological tocolytics may be expected to improve pregnancy rates; however, targeting uterine adrenergic receptors, calcium channels or prostaglandin synthesis has since proven ineffective. The novel class of drugs which could be the most useful in this indication is oxytocin antagonists. In animal models, oxytocin significantly reduced embryo implantation rates, and this was reversed by an oxytocin antagonist. In humans, peptidyl oxytocin and mixed vasopressin V1A/oxytocin antagonists have been found to significantly reduce uterine contractions in egg donors undergoing mock embryo transfer. It has further been demonstrated that the vasopressin V1A/oxytocin receptor antagonist atosiban can improve pregnancy success in patients with recurrent IVF failures. This article reviews the uterine oxytocin/vasopressin V1A receptor systems and their potential influence on embryo implantation. It is suggested that the clinical application of oxytocin antagonists might improve results of IVF/ET treatment.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Embryo Implantation; Female; Humans; Indoles; Infertility; Oligopeptides; Oxytocin; Pregnancy; Pyrrolidines; Receptors, Oxytocin; Reproductive Techniques, Assisted; Tocolytic Agents; Uterine Contraction; Vasopressins; Vasotocin

Effects of vasopressin via V1a- and V2-receptors are closely implicated in a variety of water-retaining diseases and cardiovascular diseases, including heart failure, hyponatraemia, hypertension, renal diseases, syndrome of inappropriate antidiuretic hormone secretion, cirrhosis and ocular hypertension. As vasopressin receptors are found in many different tissues, vasopressin antagonists may benefit the treatment of disorders such as cerebral ischaemia and stroke, Raynaud's disease, dysmenorrhoea and tocolytic treatment. V1b selective vasopressin antagonists are discussed in terms of their usefulness in the treatment of emotional and psychiatric disorders. The vaptans are vasopressin receptor antagonists with V1a (relcovaptan) or V2 (tolvaptan, lixivaptan) selectivity or non-selective activity (conivaptan) which may be advantageous in some disorders. The V1a/V2 non-selective vasopressin antagonist conivaptan is the first vaptan which is approved by the FDA for the treatment of euvolaemic hyponatraemia.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Binding Sites; Cardiovascular Diseases; Clinical Trials as Topic; Hormone Antagonists; Humans; Indoles; Pyrroles; Pyrrolidines; Tolvaptan; Vasopressins; Water-Electrolyte Imbalance

Arginine vasopressin (AVP) stimulates steroid secretion from the normal human adrenal gland and some cortisol-producing adrenocortical tumors or hyperplasia through activation of the V(1a) receptor.. The objective of the study was to investigate in vitro and in vivo the possible involvement of AVP in the physiopathology of primary aldosteronism.. The design of the study included immunohistochemical, pharmacological, and molecular studies on aldosterone-producing adenoma (APA), followed by a monocentric, crossover trial of the orally active V(1a) receptor antagonist, SR 49059, in a double blind, randomized, and placebo-controlled fashion.. The study was conducted at a university hospital and research laboratory.. The study population included eight untreated patients with primary aldosteronism, four with APA and four with idiopathic hyperaldosteronism.. Aldosterone secretion of APA cells in vitro and plasma aldosterone, renin, and ACTH were measured.. SR 49059 (200 mg once daily) or placebo was administered during two 1-wk treatment periods separated by a 2-wk washout.. We observed the occurrence of AVP-containing cells in APA tissues. Administration of AVP to perifused APA cells induced an increase in aldosterone production, which was inhibited by a specific V(1a) antagonist. RT-PCR analysis showed the expression of V(1a) receptor mRNA in most APAs studied. In APA patients, SR 49059 did not induce any effect on basal aldosterone secretion but provoked a plasma aldosterone response to orthostatism (P < 0.03) and strengthened the positive correlation between plasma aldosterone and ACTH.. The present study indicates that functional V(1a) receptors are present in APA and suggests that AVP may exert an autocrine/paracrine control of aldosterone secretion in APA tissues.

Topics: Adenoma; Adrenocorticotropic Hormone; Aldosterone; Cross-Over Studies; Double-Blind Method; Female; Fluorescent Antibody Technique; Hormone Antagonists; Humans; Hyperaldosteronism; Immunohistochemistry; Indoles; Male; Middle Aged; Pituitary Neoplasms; Pyrrolidines; Receptors, Vasopressin; Reverse Transcriptase Polymerase Chain Reaction; RNA; Vasopressins

Compounds that block uterine oxytocin and vasopressin V1a receptors have a therapeutic potential in preterm labor and primary dysmenorrhoea. The orally active vasopressin V1a receptor antagonist, SR49059, inhibits the effect of vasopressin on human uterine activity in vivo, but the influence on the response to oxytocin is unknown.. In a placebo-controlled, double-blind, parallel-group, four-dose comparison, the inhibitory effect of SR 49059 on oxytocin- and vasopressin-induced uterine contractions in humans was investigated. Sixteen healthy female subjects, who had previously undergone sterilization with tubal ligation, participated in intrauterine pressure recordings at one of the first 3 days of bleeding of two menstrual cycles. Intravenous bolus injections of 10 pmol/kg body weight of vasopressin (Period 1) and of 50 pmol/kg body weight of oxytocin (Period 2) were given 1 h before and 1, 2 and 4 h after oral administration of 0 (placebo), 25, 75 or 200 mg of SR 49059. The area between the recording curve and zero level of intrauterine pressure (AUC) was calculated. Vital signs as well as urine and plasma safety parameters were measured. The plasma concentrations of oxytocin, vasopressin and the study drug were also estimated.. The plasma concentrations of SR 49059 appeared to be dose related, with mean maximal values of 62.0, 163.7 and 468.0 ng/ml in the 25, 75 and 200 mg dose groups, respectively, in Period 1 with vasopressin and 34.4, 116.7 and 418.0 ng/mL, respectively, in Period 2 with oxytocin. Tmax was observed at about 1 h. The cumulative AUC over 50 min after vasopressin injection per se was significantly higher than that after oxytocin in spite of a five times lower dose and lower plasma concentrations. Pretreatment by SR 49059 caused a dose-related reduction in AUCs for vasopressin, whereas no such effect was seen for oxytocin. With vasopressin as an agonist, a lower diastolic blood pressure was observed in all SR 49059 treatment groups, but not with oxytocin.. The much higher potency of vasopressin compared with oxytocin on uterine activity in non-pregnant women at menstruation was confirmed. SR 49059 dose-dependently inhibits vasopressin-induced contractions, whereas such an effect was not seen with the present doses of SR 49059 and oxytocin. A marked reduction by SR 49059 of diastolic blood pressure after vasopressin injection was observed, indicating an inhibition by this compound of vascular vasopressin receptors.

Topics: Administration, Oral; Adult; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indoles; Oxytocin; Pyrrolidines; Uterine Contraction; Vasopressins

The conventional evaluation of safety and tolerability during Phase I may not be sufficient for new exploratory non-peptide receptor antagonists as selective vasopressin (AVP) receptor antagonists. Previous research and validation of surrogate markers considerably enhance the understanding of phase I, and may even contribute with high accuracy to an early approach of dose finding. SR 49059 is a new potent and selective non peptide AVP-antagonist, with high affinity, selectivity and efficacy towards both animal and human AVP-V1a receptors. The aim of this study was to assess its tolerability and to determine both its pharmacokinetic and pharmacodynamic profiles. The safety and tolerability of SR 49059 was assessed in an ascending repeated dose tolerability trial, double-blind for each dose. 50 healthy subjects non smoker males, divided into 5 groups (doses) of 10 were included, (8 treated/2 placebo per group) and received oral doses of either 1, 10, 100, 300 or 600 mg of SR 49059 o.d. for 7 days. Clinical tolerability and biological safety was excellent for all subjects up to the highest dose of 600 mg SR 49059 appeared to have no action on AVP plasma level, hemostasis parameters, nor on blood pressure, heart rate, ECG, diuresis or plasma/urine osmolality. Two previously validated surrogate markers using exogenous vasopressin were sufficient to provide evidence of the V1a antagonistic effects of SR 49059 after the first single oral administration, and during the 7 days of treatment: Ex-vivo AVP induced platelet aggregation inhibition: SR 49059 has shown potent antagonistic properties in inhibiting AVP-induced human platelet aggregation in vitro (IC50 = 3.7 nM). Using this ex vivo qualitative test, a dose and time proportional activity was observed at doses as low as 10 mg, and an almost complete inhibition was demonstrated from 100 mg and above, from Day 1 with a steady state level of inhibition from Day 4 up to Day 7. AVP induced blanching skin area inhibition: Intradermic administration of AVP 0.1 ml (25 ng) produced a measurable vasoconstriction (computer analysis of blanching area), which was also dose dependently antagonised by the oral administration of SR 49059 with the same profile as for platelet-aggregation inhibition. Steady state SR 49059 levels were achieved on days 4-5 with moderate (1.8-2.4 fold) accumulation (t1/2: 32 hrs). Cmax values were in the range 0.8-30 ng/ml. The IC50 of AVP (50 nM) -induced platelet aggregation and cutaneous blanch. During early phase I, in addition to the conventional safety profile, validated surrogate markers may provide evidence of activity for selective vasopressin receptor antagonists. The results confirmed that SR 49059 is in human a specific V1a-antagonist without activity at V2 receptors, with a good safety profile.

Topics: Administration, Oral; Adult; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Blood Platelets; Blood Pressure; Diuresis; Dose-Response Relationship, Drug; Double-Blind Method; Hormone Antagonists; Humans; Indoles; Male; Metabolic Clearance Rate; Placebos; Platelet Aggregation Inhibitors; Pyrrolidines; Regional Blood Flow; Skin; Vasopressins

Impaired social function is a core feature of many psychiatric illnesses. Adverse experiences during childhood increase risk for mental illness, however it is currently unclear whether stress early in life plays a direct role in the development of social difficulties. Using a rat model of pre-pubertal stress (PPS), we investigated effects on social behaviour, oxytocin and arginine vasopressin (AVP) in the periphery (plasma) and centrally in the paraventricular and supraoptic hypothalamic nuclei. We also explored social performance and AVP expression (plasma) in participants with borderline personality disorder (BPD) who experienced a high incidence of childhood stress. Social behaviour was impaired and AVP expression increased in animals experiencing PPS and participants with BPD. Behavioural deficits in animals were rescued through administration of the AVPR1a antagonist Relcovaptan (SR49059). AVP levels and recognition of negative emotions were significantly correlated in BPD participants only. In conclusion, early life stress plays a role in the precipitation of social dysfunction, and AVP mediates at least part of this effect.

Topics: Adult; Adverse Childhood Experiences; Aged; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Behavior, Animal; Borderline Personality Disorder; Disease Models, Animal; Female; Humans; Indoles; Male; Middle Aged; Neurophysins; Paraventricular Hypothalamic Nucleus; Protein Precursors; Pyrrolidines; Rats; Sexual Maturation; Social Behavior; Stress, Psychological; Supraoptic Nucleus; Vasopressins; Young Adult

Vasopressin (AVP) seems to play a role as an antinociceptive neurohormone, but little is known about the peripheral site of action of its antinociceptive effects. Moreover, AVP can produce motor impairment that could be confused with behavioural antinociception. Finally, it is not clear which receptor is involved in the peripheral antinociceptive AVP effects.. In anaesthetized rats with end-tidal CO. Subcutaneous AVP (1 and 10 μg/paw) induced antinociception and a transitory reduction of the end-tidal CO. Subcutaneous AVP produces antinociception and behavioural analgesia. Both V1a and OTR participate in those effects. Our findings suggest that antinociception could be produced in a local manner using a novel vasopressin receptor located in cutaneous sensorial fibres. Additionally, subcutaneous AVP also produces important systemic effects such as respiratory and locomotor impairment.. Our findings support that AVP produces peripheral antinociception and behavioural analgesia in a local manner; nevertheless, systemic effects are also presented. Additionally, this is the first detailed electrophysiological analysis of AVP antinociceptive action after subcutaneous administration. The results are reasonably explained by the demonstration of V

Topics: Analgesics; Animals; Antidiuretic Hormone Receptor Antagonists; Behavior, Animal; Camphanes; Evoked Potentials; Indoles; Injections, Subcutaneous; Locomotion; Male; Nerve Fibers, Myelinated; Nerve Fibers, Unmyelinated; Nociception; Pain Measurement; Piperazines; Pyrrolidines; Rats; Receptors, Oxytocin; Receptors, Vasopressin; Vasopressins

Oxytocin and vasopressin are important modulators of a wide variety of social behaviors, and increasing evidence is showing that these neuropeptides are important organizational effectors of later-life behavior as well. We treated day-old gerbil pups with oxytocin, vasopressin, an oxytocin receptor antagonist, a vasopressin V1a receptor antagonist, or saline control, and then measured received parental responsiveness during the early postnatal period and juvenile social behavior during weaning. Neonatal vasopressin treatment enhanced sociality in males, but not females, at both developmental time points. When pups were individually placed outside the nest, parents were more responsive to male pups treated with vasopressin compared with littermates, and vasopressin treated male pups exhibited increased play with littermates as juveniles. These results show that vasopressin during very early life can enhance social interactions throughout early development.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Behavior, Animal; Camphanes; Gerbillinae; Indoles; Oxytocin; Piperazines; Pyrrolidines; Receptors, Oxytocin; Social Behavior; Vasopressins

To investigate the dynamic expression of vasopressin and its potential role in rat brain tissue after experimental subarachnoid hemorrhage (SAH).. Male Sprague-Dawley rats were divided into 10min, 1h, 6h, 24h, 48h and 72h groups. The SAH model was established by endovascular puncture. ELISA and immunohistochemistry were performed to evaluate dynamic expression of vasopressin. Immunohistochemistry of GPIIb/IIIa integrin was used to assess platelet aggregation. Double immunofluorescence labeling was carried out to observe the reaction between vasopressin and platelet. Early brain injury was evaluated by apoptotic cells counting. Neurobehavioral score was performed to assess neuroprotective role of SR 49059 (a selective antagonists of vasopressin receptor).. In peripheral blood and hypothalamus, vasopressin increased rapidly at 6h and 24h. Expression of GPIIb/IIIa integrin peaked at 24h in cortex and hippocampus. Immunofluorescence showed that vasopressin and GPIIb/IIIa integrin located at the same site. Administration of SR 49059 significantly decreased platelet aggregation and number of apoptotic cells. The neurobehavioral score was promoted significantly after the intervention.. The results indicate that rapidly increased vasopressin could induce platelet aggregation and contribute to early brain injury after SAH.

Topics: Animals; Apoptosis; Brain; Disease Models, Animal; Disease Progression; Enzyme-Linked Immunosorbent Assay; Hormone Antagonists; Immunohistochemistry; Indoles; Male; Neuroprotective Agents; Platelet Aggregation; Pyrrolidines; Random Allocation; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Time Factors; Vasopressins

High plasma copeptin, a marker of vasopressin (VP) secretion, has been shown to be associated with the metabolic syndrome and development of type 2 diabetes in humans. The present study was designed to determine the long-term influence of plasma VP concentration in a rodent model prone to metabolic dysfunction.. Obese Zucker rats and their lean counterparts were submitted for 4 weeks to one of three protocols inducing different levels of VP. Circulating VP was either reduced by increasing the daily water intake (low-VP), or increased by a chronic i.p. infusion of VP (high-VP). The control rats had normal VP levels that depended on their own regulation of water intake and VP secretion.. Compared with controls with normal VP, lean rats with high-VP had a higher fasting glycaemia after 4 weeks. In obese rats, high-VP promoted hyperinsulinaemia, glucose intolerance, assessed by glucose and insulin tolerance tests, and an impaired response to a pyruvate challenge. Conversely, treatment with a selective arginine vasopressin receptor 1A (V1aR) antagonist reduced glucose intolerance. Low-VP obese rats had unchanged glucose tolerance but exhibited a drastic decrease in liver steatosis compared with control obese rats, associated with low hepatic triacylglycerol and cholesterol content, and reduced expression of hepatic lipogenic genes. These effects were independent of changes in body adiposity, and plasma sodium and osmolality did not differ among groups.. These findings show a causal relationship between the VP-hydration axis and the metabolic risk. Therapeutic perspectives include diet recommendations regarding hydration, but also potential pharmacological interventions targeting the VP V1aR.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Blood Glucose; Drinking; Fatty Liver; Glucose Intolerance; Glucose Tolerance Test; Indoles; Male; Obesity; Pyrrolidines; Rats, Zucker; Vasopressins

Recent in vitro studies suggest that the oxytocin receptor (OTR) agonist WAY 267,464 has vasopressin 1A receptor (V1AR) antagonist effects. This might limit its therapeutic potential due to the positive involvement of the V1AR in social behavior.. The objective of this study was to assess functional V1AR antagonist-like effects of WAY 267,464 in vivo using a test of social recognition memory.. Adult experimental rats were tested for their recognition of a juvenile conspecific rat that they had briefly met 30 or 120 min previously. The modulatory effects of vasopressin (AVP), the selective V1AR antagonist SR49059, and WAY 267,464 were examined together with those of the selective OTR antagonist Compound 25 (C25). Drugs were administered immediately after the first meeting.. Control rats showed recognition of juveniles at a 30 min, but not a 120 min retention interval. AVP (0.005, but not 0.001 mg/kg intraperitoneal (i.p.)) improved memory such that recognition was evident after 120 min. This was prevented by pretreatment with SR49059 (1 mg/kg) and WAY 267,464 (10, 30, and 100 mg/kg). Given alone, SR49059 (1 mg/kg) and WAY 267,464 (30 and 100 mg/kg) impaired memory at a 30 min retention interval. The impairment with WAY 267,464 was not prevented by C25 (5 mg/kg), suggesting V1AR rather than OTR mediation of the effect. Given alone, C25 also impaired memory.. These results highlight a tonic role for endogenous AVP (and oxytocin) in social recognition memory and indicate that WAY 267,464 functions in vivo as a V1AR antagonist to prevent the memory-enhancing effects of AVP.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Behavior, Animal; Benzodiazepines; Indoles; Male; Pyrazoles; Pyrrolidines; Rats; Rats, Wistar; Receptors, Oxytocin; Recognition, Psychology; Social Behavior; Vasopressins

To investigate the effects of V1A receptor antagonist through inhibition of vasopressin-induced VEGF secretion in an experimental model.. Thirty rats were randomly divided into five groups. Four groups were given 10IU pregnant mare serum gonadotropin/day (sc) at 8:00-8:30am on days 22-25 of life. They were administered 30IU hCG at 8:00-8:30am on day 26 of life. On days 26 and 27 of life at 8:00am and 4:00pm, (ip) per animal, 50μg/kg/day GnRH antagonist in the GnRH antagonist group, 0.3mg relcovaptan in the high dose relcovaptan group, and 0.15mg relcovaptan in the low dose relcovaptan group were administered. The control group was given the same dosage of 0.9% saline solution (ip) on days 22-26 day of life. The main outcomes were weight gain, ovarian weights, peritoneal fluid VEGF values, corpus luteum count, and atretic follicle count.. Weight gain was highest in the OHSS group; it was almost twice as much in the OHSS group than it was in the control group. Ovarian weights were significantly lower in all treatment groups (p=0.03). There was no statistically significant difference in ovarian weights between the GnRH antagonist and relcovaptan groups (p=0.176). The evaluation of peritoneal fluid VEGF-A levels revealed statistically significant differences between levels in the treatment groups and in the OHSS group (p=0.005). Atretic follicle count in the OHSS group was significantly lower (p=0.048). In all treatment groups, CL counts were prominently lower than they were in the OHSS group (p=0.002).. Relcovaptan may be a novel strategy for decreasing risk of OHSS by inhibition of vasopressin-induced VEGF secretion through V1A receptor antagonist.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Ascitic Fluid; Chorionic Gonadotropin; Corpus Luteum; Disease Models, Animal; Female; Follicular Atresia; Gonadotropin-Releasing Hormone; Gonadotropins, Equine; Indoles; Organ Size; Ovarian Hyperstimulation Syndrome; Ovary; Ovulation Induction; Pyrrolidines; Rats; Rats, Wistar; Vascular Endothelial Growth Factor A; Vasopressins; Weight Gain

There is current interest in oxytocin (OT) as a possible therapeutic in psychiatric disorders. However, the usefulness of OT may be constrained by peripheral autonomic effects, which may involve an action at both OT and vasopressin V1A receptors. Here, we characterized the cardiovascular and thermoregulatory effects of OT, vasopressin (AVP) and the non-peptide OT receptor agonist WAY 267,464 in rats, and assessed the relative involvement of the OT and V1A receptors in these effects.. Biotelemetry in freely moving male Wistar rats was used to examine body temperature and heart rate after OT (0.01 - 1 mg kg(-1); i.p.), AVP (0.001 - 0.1 mg kg(-1); i.p.) or WAY 267,464 (10 and 100 mg kg(-1); i.p.). The actions of the OT receptor antagonist Compound 25 (C25, 5 and 10 mg kg(-1)) and V1A receptor antagonist SR49059 (1 and 10 mg kg(-1)) were studied, as well as possible V1A receptor antagonist effects of WAY 267,464.. OT and AVP dose-dependently reduced body temperature and heart rate. WAY 267,464 had similar, but more modest, effects. SR49059, but not C25, prevented the hypothermia and bradycardia induced by OT and AVP. WAY 267,464 (100 mg·kg(-1)) prevented the effects of OT, and to some extent AVP.. Peripherally administered OT and AVP have profound cardiovascular and thermoregulatory effects that appear to principally involve the V1A receptor rather than the OT receptor. Additionally, WAY 267,464 is not a simple OT receptor agonist, as it has functionally relevant V1A antagonist actions.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzodiazepines; Body Temperature; Heart Rate; Hormone Antagonists; Indoles; Male; Oxytocin; Pyrazoles; Pyrrolidines; Rats, Wistar; Receptors, Oxytocin; Receptors, Vasopressin; Vasopressins

Individuals in many species increase their proximity to others in threatening situations (defensive aggregation), increasing their chance of survival and reducing the adverse psychological impact of stressors. However, the basic neurobiology of defensive aggregation is not well understood. Here we examined the role of the social neuropeptides oxytocin (OT) and vasopressin (AVP) in this response. Groups of rats were exposed to a ball of cat fur (an innate threat stimulus) in a large arena, causing prolonged periods of tight social grouping (huddling). The modulatory effects of OT and AVP on huddling were examined both alone and in conjunction with relevant antagonists. To determine specificity of treatment effects to social grouping, the effects of the same treatments were also assessed in individual rats exposed to cat fur and given the opportunity to hide. OT (0.5 mg/kg, i.p.) and AVP (0.01 mg/kg, i.p.) increased huddling in rats socially exposed to cat fur, whereas the selective V1A AVP receptor antagonist SR49059 (3 mg/kg, i.p.) decreased huddling. The effects of OT were prevented by pre-treatment with SR49059 (3 mg/kg), while those of AVP were prevented by the V1B receptor antagonist SSR149415 (30 mg/kg, i.p.). OT had no effect on huddling when groups of four rats were tested with no cat fur present whereas AVP increased huddling under these conditions. Neither OT, nor SR49059, affected hiding in individual rats exposed to cat fur. However, AVP increased hiding, an effect prevented by SSR149415 (30 mg/kg, i.p.). These results suggest that OT acts on V1A receptors to promote a social response to threat without altering the more general defensive response. Conversely, AVP appears to increase generalised anxiety via V1B receptors, which subsequently results in huddling. A hitherto unrecognised function of oxytocin is therefore to promote social affiliation during threatening situations.

Topics: Aggression; Analysis of Variance; Animals; Cats; Disease Models, Animal; Drug Interactions; Hormone Antagonists; Indoles; Male; Odorants; Oxytocin; Pyrrolidines; Rats; Rats, Wistar; Stress, Psychological; Vasopressins

The neuropeptides oxytocin (OT) and vasopressin (AVP) are recognized for their modulation of social processes in humans when delivered peripherally. However, there is surprisingly little evidence for acute social effects of peripherally administered OT or AVP in animal models. On the other hand, the party drug 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') has powerful prosocial effects in rats that appear to occur through stimulation of central OT release. Here, we directly compared the social effects of peripherally administered OT and AVP with those of MDMA, and examined a possible role for the vasopressin 1A receptor (V1AR) in the observed prosocial effects. Adult male Long-Evans rats were tested in a social interaction paradigm after OT (0.1, 0.25, 0.5, and 1 mg/kg, intraperitoneal (IP)), AVP (0.001, 0.0025, 0.005, 0.01, and 0.1 mg/kg, IP), and MDMA (2.5, 5 mg/kg, IP), or combined low doses of OT and MDMA, or AVP and MDMA. The effects of pretreatment with the non-peptide OT receptor antagonist compound 25 (C25; 5 mg/kg, IP) and the V1AR antagonist SR49059 (1 mg/kg, IP) were also examined. OT (0.5 mg/kg), AVP (0.01 mg/kg), and MDMA (5 mg/kg) potently increased 'adjacent lying', where rats meeting for the first time lie passively next to each other. C25 did not inhibit adjacent lying induced by OT, whereas SR49059 inhibited adjacent lying induced by MDMA (5 mg/kg), OT (0.5 mg/kg), and AVP (0.01 mg/kg). Interestingly, when ineffective doses of OT and MDMA, or AVP and MDMA, were combined, a robust increase in adjacent lying was observed. These results show for the first time acute prosocial effects of peripherally injected OT and AVP in laboratory rats, and suggest a commonality of action of OT, AVP, and MDMA in stimulating social behavior that involves V1ARs.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Dose-Response Relationship, Drug; Drug Synergism; Hallucinogens; Hormone Antagonists; Indoles; Male; N-Methyl-3,4-methylenedioxyamphetamine; Oxytocin; Pyrrolidines; Rats; Receptors, Oxytocin; Receptors, Vasopressin; Social Behavior; Vasopressins

Oxytocin (OT) and arginine-vasopressin (AVP) regulate social behavior in mammals. Zebrafish (Danio rerio) allows higher throughput and ease in studying human brain disorders.. This study investigated in zebrafish the effect of non-mammalian homologs isotocin (IT) and vasotocin (AVT) in comparison with OT/AVP on social behavior and fear response to predator. The mechanism was studied using the most human selective OT and AVP receptor antagonists.. Zebrafish were injected i.m. with increasing doses (0.001-40 ng/kg) of the neuropeptides. DesGly-NH(2)-d(CH(2))(5)-[D-Tyr(2),Thr(4)]OVT) for OT receptor, SR 49059 for V1a subtype receptor, and SSR-149415 for V1b subtype receptor were injected i.m. 10 min before each agonist.. All the peptides increased social preference and reduced fear to predator response in a dose-dependent manner interpolated by symmetrical parabolas. AVT/AVP were more potent to elicit anxiolytic than social effect while IT and OT were equally potent. All the antagonists dose-dependently inhibited both the effects induced by the neuropeptides. The ratio between the ED50 obtained for blocking the OT-induced effects on social preference and fear response to predator was very high only for desglyDTTyrOVT (160). SR49059 showed the highest ratio in blocking AVP-induced effects (807). The less selective antagonist appeared to be SSR149415.. For the first time, IT/AVT and OT/AVP were found to modulate in zebrafish, social behavior, unrelated to sex, and fear to predator response through at least two different receptors. Zebrafish is confirmed as a valid, reliable model to study deficit in social behavior characteristic of some psychiatric disorders.

Topics: Animals; Anti-Anxiety Agents; Antidiuretic Hormone Receptor Antagonists; Dose-Response Relationship, Drug; Fear; Indoles; Ornipressin; Oxytocin; Pituitary Hormones, Posterior; Pyrrolidines; Radioligand Assay; Receptors, Oxytocin; Receptors, Vasopressin; Social Behavior; Swimming; Vasopressins; Vasotocin; Zebrafish

In the last two decades, the role of the alveolar active sodium transport was extensively studied and was found to play a crucial role in regulating alveolar fluid clearance (AFC), and thus in keeping the airspaces free of edema. The recent development of highly selective nonpeptide vasopressin-receptor antagonists gives us a rare chance to explore the role of vasopressin in the pathogenesis of lung edema. Therefore, the present study examined the involvement of vasopressin in modulating the ability of the lung to clear edema. Vasopressin enhanced the rate of lung edema clearance by 30% as compared with untreated control rats (from 0.49 ± 0.02 to 0.64 ± 0.02 ml/h), whereas V(2) receptor antagonists significantly decreased the ability of the lung to clear water (from 0.64 ± 0.02 to 0.31 ± 0.06 ml/h; P < 0.0001). In contrast, V(1) receptor antagonist did not change the rate of AFC. The administration of ouabain (a Na,K-ATPase inhibitor) and amiloride (a Na(+) channel blocker) inhibited the stimulatory effects of vasopressin (from 0.64 ± 0.02 to 0.22 ± 0.02 ml/h [P < 0.0001] and from 0.64 ± 0.017 to 0.23 ± 0.02 ml/h [P < 0.0001], respectively). Vasopressin significantly increased Na,K-ATPase protein abundance in the basolateral membranes of the alveolar epithelial cells via V(2) receptor activation. We report a novel role of the vasopressin pathway in AFC. This observation indicates a beneficial role of vasopressin in AFC by up-regulating active sodium transport.

Topics: Alveolar Epithelial Cells; Amiloride; Animals; Antidiuretic Hormone Receptor Antagonists; Cells, Cultured; Colchicine; In Vitro Techniques; Indoles; Male; Morpholines; Ouabain; Permeability; Pulmonary Alveoli; Pulmonary Edema; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; Sodium-Potassium-Exchanging ATPase; Spiro Compounds; Vasopressins

The aim of this study was to compare the cardiorespiratory and neurohormonal effects of methadone in conscious and in isoflurane anaesthetised dogs. Six mature dogs (28.0 ± 3.8 kg bodyweight) received intravenous (IV) methadone (1mg/kg) three times, once when conscious and twice during isoflurane anaesthesia (with a wash-out period of 1 week). The vasopressin antagonist relcovaptan (0.1mg/kg IV) was administered before the methadone either during the first or second (selected randomly) isoflurane anaesthesia to evaluate the contribution of vasopressin to methadone-associated vasoconstriction. Cardiorespiratory data, plasma catecholamines and serum vasopressin were recorded before (baseline) and for 90 min after methadone. Methadone induced dysphoria in all conscious dogs and significantly (P<0.05) increased mean arterial pressure (MAP), catecholamines, and vasopressin concentrations. During anaesthesia, in addition to significantly greater decreases in heart rate (HR) and cardiac index (CI) than during the conscious state, methadone induced apnoea and mechanical ventilation was necessary in all dogs. In anaesthetised animals, methadone administration significantly increased vasopressin concentrations and systemic vascular resistance index (SVRI), while MAP did not differ from baseline. Relcovaptan administration did not modify the increase in SVRI associated with methadone injection during anaesthesia. Increases in plasma catecholamines may account for the slight decreases in HR and CI seen after methadone administration in conscious dogs. In contrast, isoflurane enhanced the intensity of the cardiorespiratory changes induced by methadone. Vasoconstrictive responses associated with methadone did not appear to be induced by vasopressin.

Topics: Administration, Intravenous; Analgesics, Opioid; Anesthetics, Inhalation; Animals; Cardiovascular Physiological Phenomena; Catecholamines; Dogs; Female; Hormone Antagonists; Indoles; Isoflurane; Male; Methadone; Pyrrolidines; Respiratory Physiological Phenomena; Vasopressins

The aim of the present study was to investigate the protective effect of various doses of exogenous vasopressin (AVP) against ischemia-reperfusion injury in anesthetized rat heart. Anesthetized rats were randomly divided into seven groups (n=4-13) and all of them subjected to prolonged 30 min regional ischemia and 120 min reperfusion. Group I served as saline control with ischemia, in treatment groups II, III, IV and V, respectively different doses of AVP (0.015, 0.03, 0.06 and 1.2 μg/rat) were infused within 10 min prior to ischemia, in group VI, an AVP-selective V1 receptor antagonist (SR49059, 1mg/kg, i.v.) was administrated prior to effective dose of AVP injection and in group VII, SR49059 (1 mg/kg, i.v.) was only administrated prior to ischemia. Various doses of AVP significantly prevented the decrease in heart rate (HR) at the end of reperfusion compared to their baseline and decreased infarct size, biochemical parameters [LDH (lactate dehydrogenase), CK-MB (creatine kinase-MB) and MDA (malondialdehyde) plasma levels], severity and incidence of ventricular arrhythmia, episodes and duration of ventricular tachycardia (VT) as compared to control group. Blockade of V1 receptors by SR49059 attenuated the cardioprotective effect of AVP on ventricular arrhythmias and biochemical parameters, but partially returned infarct size to control. AVP 0.03 μg/rat was known as effective dose. Our results showed that AVP owns a cardioprotective effect probably via V1 receptors on cardiac myocyte against ischemia/reperfusion injury in rat heart in vivo.

Topics: Anesthesia; Animals; Antidiuretic Hormone Receptor Antagonists; Arrhythmias, Cardiac; Blood Pressure; Cardiotonic Agents; Creatine Kinase, MB Form; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Hemodynamics; Indoles; L-Lactate Dehydrogenase; Male; Malondialdehyde; Models, Animal; Myocardial Reperfusion Injury; Pyrrolidines; Rats; Tachycardia, Ventricular; Time Factors; Vasopressins

Mesangial cells are centrally-located glomerular pericytes with contractile, endocrine, and immunity-regulating functions. These cells are thought to maintain normal glomerular function, since mesangial cell proliferation and extracellular matrix formation are hallmarks of chronic glomerular disease. Vasopressin causes mesangial cell contraction, proliferation and hypertrophy. Consequently, the effects of YM218, a potent, nonpeptide vasopressin V(1A) receptor-selective antagonist, on the growth responses of human mesangial cells to vasopressin were investigated. YM218 showed high affinity for vasopressin V(1A) receptors, exhibiting a K(i) value of 0.18 nM. Vasopressin concentration-dependently increased intracellular Ca(2+) levels and induced hyperplasia and hypertrophy in cultured mesangial cells, YM218 potently inhibited these vasopressin-induced responses. These results clearly show that YM218 has both strong affinity for human mesangial cell vasopressin V(1A) receptors and great potency in inhibiting the vasopressin-induced growth responses of mesangial cells controlled by the vasopressin V(1A) receptors. The hyperplasia and hypertrophy of mesangial cells in vitro caused by vasopressin indicate its possible in vivo role in glomerular disease pathogenesis. Therefore, YM218 is a potent pharmacologic probe to investigate the physiologic and pathophysiologic roles of vasopressin in the development of renal disease.

Topics: Antidiuretic Hormone Receptor Antagonists; Benzazepines; Binding, Competitive; Calcium; Cell Membrane; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Indoles; Mesangial Cells; Piperidines; Proteins; Pyrrolidines; Tritium; Vasopressins

Vasopressin (AVP) receptors present in In-R1-G9 cells, a hamster glucagon-secreting alpha-pancreatic cell line, were characterized using SSR-149415, a selective nonpeptide V1b receptor antagonist, and reference AVP compounds. Binding experiments, using [3H]AVP as a ligand, identified a single population of high-affinity binding sites. SSR-149415 competitively inhibited this binding and exhibited nanomolar and stereospecific affinity for these sites. The affinity of various AVP/oxytocin ligands confirmed a V1b binding profile. In functional studies, AVP was a potent stimulant in inducing intracellular Ca2+ increase, glucagon secretion, and cell proliferation. These effects were fully antagonized by SSR-149415 with a nanomolar potency, whereas its diasteroisomer as well as two selective V1a and V2 receptor antagonists were much less potent. Additionally, the order of potency of AVP agonists and antagonists was in agreement with V1b-mediated effects. By RT-PCR, we confirmed the presence of V1b receptor mRNA in both In-R1-G9 cells and in human pancreas. The distribution pattern of V1b receptors investigated in human pancreas by immunohistochemistry showed strong labeling in islets of Langerhans, and colocalization studies indicated that this receptor was expressed in alpha-glucagon, beta-insulin, and somatostatin pancreatic cells. Thus, in In-R1-G9 cells, AVP mediates intracellular Ca2+ increase, glucagon secretion, and cell proliferation by activating V1b receptors, and these effects are potently antagonized by SSR-149415. Moreover, the presence of V1b receptors also found in human Langerhans islets could suggest hormonal control of AVP in human pancreas.

Topics: Animals; Binding, Competitive; Calcium; Cell Division; Cricetinae; Glucagon; Glucagonoma; Hormone Antagonists; Humans; Immunohistochemistry; Indoles; Islets of Langerhans; Pyrrolidines; Receptors, Vasopressin; RNA, Messenger; Tritium; Tumor Cells, Cultured; Vasoconstrictor Agents; Vasopressins

1. The present study was designed to analyse the possible involvement of V1- and V2-receptors in vasopressin (AVP)-induced facilitation of the sympathetic nervous system. Furthermore, we aimed to determine whether the site of facilitation by AVP is located pre- or postsynaptically. 2. Electrical field stimulation (EFS) was applied on the rat mesteric artery to activate the sympathetic nervous system. In addition, we evaluated the direct vascular effects of AVP. The postsynaptic effect of AVP on the sympathetic nervous system was investigated by exposing the vessels to exogenous noradrenaline. These experiments were performed in the absence or presence of selective V1 and V2 receptor antagonists SR 49059 and SR 121463, respectively. Desmopressin was applied as a selective V2 agonist. 3. The direct vasoconstrictor effect of AVP was antagonized by SR 49059 and not by SR 121463. Desmopressin neither showed any direct vasoconstrictor effect nor produced vasodilatation after a precontraction induced by noradrenaline (10 microM). The EFS-induced rise in vascular tone could be increased by a sub-pressor concentration of AVP. This fascilitation could be antagonized by SR 49059, but not by SR 121463. Desmopressin did not influence the increase in vascular tone during EFS. Vasoconstriction induced by exogenous noradrenaline could be facilitated by a sub-pressor concentration of AVP and this selective postsynaptic effect could be antagonized by V1-receptor blockade. 4. In conclusion, the AVP-induced facilitation of the sympathetic nervous system is completely V1-receptor dependent and at least partly postsynaptically mediated.

Topics: Adrenergic Fibers; Animals; Antidiuretic Hormone Receptor Antagonists; Deamino Arginine Vasopressin; In Vitro Techniques; Indoles; Male; Mesenteric Arteries; Pyrrolidines; Rats; Rats, Wistar; Receptors, Vasopressin; Vasoconstriction; Vasopressins

Acute myocardial infarction evokes activation of, among others, the arginine-vasopressin system, resulting in vasoconstriction and fluid retention. In the present study, the vasoconstrictor and antidiuretic effects of vasopressin were examined in vivo in conscious rats with chronic myocardial infarction, in the absence or presence of the V(1a) receptor antagonist SR-49059 or the V(2) receptor antagonist OPC-31260. In sham rats, vasopressin dose-dependently increased mean arterial pressure (maximum response: 45+/-3 mm Hg), which was significantly suppressed in infarcted rats (maximum response: 32+/-3 mm Hg). SR-49059, but not OPC-31260, caused a significant rightward shift of the dose pressure response curve in sham rats, indicating V(1a) receptor mediation. This rightward shift by SR-49059 was significantly more in infarcted rats. The suppressed response to the agonist and enhanced sensitivity to the antagonist suggest a reduction of V(1a) receptor number in infarcted rats. In both sham and infarcted rats, the urine production after OPC-31260 (337+/-14 and 329+/-30 microl/min, respectively) was about twice of that in vehicle-treated rats (188+/-25 and 155+/-24 microl/min, respectively). However, the response in infarcted rats reached its peak quicker and lasted for a shorter period, resulting in a 40% lower area under the curve. Although only measurable during V(2) receptor blockade, the reduction of urine production by vasopressin was significantly more in infarcted compared to sham rats. The enhanced renal response to the agonist and reduced response to the antagonist suggest an increase in V(2) receptor number in infarcted rats. In conclusion, in chronically infarcted rats, vasopressin causes vasoconstriction and fluid retention through the V(1a) and V(2) receptors, respectively. Altered responses after infarction indicate a shift from V(1a) to V(2) receptors.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Pressure; Chronic Disease; Consciousness; Coronary Vessels; Dose-Response Relationship, Drug; Indoles; Kidney; Ligation; Male; Myocardial Infarction; Pyrrolidines; Rats; Rats, Wistar; Receptors, Vasopressin; Urination; Urodynamics; Vasopressins

Nitric oxide attenuates both vasopressin-induced vasoconstriction and vasopressin release. We tested whether hypertension and renal dysfunction elicited by chronic inhibition of nitric oxide (NO) synthesis using N(G)-nitro-L-arginine (L-NNA) could be mediated in part by vasopressin V(1A) receptors. Male rats were treated orally for 6 weeks with L-NNA (15 mg/kg per day), a nonpeptide V(1A) receptor antagonist (2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3, 4-dimethoxybenzene-sulfonyl)-3-hydroxy-2, 3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide (SR 49059, 30 mg/kg per day), or a combination of SR 49059 and L-NNA (same doses), or they received no treatment. Both drugs were added to the food. Measurements were performed in conscious rats (urine collection in metabolic cages, tail-cuff arterial pressure) and at the end of the study in anesthetized rats (clearance measurements). L-NNA produced sustained hypertension, decreased glomerular filtration rate, and increased renal vascular resistance, plasma renin activity, and urinary albumin excretion. SR 49059 had no effect per se on these parameters and also did not attenuate the hypertension and renal dysfunction induced by L-NNA. Surprisingly, SR 49059 potentiated L-NNA-induced hypertension at the end of the 6-week treatment. However, the blood pressure response and the renal and mesenteric vasoconstriction elicited by exogenous vasopressin were attenuated in rats treated with SR 49059. L-NNA did not change plasma vasopressin concentration or 24-hour urinary vasopressin excretion. Our findings suggest that activation of vasopressin V(1A) receptors does not contribute to the hypertension and renal dysfunction induced by chronic NO synthesis inhibition. They also document unchanged plasma vasopressin concentration in NO-deficient hypertension.

Topics: Albuminuria; Animals; Antidiuretic Hormone Receptor Antagonists; Blood Pressure; Enzyme Inhibitors; Heart; Heart Rate; Hypertension; Indoles; Kidney; Male; Nitric Acid; Nitric Oxide Synthase; Nitroarginine; Organ Size; Pyrrolidines; Rats; Rats, Sprague-Dawley; Systole; Time Factors; Vasopressins

The renal vascular response to vasopressin and its modulation were evaluated in vivo by infusing the peptide directly into the renal artery of anaesthetized rats. The intra-renal artery (i.r.a) infusion of vasopressin induced a dose-dependent decrease in renal blood flow. Vasoconstriction was obvious at a dose of 3 ng/kg per min and reached a maximum at 100 ng/kg per min. The dose required for a half-maximal response (ED50) was 24+/-4 ng/kg per min (mean+/-SEM, n=8), corresponding to an estimated concentration in renal arterial blood required for a half-maximal response (EC50) of 1.9+/-0.6 nM. Thiobutabarbitone anaesthesia markedly increased plasma vasopressin concentration. This increase was prevented partially by hypotonic hydration of the rats without any change in the renal vascular response to exogenous vasopressin. Vasopressin-induced vasoconstriction dose/response curves were similar in homozygous and heterozygous Brattleboro rats. Infusion of desmopressin (1-1000 ng/kg per min, i.r.a.), a vasopressin V2 receptor-selective agonist, failed to induce renal vasodilation or vasoconstriction. In the presence of SR 49059 (1 mg/kg i.v.), a vasopressin V1A receptor antagonist that completely abolished the vasopressin-induced renal vasoconstriction, desmopressin again failed to induce vasodilation. Inhibition of nitric oxide synthase by N(omega)-nitro-L-arginine (L-NNA, 100 microg/kg for 10 min and 7.5 microg/kg per min, i.r.a.) enhanced vasopressin-induced renal vasoconstriction (EC50 0.6+/-0.1 nM, P<0.05). In contrast, cyclooxygenase blockade by indomethacin (5 mg/kg, i.v.) neither modified the vasopressin-induced decrease in renal blood flow nor altered the potentiation of vasoconstriction by L-NNA. These results show that the constrictor response of the rat renal vascular bed in vivo is observed only with high local concentrations of vasopressin. This hyporeactivity in vivo was not explained by an anaesthesia-elicited increase in endogenous vasopressin, nor by a modulatory effect linked to V2 receptor activation or prostanoid release. In contrast, NO release contributed to the attenuation of vasopressin-induced renal vasoconstriction.

Topics: Anesthesia; Animals; Antidiuretic Hormone Receptor Antagonists; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Drug Interactions; Hemodynamics; Hormone Antagonists; Indoles; Male; Nitric Oxide; Pyrrolidines; Rats; Rats, Brattleboro; Rats, Sprague-Dawley; Renal Agents; Renal Artery; Renal Circulation; Thiopental; Vasoconstriction; Vasodilator Agents; Vasopressins

Mature oxytocin (OT) and vasopressin (AVP) magnocellular neurons of the hypothalamic supraoptic nuclei (SON) autocontrol their electrical activity via somatodendritic release of their respective peptides. Because OT and AVP are synthesized early in development and could play an important role in the maturation of these neurons, we checked whether the peptides are released within the SON and act on their secreting neurons during 3 weeks of postnatal development. We used patch-clamp recordings from SON neurons in rat hypothalamic horizontal slices to show that the spontaneous electrical activity of immature SON neurons is blocked by OT or AVP receptor antagonists, demonstrating a basal somatodendritic release of the peptides. Application of OT or AVP depolarizes SON neurons and stimulates activity typical of the corresponding mature neurons. This effect is directly on SON neurons because it is recorded in dissociated neurons. Radioimmunoassays from isolated SON were used to show that each peptide facilitates its own release at a somatodendritic level, exhibiting a self-sustaining positive feedback loop. This autocontrol is not uniform during development because the proportion of neurons depolarized by the peptides, the amplitude of the depolarization, and the propensity of the peptides to facilitate their own release are maximal during the second postnatal week and decrease thereafter. These data are consistent with a role of autocontrol in the maturation of SON neurons because it is maximal during the delimited period of postnatal development that corresponds to the period of major synapse formation.

Topics: Action Potentials; Animals; Electrophysiology; Homeostasis; Hormone Antagonists; In Vitro Techniques; Indoles; Male; Morpholines; Neurons; Oxytocin; Pyrrolidines; Rats; Rats, Wistar; Spiro Compounds; Supraoptic Nucleus; Synapses; Vasopressins

Vasopressin V(2) receptors at high-density and V(1B) receptors are candidates for the V(2)-like receptor, which evokes an increase in [Ca(2+)](i) when stimulated by the vasopressin V(2) receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP) in kidney inner medullary collecting duct. We compared the pharmacological characteristics of vasopressin V(2) and V(1B) receptors in Chinese hamster ovary (CHO) cells to those of vasopressin V(2)-like receptors in rat inner medullary collecting duct cells. The vasopressin V(1B) receptor-selective agonist [deamino-Cys(1), D-3-(Pyridyl)-Ala(2), Arg(8)]vasopressin (D3PVP) did not stimulate the [Ca(2+)](i) increase in high-density vasopressin V(2) receptor-expressing CHO cells, but did in inner medullary collecting duct cells. Moreover, the vasopressin V(1A)/V(2) receptor dual antagonist 4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1] benzazepin-6-yl)carbonyl] 2-phenylbenzanilide (YM087), which has no effect on vasopressin V(1B) receptors, did not block the [Ca(2+)](i) increase in inner medullary collecting duct cells when stimulated by dDAVP and D3PVP. On reverse transcription-polymerase chain reaction (RT-PCR) analysis of kidney, vasopressin V(1B) receptor mRNA was detected only in the medulla. We propose that the true nature of the vasopressin V(2)-like receptor in the inner medullary collecting duct is the vasopressin V(1B) receptor, rather than the vasopressin V(2) receptor expressed at high-density.

Topics: Animals; Benzazepines; Calcium; CHO Cells; Cricetinae; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Humans; Indoles; Inositol Phosphates; Kidney Medulla; Morpholines; Pyrrolidines; Rats; Receptors, Vasopressin; Renal Agents; RNA, Messenger; Spiro Compounds; Vasopressins

Vascular endothelial growth factor (VEGF) is a potent and specific mitogen of vascular endothelial cells which promotes neovascularization in vitro. To determine whether vasopressin induces VEGF secretion in human vascular smooth muscle cells, we performed enzyme-linked immunosorbent assays. Vasopressin potently induced a time-dependent and concentration-dependent (maximal, 10(-7) M) increase in VEGF secretion by human vascular smooth muscle cells that was maximal after 24 h. Furthermore, vasopressin also concentration-dependently caused mitogenic effect, as reflected by total protein content of cells per culture well. These vasopressin-induced VEGF secretion increase and mitogenic effect of these cells were potently inhibited by vasopressin V1A receptor antagonists, confirming this is a vasopressin V1A receptor-mediated event. These results indicate that vasopressin increases VEGF secretion in human vascular smooth muscle cells, the magnitude of VEGF secretion being temporally related to the mitogenic effect of vascular smooth muscle cells and the potency of the growth-promoting stimulus. Vasopressin-induced VEGF secretion by proliferating vascular smooth muscle cells could act as a paracrine hormone to powerfully influence the permeability and growth of the overlying vascular endothelium, vasopressin play a more fundamental role in the regulation of vascular function than has previously been recognized.

Topics: Antidiuretic Hormone Receptor Antagonists; Benzazepines; Cell Line; Dose-Response Relationship, Drug; Endothelial Growth Factors; Humans; Indoles; Lymphokines; Morpholines; Muscle, Smooth, Vascular; Pyrrolidines; Spiro Compounds; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vasoconstrictor Agents; Vasopressins

1. The pharmacological profile of receptors activated by vasopressin (AVP) in freshly dissociated supraoptic magnocellular neurones was investigated using specific V1a- and V2-type AVP receptor agonists and antagonists. 2. In 97 % of AVP-responding neurones (1-3000 nM) V1a or V2 receptor type agonists (F-180 and dDAVP, respectively) elicited dose-dependent [Ca2+]i transients that were suppressed by removal of external Ca2+. 3. The [Ca2+]i response induced by 1 microM F-180 or dDAVP was selectively blocked by 10 nM of V1a and V2 antagonists (SR 49059 and SR 121463A, respectively). The response to V1a agonist was maintained in the presence of the V2 antagonist, and the V2 agonist-induced response persisted in the presence of the V1a antagonist. 4. The [Ca2+]i response induced by 1 microM AVP was partially (61 %) blocked by 10 nM SR 121463A. This blockade was increased by a further 31 % with the addition of 10 nM SR 49059. Similarly, the AVP-induced response was partially (47 %) decreased by SR 49059, and a further inhibition of 33 % was achieved in the presence of SR 121463A. 5. We demonstrate that AVP acts on the magnocellular neurones via two distinct types of AVP receptors that exhibit the pharmacological profiles of V1a and V2 types. However, since V2 receptor mRNA is not expressed in the supraoptic nucleus (SON), and since V1b receptor transcripts are observed in the SON, we propose that the V2 receptor agonist and antagonist act on a 'V2-like' receptor or a new type of AVP receptor that remains to be elucidated. The possibility that V2 ligands act on the V1b receptor cannot be excluded.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Calcium; Deamino Arginine Vasopressin; In Vitro Techniques; Indoles; Kinetics; Male; Morpholines; Neurons; Pyrrolidines; Rats; Rats, Wistar; Receptors, Vasopressin; Spiro Compounds; Supraoptic Nucleus; Transcription, Genetic; Vasoconstrictor Agents; Vasopressins

We assessed the role of vasopressin (VP) for the hemodynamic response to pneumoperitoneum in pigs. Four groups of anesthetized pigs were investigated. Nine pigs were intraabdominally insufflated with CO2 and eight were intraabdominally insufflated with argon; eight pigs received an i.v. injection of 1 mg/kg SR 49059, a VP antagonist, before CO2 insufflation; and six pigs received SR 49059 alone. Hemodynamics, plasma concentrations of VP and vasoactive hormones, and Paco2 were measured. Data were analyzed by using analysis of variance, Student's t-test, and Mann-Whitney U-test. Five minutes after insufflation, changes in systemic vascular resistance (SVR) were significantly correlated with changes in VP (r = 0.72; P = 0.005) but not with changes in epinephrine, norepinephrine, renin activity, or Paco2. SVR increased during CO2 insufflation but not during argon insufflation or CO2 insufflation with a preceding infusion of SR 49059. The SR 49059 injection itself resulted in increases in heart rate and cardiac output and decreases in blood pressure and SVR. We conclude that, during CO2 pneumoperitoneum in pigs, absorbed CO2 initiates a pathophysiological process that stimulates VP release. Hence, VP most likely plays a key role in the hemodynamic response to a CO2-induced pneumoperitoneum.. Intraabdominal insufflation of CO2 is associated with hemodynamic and hormonal changes. Investigating CO2 and argon-insufflated pigs and using a vasopressin antagonist, we found that CO2 insufflation released vasopressin, which, in turn, induced hemodynamic perturbances.

Topics: Animals; Argon; Blood Pressure; Carbon Dioxide; Epinephrine; Heart Rate; Hemodynamics; Hormone Antagonists; Indoles; Male; Norepinephrine; Pneumoperitoneum, Artificial; Pyrrolidines; Renin; Swine; Vascular Resistance; Vasopressins

To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential.. Receptor binding studies on transfected cell lines. In vitro contractility studies of human myometrium.. The Research Laboratory of Sanofi Recherche, Centre de Toulouse, France and the Departments of Obstetrics and Gynecology, Lund University Hospital, Sweden and Bialystok University Hospital, Poland.. Nine women delivered by caesarean section preterm and 37 delivered at term for routine obstetric indications.. The binding affinities of oxytocin, arginine vasopressin, atosiban (1-deamino-2-D-Tyr(OEt)-4-Thr-8-Om-oxytocin), SR 49059 and SR 121463 for the human oxytocin and different subtypes of vasopressin receptors were determined. Concentration-response curves with oxytocin and arginine vasopressin were recorded on myometrium from preterm- and term-delivered women in control experiments and in the presence of 2.5 and 10 nmol/L of SR 49059. Furthermore, using term myometrium, the influence of SR 49059 and SR 121463 in concentrations of 3, 10, 30 and 100 nmol/L on responses to the EC50 concentrations of oxytocin and vasopressin were compared.. Receptor binding affinities. In vitro contractile effects and their inhibitions.. Oxytocin had a high affinity for the oxytocin receptor (K(i) in mean = 6.8 nmol/L) and bound, to some extent, to the vasopressin V1a receptor (K(i) = 34.9 nmol/L). Vasopressin displayed higher affinities for vasopressin V1a, V1b and V2 receptors (K(i) = 1.4, 0.8 and 4.2 nmol/L, respectively) than for the oxytocin receptor (K(i) = 48 nmol/L). Atosiban and SR 49059 both had a high affinity for the vasopressin V1a receptor (K(i) = 4.7 and 7.2 nmol/L, respectively, and a moderate one for the oxytocin receptor (K(i) = 397 and 340 nmol/L, respectively). SR 121463 exerted a predominant binding to the V2 receptor (K(i) = 3.0 nmol/L). In the concentration-response experiments levels of up to 10 nmol/L of SR 49059 had no influence on the effect of oxytocin on myometrium from women preterm and at term pregnancy. However, a concentration-dependent inhibition of the responses of both these type of tissues to vasopressin was seen. The effects of EC50 concentrations of oxytocin and vasopressin on term pregnant myometrium were markedly inhibited by 10 nmol/L and higher concentrations of SR 49059, the inhibition of the response to vasopressin being more pronounced than that of the oxytocin response. SR 121463 at maximal concentration only caused slight inhibitions of the oxytocin and vasopressin responses.. Atosiban and SR 49059 both have moderate binding affinities for the human oxytocin receptor and high binding affinities for the vasopressin V1a one. We demonstrated that SR 49059 inhibits the response of term myometrium to oxytocin and that of both preterm and term myometrium to vasopressin. These observations suggest a therapeutic potential of SR 49059 in preterm labour. The vasopressin V2 receptor is apparently not involved to any significant degree in the activation of the pregnant human uterus.

Topics: Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Cell Line; Cesarean Section; Female; Hormone Antagonists; Humans; Indoles; Morpholines; Myometrium; Obstetric Labor, Premature; Oxytocin; Pregnancy; Pyrrolidines; Receptors, Oxytocin; Spiro Compounds; Vasopressins

The effects of SR-49059, a new nonpeptide and selective arginine vasopressin (AVP) V1a antagonist, were investigated in binding and functional studies on cultured human aortic vascular smooth muscle cells (VSMC). Characterization of human vascular V1a receptors, using a specific V1a radioiodinated ligand, showed that [125I]-linear AVP antagonist binding to human VSMC membranes was time dependent, reversible, and saturable. A single population of high-affinity binding sites (apparent equilibrium dissociation constant = 15 +/- 6 pM; maximum binding density = 36 +/- 5 fmol/mg protein, i.e., approximately 3,000 sites/cell) with the expected V1a profile was identified. Exposure of these cells to AVP dose-dependently produced cytosolic free [Ca2+] increase [AVP concentration required to obtain a half-maximal response (EC50) = 23 +/- 9 nM] and proliferation (EC50 = 3.2 +/- 0.5 nM). SR-49059 strongly and stereospecifically inhibited [125I]-linear AVP antagonist binding to VSMC V1a receptors [inhibition constant (Ki) = 1.4 +/- 0.3 nM], AVP-evoked Ca2+ increase [concentration of inhibitor required to obtain 50% inhibition of specific binding (IC50) = 0.41 +/- 0.06 nM], and the mitogenic effects induced by 100 nM AVP (IC50 = 0.83 +/- 0.04 nM). OPC-21268, another nonpeptide V1a antagonist, was more than two orders of magnitude less potent than SR-49059 in these models. However, the consistent affinity (Ki = 138 +/- 21 nM) and activity found with OPC-21268 on human VSMC in comparison with the inactivity already observed for other human V1a receptors (liver, platelets, adrenals, and uterus) strongly suggested the existence of human AVP V1a-receptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aorta; Arginine Vasopressin; Calcium; Cell Division; Cell Membrane; Cells, Cultured; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Humans; Indoles; Iodine Radioisotopes; Kinetics; Muscle, Smooth, Vascular; Oxytocin; Piperidines; Pyrrolidines; Quinolones; Radioligand Assay; Receptors, Vasopressin; Vasopressins