Arginine Vasopressin V1 Antagonist Research Articles

Neural responses to territorial challenge and nonsocial stress in male song sparrows: segregation, integration, and modulation by a vasopressin V 1 antagonist

The present experiments were conducted to determine (1) which basal forebrain regions and/or their peptidergic components are responsive to social challenge and nonsocial stress, and (2) the influence of an arginine vasopressin V 1 antagonist (AVPa) on these responses. Experiments were conducted in wild-caught male song sparrows ( Melospiza melodia) that were housed on seminatural territories (field-based flight cages). Subjects were each fitted with a chronic guide cannula directed at the lateral ventricle and exposed to one of five conditions before sacrifice and histochemistry: saline + simulated territorial intrusion (STI; consisting of song playback and presentation of a caged conspecific male), AVPa + STI, saline + empty cage, AVPa + empty cage, unhandled. Two tissue series were prepared and immunofluorescently double-labeled for ZENK (egr-1) protein and either arginine vasotocin (AVT; avian homologue of AVP) or corticotropin releasing factor (CRF). The results indicate that the neuronal populations that are sensitive to nonsocial stress (capture, handling and infusion) and STI are at least partially segregated. Increases in ZENK-immunoreactive (-ir) nuclei following handling and infusion were observed in a large number of areas, whereas neural responses that were specific to STI were more limited. However, multiple areas showed responses to both handling and STI. AVPa infusions significantly reduced or eliminated most experimental increases in ZENK-ir, suggesting a broad role for endogenous AVT in the modulation of baseline activity and/or stress responsivity, and a much more limited role in the specific response to social challenge. Particular attention is given to the numerous zones of the lateral septum (LS), which are differentially responsive to handling, STI, and V 1-like receptor blockade. These data suggest that septal AVT modulates neural responses to general stressors, not social stimuli specifically. Thus, species differences in septal AVT function (as previously described in songbirds) likely reflect differences in the relationship of stress or anxiety to species-specific behaviors, or to behavior in species-typical contexts.

Arginine Vasopressin Increases Renal Sodium Excretion in the Anesthetized Rat Through V1 Receptors

We have previously suggested that the increase in renal Na+ excretion in response to physiological doses of arginine vasopressin (AVP) is not directly linked to the V2-mediated antidiuretic effect. In the present study we investigated the possible involvement of AVP V1 receptors in this natriuresis using a specific AVP V1 antagonist [I-(β-mercapto-β,β-cyclopentamethylenepropionic acid), 2-O-methyltyrosine arginine vasopressin, d(CH2)5(Me)2]AVP, infused at a rate of 15 ng·min-1. Male anesthetized Sprague-Dawley rats were placed on a continuous jugular infusion of 0.077 M NaCl at 150 μL·min-1. After a 3-h equilibration period, samples were collected at 20-min intervals for 4 h for the determination of urine flow, and Na+ and K+ excretion rates. In those animals in which the effects of AVP were studied, a 1-h control period was allowed following which AVP was infused at 0.02–0.08 pmol·min-1 for 1 h 20 min in separate groups of animals and then returned to the infusate alone for the last part of the experiment. In other groups the AVP V1 antagonist d(CH2)5[Tyr(Me)2]AVP (15 ng · min-1) alone or in combination with AVP (at various dose rates) was also administered for 1 h 20 min. All dose rates of AVP produced an antidiuresis which was associated significantly to increased Na+ excretion rate. However, AVP administration at the median dose rate (0.04 pmol · min-1) significantly (p < 0.01) decreased the amount of urine voided by comparison with control animals (6.34 ± 1.05 mL vs. 11.892 ± 0.03 mL, n = 7) although the urinary Na+ was elevated (967 ± 18 μmol vs. 742 ± 81 μmol, n = 7). This AVP-induced increase in urinary Na+ loss was abolished in animals receiving combined AVP (0.04 pmol · min-1) and AVP V1 antagonist (674 ± 47 μmol, n = 7) although the antidiuretic effect persisted. Urine flow and Na+ excretion rates remained unchanged in groups of animals administered AVP V1 antagonist alone. In all groups, the K+ excretion rates did not significantly differ. It is concluded that the V1 receptor mediates the natriuretic effect of AVP.

Subcellular mechanisms of angiotensin II and arginine vasopressin activation of area postrema neurons.

Angiotensin II (ANG II) and arginine vasopressin (AVP) act on area postrema (AP) neurons to modulate the baroreflex. Because activation of AP neurons by either ANG II or AVP increases intracellular free Ca2+ concentrations ([Ca2+]i), the goal of this study was to analyze the factors affecting the [Ca2+]i responses to ANG II and AVP. Neurons were recovered from 14- to 16-day old rats and studied after 8-14 days in culture by use of the microscopic digital image analysis for fura 2-loaded cells. The effects of ANG II (100 nM) and AVP (100 nM) on [Ca2+]i were determined in normal (2 mM) and low (< 10 nM) extracellular Ca2+ concentrations. In 143 of 240 neurons, ANG II increased [Ca2+]i 4.65-fold after 20 s, and a similar response was observed in the absence of extracellular Ca2+ (3.65-fold after 20 s). After 60 s of observation, steady-state levels of increased [Ca2+]i were still present under both conditions. Pretreatment with AT1 antagonist or pertussis toxin abolished the response to ANG II. AVP also increased [Ca2+]i (3.6-fold at peak, 20 s) in normal and low extracellular Ca2+. Pretreatment with AVP V1 antagonist or pertussis toxin abolished the response to AVP. This study indicates that ANG II-induced increases in [Ca2+]i are independent of extracellular Ca2+ concentrations and involve the activation of AT1 receptors and a pertussis toxin-sensitive G protein. Although AVP affects a fewer number of AP neurons, the mechanisms of activation are also independent of extracellular Ca2+ concentration and are mediated by a pertussis toxin-sensitive G protein.

Hypertension induced by high salt intake in absence of volume retention in reduced renal mass rats

Reduction of renal mass (RRM) combined with a high-salt diet results in volume retention, a rise of cardiac output, and hypertension. The present studies were designed to determine whether prevention of volume retention would alter the rise of mean arterial pressure (MAP) in RRM rats given high salt. Rats were studied in a modified metabolic cage to permit continuous determination of total body weight (TBW). In group 1, NaCl was increased from 1 to 14.5 meq/day and delivered isotonically. In group 2, NaCl was increased while TBW was servo-controlled to a constant level. Group 3 was also servo-controlled, but rats received an intravenous infusion of an arginine vasopressin V1 antagonist throughout the study. MAP in group 1 rose 24 mmHg by day 4 of high salt with a parallel increase of TBW of 26 g. In group 2, MAP rose 48 mmHg by day 4 of high salt, while TBW was controlled to within 0.6% of control body weight. With inhibition of vasopressin V1 receptors (group 3), MAP rose 39 mmHg. Nearly equivalent amounts of NaCl were retained in all groups, which was associated with no change of plasma Na in group 1 but an increase of nearly 7 meq/ml in groups 2 and 3. Hematocrit fell nearly 9% in groups 2 and 3 compared with a 4% reduction in group 1. The results suggest that under conditions where net retention cannot occur, high salt intake increases MAP by an osmotically driven fluid transfer from cells, which results in an even greater expansion of blood volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen manipulation and vasopressin binding in the rat brain and peripheral organs.

It is now widely recognized that there is a sexual dimorphism in the development of arginine vasopressin (AVP) immunoreactivity in certain parts of the brain, and that changes in brain AVP immunoreactivity change with manipulation of androgen status. The aim of this experiment was to determine specifically any AVP receptor changes in response to manipulation of androgen levels using a selective V1 antagonist radioligand. Following castration, plasma testosterone levels fell and AVP immunoreactivity was reduced in the lateral septum and bed nucleus of the stria terminalis. With testosterone supplementation in castrated animals, the immunoreactivity in these regions was restored to a higher degree than in sham-operated animals. Central and peripheral V1 AVP receptor binding (as determined using the selective AVP V1 antagonist radioligand [125I](d(CH2)5,sarcosine7)AVP was not changed in any of the brain regions studied or in liver or kidney membranes from the three groups. This study demonstrates that there is no change in brain AVP receptor binding despite changes in regional AVP immunoreactivity in the brain, and excludes any confounding interaction with changes in oxytocin receptors.

Does endogenous peripheral arginine vasopressin have a role in the febrile responses of conscious rabbits?

1. The actions of peripheral arginine vasopressin (AVP) on the febrile responses of conscious rabbits induced by peripherally administered polyinosinic:polycytidylic acid (poly(I).poly(C)) have been studied using an AVP V1 receptor antagonist ([deamino-Pen1, O-Me-Tyr2, Arg8]-vasopressin). 2. Temperature responses were monitored continuously using rectal thermistor probes. Test substances were administered intravenously (i.v.). Blood samples were taken at timed intervals from a marginal ear vein and plasma PGE2 and PGF2 alpha levels determined by radioimmunoassay. 3. Poly(I).poly(C) (2.5 micrograms/kg) stimulated a reproducible biphasic rise in body temperature with a lag phase of 45-60 min and peaks at 90 and 225 min. The febrile response was accompanied by a 5-fold rise in circulating immunoreactive (ir) PGE2, which peaked after 90 min and remained elevated up to 300 min. Poly(I).poly(C) also stimulated a 2.5-fold rise in circulating irPGF2 alpha, which peaked after 150 min and was followed by a return to basal levels after 300 min. 4. The overall magnitude of the febrile response to poly(I).poly(C) (2.5 micrograms/kg, i.v.) was significantly antagonized by the AVP V1 receptor antagonist (250 micrograms/kg, i.v.) administered 5 min prior to the pyrogen. 5. The irPGE2 response to poly(I).poly(C) (2.5 micrograms/kg, i.v.) was significantly antagonized by the AVP V1 receptor antagonist (250 micrograms/kg, i.v.) administered 5 min prior to the pyrogen. The irPGF2 alpha response was only reduced at the peak 150 min time point measurement. 6. In conclusion, these results show a modulatory role for a peripherally administered AVP V1 antagonist in the febrile responses to poly(I).poly(C), suggesting a possible propyretic role for endogenous peripheral AVP. This modulatory role appears to be mediated via actions on prostaglandin E2.

Enhanced cold pressor response in spontaneously hypertensive rats on high-NaCl diet.

This study sought to determine whether spontaneously hypertensive rats (SHR) on a high-NaCl diet have an enhanced pressor response to acute cold exposure and to define the peripheral mechanisms involved in the enhanced pressor response. SHR and normotensive Wistar-Kyoto (WKY) rats that had been on 1 and 8% NaCl diets for 3 wk were subjected to cold exposure. After a 30-min control period, animals were exposed to cold (6 +/- 2 degrees C) for 90 min. Mean arterial pressure (MAP), heart rate (HR), and lumbar sympathetic nerve activity (LSNA) were measured continuously. In a separate group of SHR on 1 and 8% NaCl diets, an arginine vasopressin (AVP) V1 receptor antagonist (10 micrograms/kg iv) was given before cold exposure, and MAP was measured throughout cold exposure. Plasma AVP was measured before and during cold exposure in a separate group of SHR. During cold exposure, there was a significant increase (P less than 0.05) in MAP (25 mmHg) in SHR on the 8% NaCl diet only. In contrast, HR and LSNA increased similarly during cold exposure in both SHR and WKY on the two diets. AVP was similar in both SHR groups (7.1 pg/ml for 1% vs. 6.1 pg/ml for 8%) before cold exposure, but during cold exposure it increased in the 8% NaCl SHR only, reaching 17.6 pg/ml at 90 min. The AVP V1 antagonist completely abolished the cold stress-induced rise in MAP in SHR. Thus SHR on a high-NaCl diet have an enhanced pressor response to acute cold exposure compared with SHR on a normal NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: Comparison with the renin-angiotensin system and the sympathetic nervous system

Ten patients with advanced congestive heart failure were treated with an arginine vasopressin V1 antagonist during hemodynamic monitoring to determine the contribution of vasopressin to vasoconstriction in this disorder. The vasopressin antagonist caused a decrease in systemic vascular resistance in the three patients whose plasma vasopressin was greater than 4.0 pg/ml (average for the group was 2.4 +/- 0.6). Plasma vasopressin concentration correlated with the percent decrease of systemic vascular resistance (r = 0.70, p less than 0.025), serum sodium (r = 0.72, p less than 0.02) and serum creatinine (r = 0.85, p less than 0.005). To compare the relative roles of vasopressin, the renin-angiotensin system and the sympathetic nervous system, these patients also received captopril and phentolamine. Captopril decreased systemic vascular resistance by 20% (p less than 0.05), mostly in patients with high plasma renin activity. Levels of plasma renin activity ranged between 1 and 46 ng/ml per h (average 14.7 +/- 5.7) and correlated with serum sodium (r = 0.77, p less than 0.025), serum creatinine (r = 0.73, p less than 0.025) and right atrial pressure (r = 0.67, p less than 0.05). Phentolamine decreased systemic vascular resistance in all patients (average 34%, p less than 0.01), but the decrease did not correlate with the pretreatment norepinephrine concentration. Norepinephrine levels were elevated in all patients (694 +/- 110 pg/ml) and correlated with baseline stroke volume index (r = 0.75, p less than 0.025) and plasma renin activity (r = 0.67, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)