Vasopressin increases human risky cooperative behavior.

The history of humankind is an epic of cooperation, which is ubiquitous across societies and increasing in scale. Much human cooperation occurs where it is risky to cooperate for mutual benefit because successful cooperation depends on a sufficient level of cooperation by others. Here we show that arginine vasopressin (AVP), a neuropeptide that mediates complex mammalian social behaviors such as pair bonding, social recognition and aggression causally increases humans' willingness to engage in risky, mutually beneficial cooperation. In two double-blind experiments, male participants received either AVP or placebo intranasally and made decisions with financial consequences in the "Stag hunt" cooperation game. AVP increases humans' willingness to cooperate. That increase is not due to an increase in the general willingness to bear risks or to altruistically help others. Using functional brain imaging, we show that, when subjects make the risky Stag choice, AVP down-regulates the BOLD signal in the left dorsolateral prefrontal cortex (dlPFC), a risk-integration region, and increases the left dlPFC functional connectivity with the ventral pallidum, an AVP receptor-rich region previously associated with AVP-mediated social reward processing in mammals. These findings show a previously unidentified causal role for AVP in social approach behavior in humans, as established by animal research.

[Absorption of arginine-vasopressin and arginine-vasotocin in small intestine of the frog Rana temporaria].

Experiments in vitro demonstrated a partial absorption of arginine-vasopressin (AVP) in the frog small intestine. Dynamics and efficiency of the nonapeptide absorption are studied with use of hydroosmotic method of recording of the osmotic permeability of the frog urinary bladder epithelium and immunoenzyme analysis. In the process of absorption there were preserved intactness of the hormone cyclic structure and its physiological activity, like in the case of the arginine-vasotocin (AVT) absorption. The AVP absorption increased at its administration into the gut with inhibitor of proteases. By methods of immunoelectron and immunofluorescent microscopy with use of polyclonal antibody to AVP, location of the label to the hormone was shown in the enterocyte cytoplasm. Thus, there was obtained a morphological evidence for the AVP absorption and transepithelial transfer in the frog small intestine. These data enlarge the concept of the poorly studied properties of the absorbing epithelium of the vertebrate intestine with respect to absorption of intact molecules of polypeptides.

Binding affinities of oxytocin, vasopressin and Manning compound at oxytocin and V1a receptors in male Syrian hamster brains.

Oxytocin (OT) and arginine vasopressin (AVP), as well as synthetic ligands targeting their receptors (OTR, V1aR), are used in a wide variety of research contexts, although their pharmacological properties are determined in only a few species. Syrian hamsters (Mesocricetus auratus) have a long history of use as a behavioural and biomedical model for the study of OT and AVP and, more recently, hamsters have been used to investigate behavioural consequences of OT-mediated activation of V1aR. We aimed to determine the binding affinities of OT, AVP and the selective V1aR antagonist, Manning compound, for OTR and V1aR in hamster brains. We performed saturation binding assays to determine the Kd values for the selective OTR and V1aR radioligands, [125 I]ornithine vasotocin analogue and [125 I]linear vasopressin antagonist. We then performed competition binding assays to determine Ki values for OT, AVP and Manning compound at both the OTR and V1aR. We found that OT and AVP each had the highest affinity for their canonical receptors (OT-OTR Ki = 4.28 [95% confidence interval (CI) = 2.9-6.3] nmol L-1 ; AVP-V1ar Ki = 4.70 [95% CI = 1.5-14.1] nmol L-1 ) and had the lowest affinity for their non-canonical ligands (OT-V1aR = 495.2 [95% CI = 198.5-1276] nmol L-1 ; AVP-OTR Ki = 36.1 [95% CI = 12.4-97.0] nmol L-1 ). Manning compound had the highest affinity for the V1aR (MC-V1aR Ki = 6.87 [95% CI = 4.0-11.9] nmol L-1 ; MC-OTR Ki = 213.8 [95% CI = 117.3-392.7] nmol L-1 ), although Manning compound was not as selective for the V1aR in hamsters as has been reported for the receptor in rats. When comparing these data with previously published work, we found that the promiscuity of the V1aR in hamsters with respect to OT and AVP binding is more similar to the promiscuity of the human V1aR than to the rat V1aR receptor. Moreover, the selectivity of OT at hamster receptors is more similar to the selectivity of OT at human receptors than the selectivity of OT at rat receptors. These data highlight the importance of determining the pharmacological properties of behaviourally relevant compounds in diverse model species.

Osmotic and nonosmotic regulation of arginine vasopressin during prolonged endurance exercise.

CONTEXT: Although the primary cause of exercise-associated hyponatremia (EAH) is relative overconsumption of fluids beyond the kidneys' ability to excrete excess fluid, the mechanisms limiting maximum renal excretory ability during exercise remain to be elucidated. OBJECTIVE: The objective of the study was to: 1) perform a comprehensive evaluation of the endocrine secretion of pituitary, natriuretic and adrenal steroid hormones, and cytokines immediately before and after running an ultramarathon; and 2) evaluate the relationship between osmotic and nonosmotic stimuli to arginine vasopressin (AVP) secretion within the overall context of assessing the hormonal regulation of fluid balance during prolonged endurance exercise. DESIGN: This was an observational study. SETTING: The study setting was a 56-km ultramarathon. PARTICIPANTS: Eighty-two runners participated in the study. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Plasma sodium concentration [Na(+)] and plasma volume [(AVP)(p)] were measured. RESULTS: Fluid homeostasis during exercise (356 +/- 4 min) was maintained with ad libitum fluid intakes. [Na(+)] was maintained from before the race (139.3 +/- 0.3 mmol/liter) to after the race (138.1 +/- 0.4 mmol/liter) with a significant decrease in plasma volume (-8.5 +/- 0.1%, P < 0.01). Increases in the plasma (AVP)(p) (3.9-fold), oxytocin (1.9-fold), brain natriuretic peptide (4.5-fold), and IL-6 (12.5-fold) were highly significant (P < 0.0001). Changes in brain natriuretic peptide, oxytocin, and corticosterone were associated with 47% of the variance noted in (AVP)(p) and 13% of the variance in plasma [Na(+)] in pathway analyses. CONCLUSIONS: (AVP)(p) was markedly elevated after the ultramarathon despite unchanged plasma [Na(+)](.) Therefore, an inability to maximally suppress (AVP)(P) during exercise as a result of nonosmotic stimulation of AVP secretion may contribute to the pathogenesis of exercise-associated hyponatremia if voluntary fluid intake were to exceed fluid output.

Vasopressin vs. terlipressin in the treatment of cardiovascular failure in sepsis.

BACKGROUND: Arginine vasopressin (AVP) and terlipressin (TP) are increasingly used as adjunct vasopressors in the treatment of septic shock. Despite important pharmacological differences between the two drugs (e.g., receptor selectivity, effective half-life) the use of either substance is determined mainly by local availability and institutional inventory. We briefly describe the pathophysiology and pharmacology of septic shock relevant to the treatment with vasopressin analogues. In addition, differences in pharmacokinetics and pharmacodynamics between AVP and TP are discussed. DISCUSSION: The current literature suggests that neither AVP nor TP should be administered in high doses in patients with septic shock. Furthermore, increasing evidence indicates that early administration of vasopressin analogues may improve outcome as compared to a last-resort treatment. Low-dose infusion of AVP (0.6-2.4 U/h) has been demonstrated to be a safe adjunct in the management of septic shock. The V2 agonistic effects of AVP may exert favorable effects on hepatosplanchnic, renal, pulmonary, and coronary perfusion. However, the higher V1 receptor selectivity of TP may prove more potent in restoring arterial blood pressure and avoiding rebound hypotension, while carrying the risk of sustained global and regional vasoconstriction after bolus injection. CONCLUSIONS: Evidence from experimental studies and initial clinical reports suggests that continuous low-dose infusion of TP may stabilize hemodynamics in septic shock with reduced side effects. However, randomized, controlled trials are necessary to determine the role of bolus or continuous infusion of TP in the treatment of septic shock before this approach can be recommended for routine clinical use.

Changes in the metabolic clearance of vasopressin and in plasma vasopressinase throughout human pregnancy.

Metabolic clearance rates (MCR) of arginine vasopressin (AVP) were measured serially in five women starting before conception, during gestational weeks 7-8 (early), 22-24 (middle), and 36-38 (late pregnancy), and again 10-12 wk postpartum. Hormonal disposal rates were determined after water loading to suppress endogenous AVP release using a constant infusion method designed to achieve three different steady-state concentrations of plasma AVP (PAVP) on each test occasion. Dose schedules were altered in mid- and late pregnancy to obtain comparable AVP levels at each stage of the protocol. Prehydration decreased plasma osmolality sufficiently to suppress AVP release, as circulating AVP-neurophysin measured serially in three of the women was undetectable. The MCR of AVP was similar before conception (0.75 +/- 0.31, 0.79 +/- 0.34, and 0.76 +/- 0.28 liters/min at PAVP of 2.6 +/- 1.9, 4.7 +/- 2.4, and 8.3 +/- 3.9 pg/ml), in early pregnancy (0.89 +/- 0.34, 0.97 +/- 0.04, and 0.95 +/- 0.40 liters/min at PAVP of 2.2 +/- 2.1, 3.9 +/- 3.2, and 7.9 +/- 3.4 pg/ml), and postpartum (0.70 +/- 0.21, 0.69 +/- 0.24, and 0.75 +/- 0.20 liters/min at PAVP 3.5 +/- 1.8, 5.1 +/- 3.7, and 9.1 +/- 4.2 pg/ml). Values at mid-pregnancy (2.8 +/- 1.3, 3.0 +/- 1.2, and 2.7 +/- 1.2 liters/min at PAVP 2.3 +/- 2.2, 4.0 +/- 3.6, and 7.7 +/- 3.9 pg/ml) and late pregnancy (3.2 +/- 1.4, 3.3 +/- 1.4, and 2.9 +/- 1.2 liters/min at PAVP 1.9 +/- 2.0, 3.8 +/- 2.6, and 7.4 +/- 4.1 pg/ml) increased 3-4-fold (all P less than 0.01). Plasma vasopressinase, undetectable at 7-8 gestational wk, increased markedly by mid- and slightly more by late gestation. Finally, relationships between PAVP and urine osmolality were similar before, during, and after pregnancy. We conclude that marked increments in the MCR of AVP occur between gestational weeks 7 and 8 and mid-pregnancy, which parallel the period of greatest rise in both trophoblastic mass and plasma vasopressinase. There was no evidence of a renal resistance to AVP during gestation.

Biological half-life and organ distribution of [3H]8-arginine vasopressin following administration of vasopressin receptor antagonist OPC-31260.

The effects of the antidiuretic (V(2)) non-peptide receptor antagonist OPC-31260 on the plasma vasopressin level and the biological half-life and organ distribution of radiochemically pure, biologically active [(3)H]8-arginine vasopressin [spec. act.: 15.9 mCi/mmol (588 GBq/mmol)] were studied in Wistar rats. The plasma vasopressin level increased significantly throughout the whole experimental period (24 h). There was no change in the fast phase of the curves of total radioactivity disappearance from the plasma after the administration of [(3)H]arginine vasopressin (control: 1.51+/-0.17 min, OPC-31260-treated: 1.42+/-0.12 min, n=10). The fast phase of the disappearance curves of intact [(3)H]arginine vasopressin did not change either following the administration of OPC-31260 in a dose of 30 mg/kg p.o. (control: 1.06+/-0.19 min, OPC-31260-treated: 1.00+/-0.15 min, n=6). The slow phase of the biological half-life, which is characteristic for the examined compound, proved to be significantly longer (total radioactivity control: 9.29+/-0.61 min, OPC-31260-treated: 12.33+/-0.42 min, P<0.05, n=10; [(3)H]arginine vasopressin radioactivity: control: 5.96+/-0.58 min, OPC-31260-treated: 8.90+/-0.37 min, P<0.05, n=6). In the control rats, the radioactivity was accumulated to the greatest extent in the neurohypophysis, adenohypophysis and kidney. Following OPC-31260 administration, significantly more radioactive compounds accumulated in the kidney (control: 0.30+/-0.052 total radioactivity %/100 mg organ weight, OPC-31260-treated: 0.50+/-0.133 total radioactivity %/100 mg organ weight, P<0.05, n=10) and neurohypophysis (control: 0.37+/-0.053 total radioactivity %/100 mg organ weight, OPC-31260-treated: 0.52+/-0.076 total radioactivity %/100 mg organ weight, P<0.05, n=10). Our results permit the conclusion that the antidiuretic antagonist OPC-31260 not only blocks the V(2) receptors, but also increases the biological half-life of vasopressin. The longer biological half-life of vasopressin following OPC-31260 administration may play a role in the elevation of the plasma vasopressin level.

Improvement of cationic albumin conjugated pegylated nanoparticles holding NC-1900, a vasopressin fragment analog, in memory deficits induced by scopolamine in mice.

NC-1900, an active fragment analog of arginine vasopressin [arginine vasopressin-(4-9)], has proved to be capable of improving the spatial memory deficits and the impairments in passive avoidance test. In this study, a novel drug carrier for brain delivery, cationic bovine serum albumin conjugated pegylated nanoparticles (CBSA-NPs) holding NC-1900, was developed and its improvement on scopolamine-induced memory deficits was investigated in mice using the platform-jumping avoidance test. CBSA-NPs loaded with NC-1900 in spherical shape and uniform size below 100 nm were prepared by the double emulsion/solvent evaporation procedure, and the zeta potential of CBSA-NPs was about -8mV with the loading capacity of NC-1900 around 0.46%. The in vitro study showed that approximately 10% NC-1900 was released from CBSA-NPs in pH 7.4 phosphate buffer saline (PBS) during 56 h incubation with about 15% NC-1900 released in pH 4.0 PBS during 7 days, indicating the sustained release of this carrier. Furthermore, the half-life of NC-1900 loaded in CBSA-NPs in plasma was about 78 h, which was 4-fold longer than that of free NC-1900 (19 h). The active avoidance behavioral results showed that the s.c. administration of NC-1900 tended to improve memory deficits, but the difference did not present any statistical significance, whereas this peptide failed to produce any positive effects by i.v. administration. However, the i.v. injection of CBSA-NPs loaded with NC-1900 greatly improved memory impairments to a normal level, but the efficacy was slight if the loaded nanoparticles (NPs) were exclusive of the conjugation of CBSA, indicating that CBSA-NP was a promising brain delivery carrier for NC-1900 with CBSA as a potent brain targetor. It was concluded that CBSA-NP loaded with NC-1900 was potentially efficacious in the treatment of memory deficits via i.v. administration.

Dopamine, oxytocin, and vasopressin receptor binding in the medial prefrontal cortex of monogamous and promiscuous voles.

Comparisons between monogamous and promiscuous vole species have proven useful in examining neurobiological mechanisms underlying social attachment. Reward processing is important for social attachment, and the medial prefrontal cortex (mPFC) exerts a direct influence on reward pathways. Dopamine (DA), oxytocin (OT), and arginine vasopressin (AVP) all have been implicated in the regulation of social attachment in monogamous voles. Therefore, we used radiolabeled ligands to examine dopamine D(1)- and D(2)-like, OT, and AVP V(1a) receptor binding densities in the mPFC of monogamous and promiscuous voles. Species differences were found; monogamous voles had higher densities of D(2)-like and OT receptor binding and lower densities of D(1)-like and V(1a) receptor binding than did promiscuous voles. Sex differences also were found; females had higher densities of OT receptor binding but lower densities of V(1a) receptor binding than did males in both species. Further, the laminar distribution of receptor binding indicates the possibility of an interaction between DA and OT systems in the mPFC in the regulation of social attachment. Differences in D(1)- and D(2)-like receptor binding between species are discussed in terms of how they might modulate cortical activity and subsequent DA release in the nucleus accumbens (NAcc).

Kinetics of arginine-vasopressin uptake at the blood-brain barrier.

Uptake of arginine-vasopressin, VP, at the luminal side of the blood-brain barrier (BBB) was studied by means of an in situ brain perfusion technique in the guinea-pig. Kinetic experiments revealed a saturable peptide influx into the parietal cortex, caudate nucleus and hippocampus with Km between 2.1 and 2.7 microM, and Vmax ranging from 4.9 to 5.6 pmol.min-1.g-1. The non-saturable component, Kd, was not significantly different from zero. Influx of VP into the brain was not altered by the presence of the peptide fragments: VP-(1-8), pressinoic acid and [pGlu4,Cyt6]VP-(4-9) at 4.5 microM, nor yet by the aminopeptidase inhibitor, bestatin (0.5 mM) and the L-amino acid transport system substrates, L-tyrosine and L-phenylalanine at 5 mM. At a perfusate concentration of 4.5 microM, the V1-vasopressinergic receptor antagonist, d(CH2)5[Tyr(Me)2]VP, reduced VP influx; regional Ki values, assuming that the observed inhibitions were purely competitive, ranged between 4.7 and 8.5 microM. It is concluded that there is an apparent cerebrovascular permeability to circulating VP due to the presence of a carrier-mediated transport system for the peptide located at the luminal side. The mechanism for VP BBB uptake exhibits no affinity for peptide fragments and large neutral amino acids, but requires reception of the intact molecule, which may be the same initial step for both the BBB VP transporter and the V1-receptor.

The Vasopressin 1b Receptor Antagonist A-988315 Blocks Stress Effects on the Retrieval of Object-Recognition Memory.

Stress-induced activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and high circulating glucocorticoid levels are well known to impair the retrieval of memory. Vasopressin can activate the HPA axis by stimulating vasopressin 1b (V1b) receptors located on the pituitary. In the present study, we investigated the effect of A-988315, a selective and highly potent non-peptidergic V1b-receptor antagonist with good pharmacokinetic properties, in blocking stress effects on HPA-axis activity and memory retrieval. To study cognitive performance, male Sprague-Dawley rats were trained on an object-discrimination task during which they could freely explore two identical objects. Memory for the objects and their location was tested 24 h later. A-988315 (20 or 60 mg/kg) or water was administered orally 90 min before retention testing, followed 60 min later by stress of footshock exposure. A-988315 dose-dependently dampened stress-induced increases in corticosterone plasma levels, but did not significantly alter HPA-axis activity of non-stressed control rats. Most importantly, A-988315 administration prevented stress-induced impairment of memory retrieval on both the object-recognition and the object-location tasks. A-988315 did not alter the retention of non-stressed rats and did not influence the total time spent exploring the objects or experimental context in either stressed or non-stressed rats. Thus, these findings indicate that direct antagonism of V1b receptors is an effective treatment to block stress-induced activation of the HPA axis and the consequent impairment of retrieval of different aspects of recognition memory.

Effects of sodium intake, furosemide, and infusion of atrial natriuretic peptide on the urinary and metabolic clearances of arginine vasopressin in normal subjects.

Arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) have important influences on water and electrolyte metabolism, and studies on the interactions between these hormones may have important implications. We have investigated the effects of sodium intake, furosemide, and infusion of ANP on the urinary and metabolic (nonurinary) clearances of AVP in hydrated normal subjects. On a high sodium diet there was an increase in urine volume, sodium excretion, osmolal clearance, plasma ANP concentration, and urinary clearance and fractional excretion of AVP, with a decrease in PRA. The infusion of furosemide increased urine volume, sodium excretion, osmolal clearance, and PRA, but decreased circulating ANP levels and urinary clearance and fractional excretion of AVP. Since there was a positive correlation between circulating ANP and urinary clearance of AVP in these experiments, we infused human alpha ANP in physiological amounts and found increases in the urinary and metabolic (nonurinary) clearances of AVP. The changes in urinary clearance of AVP in all three experiments occurred even in relation to creatinine clearance. These observations demonstrate that urinary clearance of AVP does not correlate with urine volume, sodium or solute excretion, or PRA. The observations support a physiological role for ANP in modulating the renal action of AVP, probably at the level of the renal tubules, and indicate a need for caution when using plasma or urinary AVP as an indicator of AVP release from the neurohypophysis.

Management of vasodilatory shock: defining the role of arginine vasopressin.

The rationale for an arginine vasopressin (argipressin) infusion was put forward after it was discovered that patients in shock states might have an endogenous arginine vasopressin deficiency. Subsequently, several investigations impressively demonstrated that arginine vasopressin can successfully stabilise haemodynamics even in advanced vasodilatory shock. We report on physiological and pharmacological aspects of arginine vasopressin, and summarise current clinical knowledge on employing a continuous arginine vasopressin infusion in critically ill patients with catecholamine-resistant vasodilatory shock of different aetiologies. In view of presented experimental evidence and current clinical experience, a continuous arginine vasopressin infusion of approximately 2 to approximately 6 IU/h can be considered as a supplemental strategy to vasopressor catecholamines in order to preserve cardiocirculatory homeostasis in patients with advanced vasodilatory shock. Because data on adverse effects are still limited, arginine vasopressin should be reserved for patients in whom adequate haemodynamic stabilisation cannot be achieved with conventional vasopressor therapy or who have obvious adverse effects of catecholamines that result in further significant haemodynamic deterioration. For the same reasons, arginine vasopressin should not be used as a single, alternative vasopressor agent instead of catecholamine vasopressors. Future prospective studies will be necessary to define the exact role of arginine vasopressin in the therapy of vasodilatory shock.

Intracerebroventricular infusion of glycine stimulates vasopressin release in conscious sheep.

We have previously observed that elevation of the plasma glycine concentration stimulates vasopressin (AVP) release in man and sheep. In the present study we show that this effect of glycine can be elicited directly via a cerebral site of action in conscious sheep. Intracerebroventricular infusions of 0.05 and 0.15 M glycine solutions increased the plasma AVP concentration by 6 and 50 times, respectively, while no effect on water intake was observed. Hyperhydration did not block the stimulation of AVP release. No behavioural side effects, or changes in blood pressure, were observed in response to the infusions.

Nasal delivery of a vasopressin antagonist in dogs.

The dosage form (drop or spray) and site of administration (dorsal or ventral surface of the nostril) profoundly affect the distribution and clearance of a gamma-emitting 99mTc-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) solution in dogs. The slowest nasal clearance was observed for dorsally administered drops. Administration of drops to the ventral surface or sprays to either dorsal or ventral surface results in rapid clearance and little deposition in the turbinates. The octapeptide vasopressin antagonist, SKF 101926, was administered intravenously (0.3, 1.0, 3.0, and 10 micrograms/kg) and then on separate occasions intranasally (10, 25, and 50 micrograms/kg as a drop to the ventral surface) to four conscious, trained, female, water-loaded, vasopressin-infused dogs. SKF 101926 reversed the antidiuretic response to vasopressin after administration by either the intravenous or intranasal route in a dose-dependent fashion. Peak dilution of urine occurred within 50- to 60-min postdosing by both routes. Estimated doses to reduce vasopressin antidiuresis by 50% were 1.4 micrograms/kg intravenously and 23 micrograms/kg intranasally. After recovery to at least 70% of antidiuretic base line, and then administration of a second dose of SKF 101926 (3 micrograms/kg), subsequent dilution of urine osmolality was inversely related to the magnitude of the previously administered dose. It is concluded that the estimated relative effectiveness of intranasally administered SKF 101926 is 3-21%, compared with intravenous administration. Acute tachyphylaxis to repeated dosing was observed. The mechanism of the apparent tachyphylaxic response was not elucidated. No tachyphylaxis to less frequent (weekly) dosing was observed.

Radioimmunoassay of desglycinamide-arginine vasopressin and its application in a pharmacokinetic study in the rat.

The purpose of this investigation was to develop a sensitive and selective radioimmunoassay for Desglycinamide-Arginine Vasopressin (DGAVP). DGAVP was extracted from rat plasma after protein precipitation, using Sep-Pak C18 cartridges and 50 mM glycine buffer/methanol (10:90) solution. Extraction recovery was 73 +/- 14% (mean +/- S.D.; n = 11) and good linearity was achieved in the concentration range of 0.25-128 pg/tube. Instantaneous tracer addition resulted in a detection limit of 250 fg/tube, whereas 24 hours preincubation and delayed tracer addition resulted in a detection limit of 100 fg/tube. Intra-assay variation ranged between 7.4% and 10.0% depending on the peptide concentration and inter-assay variation was 13.2%. Using this procedure, plasma pharmacokinetics of DGAVP in the rat were determined after IV administration. DGAVP plasma concentration showed a rapid distribution phase (t1/2 = 1.0 +/- 0.2 min) and a somewhat slower elimination phase (t1/2 = 7.2 +/- 2.1 min). High clearance values (CLss = 97 +/- 30 ml.min-1) suggest rapid metabolism by amino- and carboxy-peptidases.

Pharmacokinetics of DGAVP in plasma following intranasal and oral administration to healthy subjects.

A pharmacokinetic study was carried out to assess the bioavailability of desglycinamide-[Arg8]vasopressin (DGAVP, Org 5667). DGAVP (2 mg) was administered both intranasally and orally to healthy subjects with a treatment interval of 1 week. Blood samples were taken regularly between 15 min before and 210 min after administration and were assayed for DGAVP by radioimmunoassay. In all subjects endogenous vasopressin (AVP) levels were detectable. Peak levels of DGAVP occurred at 15 min after both treatments. The mean absorption half-life was 8.7 and 7.3 min and the mean elimination half-life was 38 and 34.6 min for the intranasal and oral route of administration, respectively. The bioavailability of orally administered DGAVP was low compared with the intranasally administered drug; the relative bioavailability of oral/nasal administration was 0.7%. The results indicate that DGAVP is absorbed rapidly after both oral and intranasal administration, but the intranasal route of administration of DGAVP is 100 times more effective in increasing plasma DGAVP levels.

Transport, uptake, and metabolism of blood-borne vasopressin by the blood-brain barrier.

Transport, binding, and metabolism of [phenylalanyl-3,4,5,-3H(N)]arginine vasopressin (AVP) by the blood-brain barrier (BBB) was studied in adult guinea-pigs by means of a novel vascular brain perfusion (VBP)/capillary depletion technique and HPLC. A time-dependent, progressive brain uptake of 3H-radioactivity was measured over the 10 min period of VBP both in brain homogenates and in brain tissue depleted of cerebral microvessels. The unidirectional blood-to-brain transport constant, K(IN), estimated by multiple-time tissue uptake analysis of the homogenate and postcapillary supernatant, indicated that the BBB transfer rate for [3H]AVP (K(IN) = 2.37 +/- 0.25 microliters min-1 per gram brain homogenate) was almost 10 times higher than for simultaneously perfused [14C]sucrose, a cerebrovascular space marker. In contrast to homogenate and postcapillary supernatant, the [3H]radioactivity determined in the vascular pellet after dextran density centrifugation of the brain homogenate was very low and only somewhat higher than for [14C]sucrose. HPLC analysis of the perfused brain tissue revealed time-dependent degradation of the blood-borne neuropeptide. The percentage of intact [3H]AVP as determined in the postcapillary supernatant progressively declined during brain perfusion, from 49% at 1 min to 11.9% at 10 min. The major detectable labeled metabolite was [3H]phenylalanine, the labeled amino acid residue of [3H]AVP. The aminopeptidase inhibitor bestatin (0.5 mM), perfused simultaneously with [3H]AVP by the VBP technique, did not alter tissue uptake of [3H]AVP, indicating that there was no significant hydrolysis of peptide by the luminal BBB surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Chlorpropamide alters AVP-receptor binding of rat renal tubular membranes.

The effects of chlorpropamide on AVP-receptor binding in rat renal tubular basolateral membranes were investigated utilizing [3H][Arg8]vasopressin (AVP). Our data indicate that chlorpropamide alters AVP-receptor binding in a competitive manner.

V1-like [Arg8]vasopressin binding sites occur in rat hepatocyte nuclei.

Arginine vasopressin binding site characterisation was performed on purified nuclei and plasma membranes from livers of Sprague-Dawley rats. [125I][d(CH2)5,Sarc7,Arg8]vasopressin, a selective V1 vasopressin receptor antagonist radioligand, bound to the nuclei in a protein concentration and time dependent manner. Scatchard analysis of nuclear binding sites revealed a single binding site with maximal binding site density (Bmax) of 115 +/- 13 fmol/mg protein and affinity (KD) of 5.2 +/- 0.7 nM. Plasma membrane binding demonstrated a Bmax of 529 +/- 25 fmol/mg protein and KD of 1.9 +/- 0.1 nM. The displacement profile for nuclear binding sites using vasopressin analogues was similar to that for plasma membrane binding sites and was typical of a V1 vasopressin receptor type. There was no evidence of V2-like vasopressin receptor binding using [3H]des-Gly-NH9(2)[d(CH2)5,D-Ile2,Ile4,Arg8]vasopressi n, a selective V2 vasopressin receptor radioligand, in the nuclear or membrane fractions. These results suggest the existence of nuclear V1-like vasopressin binding sites.