Characterization of oxytocin and vasopressin receptors in the Southern giant pouched rat and comparison to other rodents.

Vasopressin and oxytocin are well known and evolutionarily ancient modulators of social behavior. The distribution and relative densities of vasopressin and oxytocin receptors are known to modulate the sensitivity to these signaling molecules. Comparative work is needed to determine which neural networks have been conserved and modified over evolutionary time, and which social behaviors are commonly modulated by nonapeptide signaling. To this end, we used receptor autoradiography to determine the distribution of vasopressin 1a and oxytocin receptors in the Southern giant pouched rat (Cricetomys ansorgei) brain, and to assess the relative densities of these receptors in specific brain regions. We then compared the relative receptor pattern to 23 other species of rodents using a multivariate ANOVA. Pouched rat receptor patterns were strikingly similar to hamsters and voles overall, despite the variation in social organization among species. Uniquely, the pouched rat had dense vasopressin 1a receptor binding in the caudate-putamen (i.e., striatum), an area that might impact affiliative behavior in this species. In contrast, the pouched rat had relatively little oxytocin receptor binding in much of the anterior forebrain. Notably, however, oxytocin receptor binding demonstrated extremely dense binding in the bed nucleus of the stria terminalis, which is associated with the modulation of several social behaviors and a central hub of the social decision-making network. Examination of the nonapeptide system has the potential to reveal insights into species-specific behaviors and general themes in the modulation of social behavior.

Association between arginine vasopressin receptor 1A (AVPR1A) polymorphism and inequity aversion.

Although numerous studies have focused on brain functions related to inequity aversion, few have examined its genetic basis. Here, we show the association between estimated inequity aversion and polymorphisms in three genes associated with human sociality. Non-student adult participants took part in five economic game experiments on different days. Disadvantageous inequity aversion (DIA) and advantageous inequity aversion (AIA) were calculated from behavioural responses using Bayesian estimation. We investigated the association between genetic polymorphisms in the oxytocin receptor (OXTR rs53576), arginine vasopressin receptor 1A (AVPR1A RS3) and opioid receptor mu 1 (OPRM1 rs1799971) and inequity aversion. Regarding AVPR1A RS3, participants with the SS genotype had higher AIA than those with the SL or LL genotypes, but no association was found for DIA. Moreover, we observed no aversion associations for OXTR rs53576 or OPRM1 rs1799971. The results suggest that AVPR1A plays an important role in aversion when one's own gain is greater than that of others. Our findings may provide a solid theoretical basis for future studies on the relationship between genetic polymorphisms and inequity aversion.

Management of hyponatremia: causes, clinical aspects, differential diagnosis and treatment.

INTRODUCTION: Hyponatremia is the most frequent electrolyte disorder in hospitalised patients. Acute and severe hyponatremia may be a life-threatening situation. However, also mild and chronic hyponatremia may negatively affect the health status (i.e. gait disturbances, attention deficits, falls and fractures, and bone loss) and may increase the risk of death. Therefore, it is of paramount importance for clinicians to have an in-depth knowledge on this topic, in order to appropriately manage patients affected by hyponatremia. AREAS COVERED: This review will cover different areas related to this electrolyte disorder. Because many pathologic conditions may be associated with hyponatremia, thorough investigations have to be performed in order to establish the underlying etiology. To establish the cause of hyponatremia is of great importance, because an appropriate therapeutic strategy is strictly dependent on a correct diagnosis. A description of the different available therapeutic approaches for the correction of hyponatremia, including vaptans, will follow. EXPERT COMMENTARY: Undoubtedly, the studies that have been published in recent years and the introduction of vaptans in clinical practice have contributed to increase the awareness on hyponatremia among clinicians. Nevertheless, additional studies are needed in order to clarify some partially uncovered areas.

Vasopressin: physiology, assessment and osmosensation.

Vasopressin (AVP) plays a major role in the regulation of water and sodium homeostasis by its antidiuretic action on the kidney, mediated by V2 receptors. AVP secretion is stimulated by a rise in plasma osmolality, a decline in blood volume or stress. V1a receptors are expressed in vascular smooth muscle cells, but the role of vasopressin in blood pressure regulation is still a matter of debate. AVP may also play a role in some metabolic pathways, including gluconeogenesis, through its action on V1a receptors expressed in the liver. It is now understood that thirst and arginine vasopressin (AVP) release are regulated not only by the classical homeostatic, intero-sensory plasma osmolality negative feedback, but also by novel, extero-sensory, anticipatory signals. AVP measurement is time-consuming, and AVP level in the blood in the physiological range is often below the detection limit of the assays. Recently, an immunoassay has been developed for the measurement of copeptin, a fragment of the pre-provasopressin molecule that is easier to measure. It has been shown to be a good surrogate marker of AVP.

The V2 receptor antagonist tolvaptan raises cytosolic calcium and prevents AQP2 trafficking and function: an in vitro and in vivo assessment.

Tolvaptan, a selective vasopressin V2 receptor antagonist, is a new generation diuretic. Its clinical efficacy is in principle due to impaired vasopressin-regulated water reabsorption via aquaporin-2 (AQP2). Nevertheless, no direct in vitro evidence that tolvaptan prevents AQP2-mediated water transport, nor that this pathway is targeted in vivo in patients with syndrome of inappropriate antidiuresis (SIAD) has been provided. The effects of tolvaptan on the vasopressin-cAMP/PKA signalling cascade were investigated in MDCK cells expressing endogenous V2R and in mouse kidney. In MDCK, tolvaptan prevented dDAVP-induced increase in ser256-AQP2 and osmotic water permeability. A similar effect on ser256-AQP2 was found in V1aR -/- mice, thus confirming the V2R selectively. Of note, calcium calibration in MDCK showed that tolvaptan per se caused calcium mobilization from the endoplasmic reticulum resulting in a significant increase in basal intracellular calcium. This effect was only observed in cells expressing the V2R, indicating that it requires the tolvaptan-V2R interaction. Consistent with this finding, tolvaptan partially reduced the increase in ser256-AQP2 and the water permeability in response to forskolin, a direct activator of adenylyl cyclase (AC), suggesting that the increase in intracellular calcium is associated with an inhibition of the calcium-inhibitable AC type VI. Furthermore, tolvaptan treatment reduced AQP2 excretion in two SIAD patients and normalized plasma sodium concentration. These data represent the first detailed demonstration of the central role of AQP2 blockade in the aquaretic effect of tolvaptan and underscore a novel effect in raising intracellular calcium that can be of significant clinical relevance.

Growing up in the family or growing up alone influences behavior and hormones, but not arginine vasopressin receptor 1a expression in male African striped mice.

In many species males display alternative reproductive tactics (ARTs). While males of different tactics differ behaviorally in the field, it is often not known whether these behavioral differences would also occur under standardized laboratory conditions, nor how ARTs are regulated by the brain. In the present study we kept male African striped mice (Rhabdomys pumilio) in captivity either in family groups or solitary, to mimic ARTs observed in the field. This allowed us to study these males behaviorally under standardized conditions, to replicate physiological findings from the field, and to study the expression of the arginine vasopressin 1a receptor (AVPR1a) in their brains. Changes in either peptide release or receptor expression (or both) might regulate ARTs with differential timelines, with peptide secretion being faster than receptor expression. As observed in the field, family living males had higher corticosterone but lower testosterone levels than singly housed males. Surprisingly, singly housed males were less aggressive while at the same time having higher testosterone levels. We found no differences in AVPR1a expression. In a previous study it was shown that singly housed males have higher levels of AVP stored in their brain, which potentially could be secreted when the social situation changes, for example to establish social bonds. Our study on AVPR1a suggests the hypothesis that, given that the receptor distribution and expression of singly housed males do not differ from that of family-living males, the brains of singly-housed males have a similar capacity to be responsive to AVP when given the chance to interact socially.

[Effectiveness and adequacy of tolvaptan prescription in hospitalized patients]. / Efectividad y adecuación de la prescripción de tolvaptán en pacientes hospitalizados.

PURPOSE: To analyse the effectiveness of the use of Tolvaptan and the adequacy of Tolvaptan prescription at a tertiary level hospital. METHODS: Prospective observational study of Tolvaptan prescrip - tion from October of 2010 to December of 2011. RESULTS: 30 patients (60.0% males) were included, 50.0% of which were diagnosed with heart failure and 30.0% with SIADH. Tolvaptan allowed achieving sodium levels higher than 135 mEq/L in 53.3% of the patients with a mean baseline value of 125.3±7.3 mEq/L. The median treatment duration was 5.0 days (interquartile range=3-45). A significant increase of uric acid associated to Tolvaptan treatment was observed. The prescription was in agreement to what has been established in GFT in 63.3% of the cases. CONCLUSIONS: Tolvaptan increases sodium levels by 7.5 mEq/L, both in SIADH-associated hyponatremia and in heart failure, with an appropriate safety profile.

Objetivo: Analizar la efectividad del uso de tolvaptán y la adecuación de su prescripción en un hospital de tercer nivel. Método: Estudio observacional prospectivo de las prescripciones de tolvaptán desde octubre de 2010 hasta diciembre de 2011. Resultados: Se incluyeron 30 pacientes (60,0% varones), 50,0% diagnosticados de insuficiencia cardíaca y 30,0% de SIADH. Tolvaptán permitió alcanzar niveles de sodio superiores a 135 mEq/L en el 53,3% de los pacientes que partían con una media de 125,3±7,3 mEq/L. La mediana de días de tratamiento fue de 5,0 (rango intercuartílico = 3-45). Se observó un incremento significativo de los niveles de ácido úrico asociado al tratamiento con tolvaptán. La prescripción se adecuó a lo establecido en la GFT en el 63,3% de los casos. Conclusiones: Tolvaptán incrementa un 7,5 mEq/L los niveles de sodio tanto en hiponatremia secundaria al SIADH como en insuficiencia cardiaca.

Where vaptans do and do not fit in the treatment of hyponatremia.

The treatment of hyponatremia, an exceedingly common electrolyte disorder, has been a subject of controversy for many years. The advent of vasopressin antagonists (vaptans) has added to the treatment arsenal. This review focuses on why hyponatremia should be treated and the role of these antagonists in the treatment. Upon analysis of the available literature, we conclude that there is presently no role for vaptans in acute symptomatic hyponatremia. Although numerous therapeutic approaches are available for chronic symptomatic hyponatremia, vasopressin antagonists provide a simpler treatment option. Vaptans are efficacious in raising serum sodium in long-standing 'asymptomatic' hyponatremia. However, the cost of the only Food and Drug Administration-approved oral agent (tolvaptan) makes its use prohibitive for most patients in this setting.

Molecular evolution of the neuropeptide S receptor.

The neuropeptide S receptor (NPSR) is a recently deorphanized member of the G protein-coupled receptor (GPCR) superfamily and is activated by the neuropeptide S (NPS). NPSR and NPS are widely expressed in central nervous system and are known to have crucial roles in asthma pathogenesis, locomotor activity, wakefulness, anxiety and food intake. The NPS-NPSR system was previously thought to have first evolved in the tetrapods. Here we examine the origin and the molecular evolution of the NPSR using in-silico comparative analyses and document the molecular basis of divergence of the NPSR from its closest vertebrate paralogs. In this study, NPSR-like sequences have been identified in a hemichordate and a cephalochordate, suggesting an earlier emergence of a NPSR-like sequence in the metazoan lineage. Phylogenetic analyses revealed that the NPSR is most closely related to the invertebrate cardioacceleratory peptide receptor (CCAPR) and the group of vasopressin-like receptors. Gene structure features were congruent with the phylogenetic clustering and supported the orthology of NPSR to the invertebrate NPSR-like and CCAPR. A site-specific analysis between the vertebrate NPSR and the well studied paralogous vasopressin-like receptor subtypes revealed several putative amino acid sites that may account for the observed functional divergence between them. The data can facilitate experimental studies aiming at deciphering the common features as well as those related to ligand binding and signal transduction processes specific to the NPSR.

The assessment and treatment of water imbalance in patients with psychosis.

Polydipsia and episodic life-threatening water intoxication remain important clinical problems for a significant portion of persons with schizophrenia. The disorders are associated with increased morbidity and mortality from a number of causes. With a basic understanding of the pathophysiology, one can easily diagnose and assess the clinical conditions. We review here the scope and pathophysiology of disordered water imbalance, including both primary and secondary polydipsia and hyponatremia. Reversible factors and possible interventions are reviewed. Treatment options for preventing water intoxication have expanded from discontinuation of offending agents, targeted fluid restriction, and clozapine therapy to the addition of oral vasopressin antagonists. The latter, however, are extremely potent and must be carefully monitored.

Evolution of a behavior-linked microsatellite-containing element in the 5' flanking region of the primate AVPR1A gene.

BACKGROUND: The arginine vasopressin V1a receptor (V1aR) modulates social cognition and behavior in a wide variety of species. Variation in a repetitive microsatellite element in the 5' flanking region of the V1aR gene (AVPR1A) in rodents has been associated with variation in brain V1aR expression and in social behavior. In humans, the 5' flanking region of AVPR1A contains a tandem duplication of two approximately 350 bp, microsatellite-containing elements located approximately 3.5 kb upstream of the transcription start site. The first block, referred to as DupA, contains a polymorphic (GT)25 microsatellite; the second block, DupB, has a complex (CT)4-(TT)-(CT)8-(GT)24 polymorphic motif, known as RS3. Polymorphisms in RS3 have been associated with variation in sociobehavioral traits in humans, including autism spectrum disorders. Thus, evolution of these regions may have contributed to variation in social behavior in primates. We examined the structure of these regions in six ape, six monkey, and one prosimian species. RESULTS: Both tandem repeat blocks are present upstream of the AVPR1A coding region in five of the ape species we investigated, while monkeys have only one copy of this region. As in humans, the microsatellites within DupA and DupB are polymorphic in many primate species. Furthermore, both single (lacking DupB) and duplicated alleles (containing both DupA and DupB) are present in chimpanzee (Pan troglodytes) populations with allele frequencies of 0.795 and 0.205 for the single and duplicated alleles, respectively, based on the analysis of 47 wild-caught individuals. Finally, a phylogenetic reconstruction suggests two alternate evolutionary histories for this locus. CONCLUSION: There is no obvious relationship between the presence of the RS3 duplication and social organization in primates. However, polymorphisms identified in some species may be useful in future genetic association studies. In particular, the presence of both single and duplicated alleles in chimpanzees provides a unique opportunity to assess the functional role of this duplication in contributing to variation in social behavior in primates. While our initial studies show no signs of directional selection on this locus in chimps, pharmacological and genetic association studies support a potential role for this region in influencing V1aR expression and social behavior.

Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA.

Human altruism is a widespread phenomenon that puzzled evolutionary biologists since Darwin. Economic games illustrate human altruism by showing that behavior deviates from economic predictions of profit maximization. A game that most plainly shows this altruistic tendency is the Dictator Game. We hypothesized that human altruistic behavior is to some extent hardwired and that a likely candidate that may contribute to individual differences in altruistic behavior is the arginine vasopressin 1a (AVPR1a) receptor that in some mammals such as the vole has a profound impact on affiliative behaviors. In the current investigation, 203 male and female university students played an online version of the Dictator Game, for real money payoffs. All subjects and their parents were genotyped for AVPR1a RS1 and RS3 promoter-region repeat polymorphisms. Parents did not participate in online game playing. As variation in the length of a repetitive element in the vole AVPR1a promoter region is associated with differences in social behavior, we examined the relationship between RS1 and RS3 repeat length (base pairs) and allocation sums. Participants with short versions (308-325 bp) of the AVPR1a RS3 repeat allocated significantly (likelihood ratio = 14.75, P = 0.001, df = 2) fewer shekels to the 'other' than participants with long versions (327-343 bp). We also implemented a family-based association test, UNPHASED, to confirm and validate the correlation between the AVPR1a RS3 repeat and monetary allocations in the dictator game. Dictator game allocations were significantly associated with the RS3 repeat (global P value: likelihood ratio chi(2) = 11.73, df = 4, P = 0.019). The association between the AVPR1a RS3 repeat and altruism was also confirmed using two self-report scales (the Bardi-Schwartz Universalism and Benevolence Value-expressive Behavior scales). RS3 long alleles were associated with higher scores on both measures. Finally, long AVPR1a RS3 repeats were associated with higher AVPR1a human post-mortem hippocampal messenger RNA levels than short RS3 repeats (one-way analysis of variance (ANOVA): F = 15.04, P = 0.001, df = 14) suggesting a functional molecular genetic basis for the observation that participants with the long RS3 repeats allocate more money than participants with the short repeats. This is the first investigation showing that a common human polymorphism, with antecedents in lower mammals, contributes to decision making in an economic game. The finding that the same gene contributing to social bonding in lower animals also appears to operate similarly in human behavior suggests a common evolutionary mechanism.

AVP receptor antagonists as aquaretics: review and assessment of clinical data.

The antidiuretic hormone arginine vasopressin (AVP) is primarily responsible for regulating osmotic and volume homeostasis of body fluids, largely through binding to vasopressin type 1A (V(1A)) and type 2 (V2) receptors. Increased AVP secretion leads to decreased free water excretion with resulting water retention, and can cause dilutional hyponatremia. A new class of medications known as AVP receptor antagonists induces free water diuresis without natriuresis or kaliuresis, an effect termed aquaresis. Numerous clinical trials show AVP antagonists to be effective at increasing free water excretion and serum sodium in patients with hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion or edema-forming states such as congestive heart failure and cirrhosis. This article reviews clinical trial data on the AVP antagonists in late development (lixivaptan, satavaptan, and tolvaptan) and recently approved for marketing (conivaptan).

Hyponatremia in the neurosurgical patient: epidemiology, pathophysiology, diagnosis, and management.

OBJECTIVE: Hyponatremia is an important and common electrolyte disorder in critically ill neurosurgical patients that has been reported in association with a number of different primary diagnoses. The correct diagnosis of the pathophysiological cause is vital because it dramatically alters the treatment approach. METHODS: We review the epidemiology and presentation of patients with hyponatremia, the pathophysiology of the disorder with respect to sodium and fluid balance, and the diagnostic procedures for determining the correct cause. RESULTS: We then present the various treatment options, including discussion of one of the newest groups of agents, the arginine vasopressin receptor antagonists, currently under study for the treatment of hyponatremia in neurosurgical patients. CONCLUSION: Hyponatremia is a serious comorbidity in neurosurgical patients that requires particular attention as its treatment varies by cause and its consequences can affect neurological outcome.

Treatment of congestive heart failure: present and future.

The treatment of patients with congestive heart failure has markedly improved over the past 25 years. The most successful therapy has been attenuation of neurohumoral overactivation with antagonists of the renin-angiotensin-aldosterone system, as well as beta-adrenergic blockade. Cardiac surgical interventions, which include not only aortocoronary artery bypass surgery but also interventions that remodel the heart and repair the mitral valve, have also been advocated. However, randomized clinical trials to prove their benefit and to identify which patients could derive the most benefit from these interventions are lacking. Cardiac devices, such as biventricular pacemakers (for cardiac resynchronization) and implantable cardiac defibrillators, have proved useful in improving survival and quality of life. The treatment of sleep apnea with continuous positive airway pressure has shown some promise, as has immune modulation therapy, but more research to conclusively prove their efficacy is necessary. Cell therapy with skeletal myoblasts or pluripotential stem cells is an interesting and emerging area of research that shows enormous promise. However, fundamental questions regarding the optimal use of this therapy remain unanswered. Finally, although exciting, these developments, along with the changing demographics of the Canadian population, will require a change in the way we provide care for patients with congestive heart failure. These changes will require greater involvement of health care professionals other than physicians, and greater emphasis on outpatient care, early detection and prevention, and evidence-based practice.

Vasopressin as a target for antidepressant development: an assessment of the available evidence.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the key biological abnormalities described in major depressive disorder, occurring in 30-50% of depressed subjects. Corticotropin-releasing hormone (CRH) and vasopressin (AVP) are the main regulators of this stress system, with the two neuropeptides acting synergistically in bringing about adrenocorticotropin (ACTH) release from the anterior pituitary and cortisol from the adrenal gland. Based on the demonstration of elevated cerebrospinal fluid levels of CRH in depressives, and other evidence, it has been postulated that excess CRH and the resultant increased HPA forward drive form the basis of neuroendocrine dysregulation in depression. However, there is an accumulating body of evidence to support a significant role for AVP in the regulation of pituitary-adrenal activity in health and also in depressive disorder. This review, based on a Medline search from 1980 to 2001, focuses on the functional neuroanatomy, receptor pharmacology, VP synergism with CRH, and the data from clinical and pre-clinical studies that support an important role for AVP in the pathophysiology of major depression. We suggest that future antidepressants may target the vasopressinergic system.

Facilitation of affiliation and pair-bond formation by vasopressin receptor gene transfer into the ventral forebrain of a monogamous vole.

Behaviors associated with monogamy, including pair-bond formation, are facilitated by the neuropeptide vasopressin and are prevented by a vasopressin receptor [V1a receptor (V1aR)] antagonist in the male prairie vole. The neuroanatomical distribution of V1aR dramatically differs between monogamous and nonmonogamous species. V1aR binding is denser in the ventral pallidal region of several unrelated monogamous species compared with nonmonogamous species. Because the ventral pallidum is involved in reinforcement and addiction, we hypothesize that V1aR activation in this region promotes pair-bond formation via a mechanism similar to conditioning. Using an adeno-associated viral vector to deliver the V1aR gene, we increased the density of V1aR binding in the ventral pallial region of male prairie voles. These males exhibited increased levels of both anxiety and affiliative behavior compared with control males. In addition, males overexpressing the V1aR in the ventral pallidal region, but not control males, formed strong partner preferences after an overnight cohabitation, without mating, with a female. These data demonstrate a role for ventral pallidal V1aR in affiliation and social attachment and provide a potential molecular mechanism for species differences in social organization.

Identification of the glycosylation sites utilized on the V1a vasopressin receptor and assessment of their role in receptor signalling and expression.

Most of the large family of G-protein-coupled receptors (GPCRs) possess putative N-glycosylation sites within their N-termini. However, for the vast majority of GPCRs, it has not been determined which, if any, of the consensus glycosylation sites are actually utilized or what the functional ramifications are of modification by oligosaccharide. The occurrence and function of glycosylation of the V(1a) vasopressin receptor (V(1a)R) has been investigated in this study. Using a combination of translation systems that are either glycosylation-competent or do not support glycosylation, we established that of the four putative N-glycosylation sites at Asn(14), Asn(27), Asn(198) and Asn(333) only the first three sites are actually modified by carbohydrate. This was confirmed by disruption of consensus sites by site-directed mutagenesis, individually and in combination. The V(1a)R is not O-glycosylated. The functionality of a series of glycosylation-defective V(1a)R constructs was characterized after expression in HEK 293T cells. It was found that carbohydrate moieties are not required for the receptor to bind any of the four classes of ligand available, or for intracellular signalling. The glycosylation status of the V(1a)R did, however, regulate the level of total receptor expression and also the abundance of receptor at the cell surface. Furthermore, the nature of this regulation (increased or decreased expression) was dictated by the locus of the oligosaccharide modification. Modification of any one of the consensus sites alone, however, was sufficient for wild-type expression, indicating a redundancy within the glycosylation sites. A role for the carbohydrate in the correct folding or stabilization of the V(1a)R is indicated. Glycosylation is not required, however, for efficient trafficking of the receptor to the cell surface. This study establishes the functional importance of N-glycosylation of the V(1a)R.

Bioavailability assessment of arginine-vasopressin (AVP) using pharmacokinetic-pharmacodynamic (PK-PD) modeling in the rat.

A novel method of assessing the extent of oral bioavailability of arginine-vasopressin (AVP) from pharmacological data was presented. After intravascular administration (i.v. bolus or short-term infusion) of AVP to rats, the relationship between blood concentrations and its effect on both mean arterial pressure (hemodynamic effect) and urinary sodium concentration (anti-diuretic effect) was described on the basis of an integrated pharmacokinetic-pharmacodynamic (PK-PD) model. A direct model was used for the hemodynamic response, while an indirect response model, rather than a hypothetical link model was used for the anti-diuretic response. A sigmoid Emax model was applied to describe the drug-receptor interaction. Pharmacological responses after intravascular administration of AVP were reasonably described by the PK-PD model. However, PD parameters estimated by the PK-PD analysis suggested that apparent receptor affinity rather than efficacy in i.v. bolus study was significantly higher than that in the short-term infusion study. This fact indicated that PK-PD relationship was influenced by the intravascular input rate of AVP. We then investigated the relationship between plasma concentration and amount of AVP bound to the V2 receptors in the kidney. The result indicated that the amount of AVP bound to the receptors after i.v. bolus injection was always greater than that after short-term infusion. Since the PK-PD relationship after oral administration was almost identical with that after short-term infusion, the PK-PD model obtained in the short-term infusion study was used to assess the extent of oral bioavailability (EBAPp.o.). The EBAp.o. values, estimated from pharmacological effects (hemodynamic effect and anti-diuretic effect) after oral administration of 5 microg/kg of AVP were 0.68% to 0.93% and were almost identical with the actual EBAPp.o. value (0.81%). From these results, we concluded that oral bioavailability of AVP was reasonably predicted by the PK-PD model, provided that appropriate pharmacological effects and appropriate intravascular dosing rate as a reference formulation are available. The method may be an alternative to methods based on plasma concentrations, when drug concentration cannot be measured and when appropriate pharmacological data are available.