Low volumetric bone density is a risk factor for early complications after spine fusion surgery.

This study aims to investigate lumbar spine (LS) volumetric bone density (vBMD) as a risk factor for complications (pseudoarthrosis, instrumentation failure, adjacent fractures), re-operation, and time to complication after fusion. INTRODUCTION: Lumbar spine (LS) fusion surgery is increasingly performed worldwide. Complications after fusion result in significant morbidity and healthcare costs. Multiple factors, including osteoporosis, have been suggested to contribute to risk of complications and re-operation. However, most studies have used DXA, which is subject to artifact in patients with spine pathology, and none have investigated the relationship between BMD and timing of post-operative complications. This study aims to investigate LS volumetric bone density (vBMD) as a risk factor for complications (pseudoarthrosis, instrumentation failure, adjacent fractures), re-operation, and time to complication after fusion. METHODS: We evaluated a cohort of 359 patients who had initial LS fusion surgery at our institution, had pre-operative LS CTs and post-operative imaging available for review. Demographic factors, smoking status, vBMD, and details of surgical procedure were related to likelihood and timing of post-operative complications. RESULTS: Mean age was 60 ± 14 years, vBMD 122 ± 37 g/cm3. Median follow-up was 11 months. Skeletal complications occurred in 47 patients (13%); 34 patients (10%) required re-operation. Low vBMD (directly measured and estimated using HU) and smoking were associated with increased risk of skeletal complications. Each increase in baseline vBMD of 10 g/cm3 decreased the complication hazard and increased the complication-free duration in time-to-event analysis (hazard ratio 0.91, 95% CI 0.83-0.98, p < 0.02). CONCLUSIONS: Low vBMD was a significant risk factor for early post-operative complications in patients undergoing LS fusion. Prospective studies are needed to confirm these findings and to elucidate the optimal timing for follow-up and strategies for prevention of post-operative complications in this population.

Anabolic agents: what is beyond osteoporosis?

Osteoporosis is a common skeletal disorder characterized by low bone mass, which leads to reduced bone strength and an increased risk of fractures. Anabolic agents have been shown to improve bone mass and decrease fracture risk in osteoporosis patients by directly stimulating osteoblasts to produce new bone. Currently, two anabolic agents are available in the USA: recombinantly produced teriparatide (TPTD), which is the fully active (1-34) amino active sequence of human parathyroid hormone (PTH), and abaloparatide (APTD), a synthetic analog of parathyroid hormone-related peptide (PTHrP). At present, both agents are approved only for treatment of patients with osteoporosis at high risk of fracture. Nonetheless, their anabolic properties have led to off-label application in additional settings which include spine fusion, osteonecrosis of the jaw, arthroplasty, and fracture healing. In this article, we summarize available scientific literature regarding the efficacy, effectiveness, and safety of TPTD in these off-label settings.

Intellectual Disability Policy as Developed, Expressed, and Evaluated in AAIDD/The Arc Joint Statements: The Role of Organization Position Statements.

The American Association on Intellectual and Developmental Disabilities (AAIDD) and The Arc of the United States (The Arc) have a long history of joined efforts to develop, express, and evaluate disability policies. These efforts have resulted in a series of formal statements on critical issues such as education, healthcare, human rights, and criminal justice. Their joint efforts further important policy goals including providing clear strong communication about important policy values and directions, promulgating key principles of high quality supports and services, affirming best professional practices, and emphasizing personal outcomes. In addition, the joint efforts (a) affirm important aspects of organization identity; (b) enhance the organizations' abilities to assure the input of a wide variety of perspectives; (c) engage members' expanded ranges of experiences and talents; (d) multiply staff and leadership resources; (e) increase communication strength and avenues; and (f) establish processes for timely review and revision of policies as critical disability issues arise or change, and new opportunities for policy integration and advancement occur. This article describes the processes used to develop, express, and evaluate the position statements; summarizes the policy content of several joint statements; and discusses the role of these organization position statements.

[Common genital infections]. / Les infections gynécologiques courantes.

Vulvo-vaginal infections are frequently encountered by gynecologists and general practitioners. The diagnosis and the recurrence of these affections must lead to a discussion about sexually transmitted disease, notably when trichomonas vaginalis and herpetic infections are found. Even if they do not correspond to classical sexually transmitted diseases, their prevalence is increased by sexual intercourses reports and the number of partners which should also be treated. It is necessary to document the responsible germs, even in case of recurrence as more and more resistance to usual treatments are found together with the appearance of new germs like Candida glabrata.

Les infections vulvo-vaginales sont des affections fréquemment rencontrées par les gynécologues et les médecins généralistes. Leur apparition et leur récurrence doivent amener à une discussion quant au dépistage des maladies sexuellement transmises (MST), notamment lorsqu'il s'agit d'infections par trichomonas vaginalis et herpès. En effet, même si elles ne font pas partie des MST à proprement parler, leur prévalence est augmentée avec le nombre de rapports sexuels et le nombre de partenaires ; ceux-ci doivent également être traités. Il est nécessaire de documenter les infections primaires, mais également les récurrences parce que de plus en plus de résistances aux traitements habituels sont observées de même que de nouveaux types de germes comme les Candida glabrata.

3.0-Tesla MRI and arthroscopy for assessment of knee articular cartilage lesions.

The purpose of this study was to evaluate the ability of 3.0-Tesla magnetic resonance imaging (MRI) to accurately assess knee articular cartilage lesions. Sixteen patients who had knee 3.0-T MRI and underwent knee arthroscopy for partial meniscectomy were included. Three fellowship-trained sports medicine orthopedic surgeons reviewed all images. Articular lesions on MRI were graded from I to IV and compared with arthroscopic grading using the Outerbridge and the International Cartilage Repair Society (ICRS) classifications. The articular surface was divided into 6 regions. Based on MRI findings, of the 288 articular surface evaluations, 113 (39%) surface evaluations were classified as disease-positive (grade 2 to 4). Kappa interrater reliability scores for MRI evaluation, Outerbridge classification, and ICRS classification were 0.13, 0.54, and 0.41, respectively. Using the Outerbridge classification as a reference standard, the sensitivity, specificity, and accuracy were 57%, 71%, and 63%, respectively. Using the ICRS classification, sensitivity, specificity, and accuracy were 59%, 71%, and 69%, respectively. When isolating the articular grading to the senior author on MRI evaluation vs Outerbridge classification, the sensitivity, specificity, and accuracy were 54%, 92%, and 75%, respectively. Based on the current findings, 3.0-T MRI is as an invaluable noninvasive tool with good diagnostic value for assessing articular cartilage lesions of the knee, although it may not be as sensitive and accurate as previously reported.

Caspase-1 level is higher in the scalp in androgenetic alopecia.

BACKGROUND AND OBJECTIVES: Inflammasomes that activate caspase-1 govern the innate immune inflammatory response. Whether hair loss associated with androgenetic alopecia (AGA) involves caspase-1 activation is not known. METHODS: Immunohistochemical staining for caspase-1 was performed on scalp tissue sections, and protein lysates were analyzed from individuals with AGA (no treatment), and individuals with AGA taking finasteride with apparent hair growth, individuals with AGA taking finasteride without noted hair growth, and normal controls. In vitro studies of human keratinocytes were conducted to establish effects of finasteride, dihydrotestosterone (DHT), and testosterone on caspase-1 levels using immunoblot analysis. RESULTS: Caspase-1 is expressed in normal human adult epidermal keratinocytes. Caspase-1 expression is greater in men with AGA. In contrast, in men taking finasteride, caspase-1 levels were lower and were similar to those in normal controls. In vitro studies showed that keratinocytes treated with finasteride in combination with testosterone or DHT resulted in a significant decrease in caspase-1 expression. CONCLUSION: In vivo and in vitro finasteride treatment resulted in lower caspase-1 expression, supporting the idea that androgens influence innate immunity involved in the hair cycle in AGA. These findings may provide a basis for development of novel treatments for inflammatory skin and hair diseases.

Event-based stormwater quality and quantity loadings from elevated urban infrastructure affected by transportation.

Urban-rainfall runoff affected by transportation is a complex matrix of a very wide gradation of particulate matter (< 1 to > 10 000 microm) and dissolved inorganic and organic constituents. Particulate matter transported by rainfall runoff can be a significant vector for many reactive particulate-bound constituents, particularly metal elements. The water quality and hydrology of nine events from a representative elevated section of Interstate 10 (I-10) (eastbound average daily traffic load of 70 400 vehicles) in Baton Rouge, Louisiana, were characterized and compared with respect to the passage of each hydrograph. Residence time on the paved concrete surface was less than 30 minutes for all events. Results indicate that event-mean concentrations (EMCs) of particulate matter as total-suspended solids (TSS) (138 to 561 mg/L) and chemical-oxygen demand (COD) (128 to 1440 mg/L) were greater than those found in untreated municipal wastewater from the same service area. Particulate-matter dissolution and COD partitioned as a function of pH, pavement residence time, and organic content. In general, delivery of mass for aggregate indices, such as particulate matter (measured as TSS) and COD mass, were driven by the hydrology of the event, while concentrations of aggregate-constituent measurements, such as total-dissolved solids (TDS), illustrated an exponential-type decline during the rising limb of the hydrograph. Despite the short residence times, wide solids gradation, partitioning, and complexity of the rainfall-runoff chemistry, conductivity and dissolved solids were strongly correlated. Characterization of the transport and loads of constituents in urban-rainfall runoff, as a function of hydrology, is a necessary first step when considering treatability, structural or nonstructural controls, and mass trading for discharges from paved infrastructure.

Outcome of cats with diarrhea and Tritrichomonas foetus infection.

OBJECTIVE: To determine the long-term outcome of cats infected with Tritrichomonas foetus and identify treatment and management strategies influencing resolution of infection or associated diarrhea. DESIGN: Prospective study. SAMPLE POPULATION: 26 cats with T. foetus-associated diarrhea at least 22 months prior to the study. PROCEDURE: A standardized survey regarding clinical course and management was administered to owners of cats with T. foetus infection and associated diarrhea. Fecal samples were obtained from each cat; the presence of T. foetus was assessed via microscopic examination of smears, culture in commercial media, and polymerase chain reaction amplification of T. foetus rDNA involving species-specific primers. RESULTS: Survey responses were obtained from owners of all 26 cats. Twenty-three cats had complete resolution of diarrhea a median of 9 months after onset. Analysis of fecal samples obtained from 22 cats revealed persistent T. foetus infection in 12, with a median of 39 months after resolution of diarrhea. History of implementation of a dietary change, treatment with paromomycin, or higher numbers of cats in the household was associated with significantly longer duration of time to resolution of diarrhea. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested chronic T. foetus-associated diarrhea in most cats is likely to resolve spontaneously within 2 years of onset. Chronic infection with T. foetus (without clinical signs) after resolution of diarrhea appears to be common. Although often temporarily effective in decreasing severity of diarrhea, attempts to treat cats with T. foetus infection may result in prolongation of time to resolution of diarrhea.

A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris.

Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial with a potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function.

Percutaneous ultrasound-guided cholecystocentesis in healthy cats.

Percutaneous ultrasound-guided cholecystocentesis (PUC) is a minimally invasive technique for bile collection that is used successfully in human patients with cholecystitis. Its use in veterinary medicine for evaluation of hepatobiliary disorders has been limited because of the perceived unacceptable risk of bile peritonitis. An experimental study was conducted to evaluate the safety and efficacy of PUC, to collect data on bile cytology and bacteriologic culture, and to attempt to isolate Helicobacter spp. from the bile of healthy cats. In fasted and sedated cats, PUC was performed with a 22-gauge 1.5-in. (3.81 cm) needle with an attached 12-mL syringe via a right-sided transhepatic approach (n = 1) or into the fundus of the gallbladder (n = 11) via a right ventral abdominal approach. An attempt was made to completely empty the gallbladder. A small amount of abdominal effusion, consistent with bile or blood, was seen ultrasonographically immediately after aspiration in the 1st cat. Ultrasonographic complications with the 2nd technique were not observed in the remaining 11 cats. Decreased appetite and evidence of mild abdominal pain were detected in 4 cats within 2 days after PUC. The mean neutrophil count increased 2 days after PUC (P < .01) but remained within the reference range. The bile was acellular in 11 of 12 cats, and aerobic, anaerobic, and Helicobacter spp. cultures yielded no growth in 12 of 12 cats. There were no remarkable gross or histologic lesions of abdominal organs at the postmortem examination (8 cats) performed 7-8 days after the procedure. PUC appears to be a safe and technically simple procedure. Further studies are warranted to determine the use and safety of PUC in cats with hepatobiliary diseases.

Use of a commercially available culture system for diagnosis of Tritrichomonas foetus infection in cats.

OBJECTIVE: To evaluate the efficacy of and optimize a commercially available culture system for sensitive and specific in-clinic culture of Tritrichomonas foetus from cat feces. DESIGN: Prospective study. SAMPLE POPULATION: Samples of freshly voided feces from 117 purebred cats and pure cultures of T. foetus obtained from a cat with chronic diarrhea. PROCEDURE: Optimal conditions for use of the culture system, such as quantity of fecal inoculum (0.025 to 0.2 g) and cultivation temperature (25 or 37 degrees C [98.6 or 77.0 degrees F]), were determined. Specificity of the system was examined by attempted culture of Giardia lamblia and Pentatrichomonas hominis. Sensitivity of the system to detect T. foetus was determined by inoculation of culture system pouches with serially diluted T. foetus suspensions with and without feces. RESULTS: Detection limit of the culture system was 1 and 1,000 T. foetus organisms without and with feces from cats, respectively. Optimal fecal inoculum was < 0.1 g of feces. At 37 degrees C, cultures yielded positive results in 24 hours; organisms remained viable for 1 to 6 days, and bacterial overgrowth was common. At 25 degrees C, cultures yielded positive results in 1 to 11 days; organisms were long-lived, and bacterial overgrowth was uncommon. Neither G. lamblia or P. hominis survived in the culture system. CONCLUSIONS AND CLINICAL RELEVANCE: The culture system was sensitive and specific for culture of T. foetus in feces of cats. Performance was optimal when test kits were inoculated with < or = 0.1 g of freshly voided feces and cultured at 25 degrees C.

Effects of finasteride on apoptosis and regulation of the human hair cycle.

BACKGROUND: A number of studies have provided evidence that apoptosis is a central element in the regulation of hair follicle regression. In androgenetic alopecia (AGA), the exact location and control of key players in the apoptotic pathways remains obscure. OBJECTIVE: In the present study, we used a panel of antibodies and investigated the spatial and cellular pattern of expression of caspases and inhibitors of apoptosis (IAPs), such as XIAP and FLIP, in men with normal scalp and in men with AGA before and after 6 months of treatment with 1 mg oral finasteride treatment. METHODS AND RESULTS: Constitutive expression of caspases-1, -3, -8, and -9 and XIAP was detected predominantly within the isthmic and infundibular hair follicle area, basilar layer of the epidermis, and eccrine and sebaceous glands. AGA-affected tissues showed an increase in caspase (-1, -3, -6, -9) immunoreactivity with a concomitant decrease in XIAP staining. After 6 months of finasteride treatment, both caspases and XIAP were similar to levels exhibited by normal subjects. Immunoblot analysis was performed to determine antibody specificity and cellular expression of caspases. Purified populations of keratinocytes, melanocytes, dermal papilla, and dermal fibroblasts derived from human hair follicles were cultured in vitro and treated with 0.5 mm staurosporin. Time-course experiments revealed that processing of caspase-3 is a principal event during apoptosis of these hair cell types. CONCLUSION: These data suggest that alterations in levels of caspases and IAPs regulate hair follicle homeostasis. Moreover, finasteride appears to influence caspase and XIAP expression in hair follicle cells thus signaling anagen, active growth in the hair cycle.

Reduction of sound transmission into a circular cylindrical shell using distributed vibration absorbers and Helmholtz resonators.

A modal expansion method is used to model a cylindrical enclosure excited by an external plane wave. A set of distributed vibration absorbers (DVAs) and Helmholtz resonators (HRs) are applied to the structure to control the interior acoustic levels. Using an impedance matching method, the structure, the acoustic cavity, and the noise reduction devices are fully coupled to yield an analytical formulation of the structural kinetic energy and acoustic potential energy of a treated cylindrical cavity. Lightweight DVAs and small HRs tuned to the natural frequencies of the targeted structural and acoustic modes, respectively, result in significant acoustic and structural attenuation when the devices are optimally damped. Simulations show that significant interior noise reduction can only be achieved by adding damping to both structural and acoustic modes, which are resonant in the frequency bandwidth of interest. In order to be independent of the azimuth angle of the excitation and to avoid unwanted modal interactions, the devices are distributed evenly around the cylinder in rings. This treatment can only achieve good performance if the structure and the acoustic cavity are lightly damped.

Characterization and localization of leptin receptors in the rat kidney.

Characterization and localization of leptin binding sites were investigated in rat kidneys using [125I]leptin as a ligand. [125I]Leptin specific binding was found in high amounts in rat renomedullary membranes. This binding was specific, saturable, time-dependent (K(obs) = 0.055 +/- 0.008 min(-1)) and the dissociation of receptor-bound ligand was slowly reversible (K(-1) = 0.048 +/- 0.013 min(-1)). From saturation experiments, a single class of high-affinity binding sites for leptin was identified with an apparent K(d) of 0.57 +/- 0.14 nM and a B(max) of 45 +/- 10 fmol/mg protein. [125I]Leptin binding was inhibited in a dose-dependent manner by cold leptin and was highly selective since not displaceable by a number of other hormones or peptides. Autoradiographic experiments performed on adult rat kidney sections showed the intense presence of [125I]leptin receptors only in specific areas of the renal inner medulla and also consistent labeling associated with vascular structures in the corticomedullary region. The study of the postnatal developmental expression of leptin receptors in the kidney showed very low expression during the early postnatal period (8-21 days). Full expression of leptin sites was achieved at about 30 days and remained stable throughout adulthood (60 days and upwards). Moreover, in vivo administration of leptin (0.5 mg/kg i.p.) induced a significant and rapid diuretic effect in normally hydrated conscious rats. Thus, these data constitute the first characterization and mapping of [125I]leptin specific binding sites in the rat kidney and raise the possibility of a renal control by leptin.

Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist.

SR 121463A, a potent and selective, orally active, nonpeptide vasopressin V2 receptor antagonist, has been characterized in several in vitro and in vivo models. This compound displayed highly competitive and selective affinity for V2 receptors in rat, bovine and human kidney (0.6 < or = Ki [nM] < or = 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopressin (AVP)-stimulated adenylyl cyclase activity (Ki = 0.26+/-0.04 nM) without any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [3H]AVP labeling especially in the medullo-papillary region and confirmed that it is a suitable tool for mapping V2 receptors. In comparison, the nonpeptide V2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V2 receptors and lower efficacy to inhibit vasopressin-stimulated adenylyl cyclase (Ki in the 10 nanomolar range). Moreover, OPC-31260 exhibited a poor V2 selectivity profile and can be considered as a V2/V1a ligand. In normally hydrated conscious rats, SR 121463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) or oral (0.03-10 mg/kg) administration. The effect was dose-dependent and lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a similar aquaretic profile but with markedly lower oral efficacy. The action of SR 121463A was purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattleboro rats. Thus, SR 121463A is the most potent and selective, orally active V2 antagonist yet described and could be a powerful tool for exploring V2 receptors and the therapeutical usefulness of V2 blocker aquaretic agents in water-retaining diseases.

Autoradiographic localization of vasopressin V1a receptors in the rat kidney using [3H]-SR 49059.

Localization and characterization of binding sites of the selective non-peptide vasopressin receptor V1a ligand, [3H]-SR 49059, were investigated in the adult rat kidney by quantitative autoradiography using a fast-detecting radioluminographic phosphor-imaging plate system. [3H]-SR 49059, like the other V1a ligands used, showed a total absence of binding in the papilla, discrete and sparse labeling in the cortex and maximal binding in the outer part of the inner medulla. This labeling seemed to be mainly associated with medullary interstitial cells and vascular elements of the vasa recta. Conversely, [3H]-AVP intensely labeled the V2-enriched medulla-papillary portion of the kidney and, to a lesser extent, the cortical structures. [3H]-SR 49059 binding, quantified in the outer part of the inner medulla in rat kidney sections, was time-dependent, reversible, saturable and a single class of high affinity binding sites (Kd = 1.48 +/- 0.16 nM) was identified. The relative potencies of the reference peptide and non-peptide compounds to inhibit [3H]-SR 49059 binding confirm the V1a nature of the site and the stereospecificity of this binding. Thus, [3H]-SR 49059 allows the mapping and characterization of the V1a receptor population present in the rat kidney. The stability and the highly selective affinity of this non-peptide ligand for rat and human V1a receptors make it a suitable probe for the localization of V1a receptors in organs expressing heterogeneous populations of receptors.

SR 120819A, an orally-active and selective neuropeptide Y Y1 receptor antagonist.

An orally-active antagonist of neuropeptide Y (NPY) Y1 receptors, SR 120819A, has been characterized. This compound displays highly selective and competitive affinity for rat, guinea-pig and human (Ki = 15 nM) NPY Y1 receptors. In vitro, SR 120819A blocks the inhibitory effect of NPY on adenylyl cyclase activity in human SK-N-MC cells and that of the selective Y1 agonist, [Leu31,Pro34]NPY, on rabbit vas deferens contraction (pA2 = 7.20 +/- 0.07). In vivo, by intravenous route, this compound acts as an antagonist in anesthetized guinea-pigs and, notably, after oral administration, SR 120819A counteracts the pressor response of [Leu31,Pro34]NPY (5 micrograms/kg i.v.) with a long duration of action (> 4 h at 5 mg/kg p.o.). Thus, SR 120819A is the first orally-effective NPY Y1 receptor antagonist yet described. It could be a useful tool for exploring the role of NPY and the therapeutic relevance of an antagonist at NPY Y1 receptors.

Effect of SR-49059, a vasopressin V1a antagonist, on human vascular smooth muscle cells.

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)

Binding of [3H] SR 49059, a potent nonpeptide vasopressin V1a antagonist, to rat and human liver membranes.

The new potent and selective nonpeptide vasopressin V1a antagonist, SR 49059, was tritiated and used for the characterization of rat and human liver AVP V1a receptors. Binding of [3H] SR 49059 was time-dependent, reversible and saturable. A single class of high affinity binding sites was identified with Kd values of 0.63 +/- 0.13 and 2.95 +/- 0.64 nM, in rat and human liver membranes, respectively. The maximal binding capacity (Bmax) was about 7 times higher in rat than in human liver preparations. The relative potencies of several AVP/oxytocin agonists or antagonists to inhibit [3H] SR 49059 binding confirmed that this ligand labeled a homogeneous population of sites with the expected AVP V1a profile. Furthermore, [3H] SR 49059 or unlabeled SR 49059 displayed only slight species differences between rat and human V1a receptors, whereas OPC-21268, another nonpeptide V1a antagonist, exhibited a high species-related potency with more than 500 fold higher affinity for rat than for human liver V1a receptors. Thus, [3H] SR 49059 is the first nonpeptide AVP V1a ligand reported having highly specific activity, stability, specificity and affinity. This makes it a suitable probe for labeling AVP V1a receptors in rat and also in human tissues.