Novel Measurement of the Neutron Magnetic Form Factor from A=3 Mirror Nuclei.

The electromagnetic form factors of the proton and neutron encode information on the spatial structure of their charge and magnetization distributions. While measurements of the proton are relatively straightforward, the lack of a free neutron target makes measurements of the neutron's electromagnetic structure more challenging and more sensitive to experimental or model-dependent uncertainties. Various experiments have attempted to extract the neutron form factors from scattering from the neutron in deuterium, with different techniques providing different, and sometimes large, systematic uncertainties. We present results from a novel measurement of the neutron magnetic form factor using quasielastic scattering from the mirror nuclei ^{3}H and ^{3}He, where the nuclear effects are larger than for deuterium but expected to largely cancel in the cross-section ratios. We extracted values of the neutron magnetic form factor for low-to-modest momentum transfer, 0.6

Revealing the short-range structure of the mirror nuclei 3H and 3He.

When protons and neutrons (nucleons) are bound into atomic nuclei, they are close enough to feel significant attraction, or repulsion, from the strong, short-distance part of the nucleon-nucleon interaction. These strong interactions lead to hard collisions between nucleons, generating pairs of highly energetic nucleons referred to as short-range correlations (SRCs). SRCs are an important but relatively poorly understood part of nuclear structure1-3, and mapping out the strength and the isospin structure (neutron-proton (np) versus proton-proton (pp) pairs) of these virtual excitations is thus critical input for modelling a range of nuclear, particle and astrophysics measurements3-5. Two-nucleon knockout or 'triple coincidence' reactions have been used to measure the relative contribution of np-SRCs and pp-SRCs by knocking out a proton from the SRC and detecting its partner nucleon (proton or neutron). These measurements6-8 have shown that SRCs are almost exclusively np pairs, but they had limited statistics and required large model-dependent final-state interaction corrections. Here we report on measurements using inclusive scattering from the mirror nuclei hydrogen-3 and helium-3 to extract the np/pp ratio of SRCs in systems with a mass number of three. We obtain a measure of the np/pp SRC ratio that is an order of magnitude more precise than previous experiments, and find a marked deviation from the near-total np dominance observed in heavy nuclei. This result implies an unexpected structure in the high-momentum wavefunction for hydrogen-3 and helium-3. Understanding these results will improve our understanding of the short-range part of the nucleon-nucleon interaction.

Precision Determination of the Neutral Weak Form Factor of

We report a precise measurement of the parity-violating (PV) asymmetry A_{PV} in the elastic scattering of longitudinally polarized electrons from ^{48}Ca. We measure A_{PV}=2668±106(stat)±40(syst) parts per billion, leading to an extraction of the neutral weak form factor F_{W}(q=0.8733 fm^{-1})=0.1304±0.0052(stat)±0.0020(syst) and the charge minus the weak form factor F_{ch}-F_{W}=0.0277±0.0055. The resulting neutron skin thickness R_{n}-R_{p}=0.121±0.026(exp)±0.024(model) fm is relatively thin yet consistent with many model calculations. The combined CREX and PREX results will have implications for future energy density functional calculations and on the density dependence of the symmetry energy of nuclear matter.

New Measurements of the Beam-Normal Single Spin Asymmetry in Elastic Electron Scattering over a Range of Spin-0 Nuclei.

We report precision determinations of the beam-normal single spin asymmetries (A_{n}) in the elastic scattering of 0.95 and 2.18 GeV electrons off ^{12}C, ^{40}Ca, ^{48}Ca, and ^{208}Pb at very forward angles where the most detailed theoretical calculations have been performed. The first measurements of A_{n} for ^{40}Ca and ^{48}Ca are found to be similar to that of ^{12}C, consistent with expectations and thus demonstrating the validity of theoretical calculations for nuclei with Z≤20. We also report A_{n} for ^{208}Pb at two new momentum transfers (Q^{2}) extending the previous measurement. Our new data confirm the surprising result previously reported, with all three data points showing significant disagreement with the results from the Z≤20 nuclei. These data confirm our basic understanding of the underlying dynamics that govern A_{n} for nuclei containing ≲50 nucleons, but point to the need for further investigation to understand the unusual A_{n} behavior discovered for scattering off ^{208}Pb.

Determination of the

We report the first measurement of the parity-violating elastic electron scattering asymmetry on ^{27}Al. The ^{27}Al elastic asymmetry is A_{PV}=2.16±0.11(stat)±0.16(syst) ppm, and was measured at ⟨Q^{2}⟩=0.02357±0.00010 GeV^{2}, ⟨θ_{lab}⟩=7.61°±0.02°, and ⟨E_{lab}⟩=1.157 GeV with the Q_{weak} apparatus at Jefferson Lab. Predictions using a simple Born approximation as well as more sophisticated distorted-wave calculations are in good agreement with this result. From this asymmetry the ^{27}Al neutron radius R_{n}=2.89±0.12 fm was determined using a many-models correlation technique. The corresponding neutron skin thickness R_{n}-R_{p}=-0.04±0.12 fm is small, as expected for a light nucleus with a neutron excess of only 1. This result thus serves as a successful benchmark for electroweak determinations of neutron radii on heavier nuclei. A tree-level approach was used to extract the ^{27}Al weak radius R_{w}=3.00±0.15 fm, and the weak skin thickness R_{wk}-R_{ch}=-0.04±0.15 fm. The weak form factor at this Q^{2} is F_{wk}=0.39±0.04.

Measurement of the Nucleon F_{2}

The ratio of the nucleon F_{2} structure functions, F_{2}^{n}/F_{2}^{p}, is determined by the MARATHON experiment from measurements of deep inelastic scattering of electrons from ^{3}H and ^{3}He nuclei. The experiment was performed in the Hall A Facility of Jefferson Lab using two high-resolution spectrometers for electron detection, and a cryogenic target system which included a low-activity tritium cell. The data analysis used a novel technique exploiting the mirror symmetry of the two nuclei, which essentially eliminates many theoretical uncertainties in the extraction of the ratio. The results, which cover the Bjorken scaling variable range 0.19

Measurement of Lepton-Jet Correlation in Deep-Inelastic Scattering with the H1 Detector Using Machine Learning for Unfolding.

The first measurement of lepton-jet momentum imbalance and azimuthal correlation in lepton-proton scattering at high momentum transfer is presented. These data, taken with the H1 detector at HERA, are corrected for detector effects using an unbinned machine learning algorithm (multifold), which considers eight observables simultaneously in this first application. The unfolded cross sections are compared with calculations performed within the context of collinear or transverse-momentum-dependent factorization in quantum chromodynamics as well as Monte Carlo event generators.

Accurate Determination of the Neutron Skin Thickness of

We report a precision measurement of the parity-violating asymmetry A_{PV} in the elastic scattering of longitudinally polarized electrons from ^{208}Pb. We measure A_{PV}=550±16(stat)±8(syst) parts per billion, leading to an extraction of the neutral weak form factor F_{W}(Q^{2}=0.00616 GeV^{2})=0.368±0.013. Combined with our previous measurement, the extracted neutron skin thickness is R_{n}-R_{p}=0.283±0.071 fm. The result also yields the first significant direct measurement of the interior weak density of ^{208}Pb: ρ_{W}^{0}=-0.0796±0.0036(exp)±0.0013(theo) fm^{-3} leading to the interior baryon density ρ_{b}^{0}=0.1480±0.0036(exp)±0.0013(theo) fm^{-3}. The measurement accurately constrains the density dependence of the symmetry energy of nuclear matter near saturation density, with implications for the size and composition of neutron stars.

Precision Measurement of the Beam-Normal Single-Spin Asymmetry in Forward-Angle Elastic Electron-Proton Scattering.

A beam-normal single-spin asymmetry generated in the scattering of transversely polarized electrons from unpolarized nucleons is an observable related to the imaginary part of the two-photon exchange process. We report a 2% precision measurement of the beam-normal single-spin asymmetry in elastic electron-proton scattering with a mean scattering angle of θ_{lab}=7.9° and a mean energy of 1.149 GeV. The asymmetry result is B_{n}=-5.194±0.067(stat)±0.082 (syst) ppm. This is the most precise measurement of this quantity available to date and therefore provides a stringent test of two-photon exchange models at far-forward scattering angles (θ_{lab}→0) where they should be most reliable.

Probing Few-Body Nuclear Dynamics via

We report the first measurement of the (e,e^{'}p) three-body breakup reaction cross sections in helium-3 (^{3}He) and tritium (^{3}H) at large momentum transfer [⟨Q^{2}⟩≈1.9 (GeV/c)^{2}] and x_{B}>1 kinematics, where the cross section should be sensitive to quasielastic (QE) scattering from single nucleons. The data cover missing momenta 40≤p_{miss}≤500 MeV/c that, in the QE limit with no rescattering, equals the initial momentum of the probed nucleon. The measured cross sections are compared with state-of-the-art ab initio calculations. Overall good agreement, within ±20%, is observed between data and calculations for the full p_{miss} range for ^{3}H and for 100≤p_{miss}≤350 MeV/c for ^{3}He. Including the effects of rescattering of the outgoing nucleon improves agreement with the data at p_{miss}>250 MeV/c and suggests contributions from charge-exchange (SCX) rescattering. The isoscalar sum of ^{3}He plus ^{3}H, which is largely insensitive to SCX, is described by calculations to within the accuracy of the data over the entire p_{miss} range. This validates current models of the ground state of the three-nucleon system up to very high initial nucleon momenta of 500 MeV/c.

[Impact of physical exercise in cystic fibrosis patients: A systematic review]. / Impact de l'exercice physique chez les patients atteints de mucoviscidose : revue systématique.

INTRODUCTION: Beneficial effects of physical exercise have been previously demonstrated in patients with chronic obstructive pulmonary disease. The aim of this systematic review was to summarize the evidence supporting physical exercise to improve on lung function, exercise capacity and quality of life in cystic fibrosis patients. METHODS: Medline database was used to search clinical studies from 2000 to 2015. We also analyzed the bibliographic section of the included studies, in order to identify additional references. RESULTS: A total of 17 studies were identified. A great disparity was found in the results of the different studies. No systematic benefit was found on lung function, exercise capacity or quality of life. No relationship between the type of program and the benefits achieved was observed. CONCLUSIONS: Evidence that physical exercise benefits lung function, exercise capacity and quality of life in cystic fibrosis patient is inconsistent and evidence does not support a particular standardized program for all patients.

Impact of adjuvant chemotherapy in stage IB non-small-cell lung cancer: an analysis of 112 consecutively treated patients.

PURPOSE: The impact of adjuvant chemotherapy (CT) in the management of radically resected stage IB non-small cell lung cancer (NSCLC) is highly debated. The aim of this study was to evaluate the outcome of this category of patients treated at our institution. METHODS: We retrospectively analysed the survival data of patients with pathologic stage IB NSCLC, who received at least 1 cycle of adjuvant CT. CT was planned to be platinum based and to be delivered for 6 cycles. RESULTS: One hundred and twelve consecutively treated patients were evaluated. PATIENT CHARACTERISTICS: median age 60 years, median tumor diameter 4 cm, 87% underwent lobectomy and 13% pneumonectomy, 58% had visceral pleural involvement (VPI). After a median follow up of 46 months, the estimated 5-year disease-free (DFS) and overall survival (OS) rates were 68% and 77%, respectively. The mean number of CT cycles was 5.2 (range 3-6), with 82% of patients receiving ≥ 5 cycles. The median cisplatin dose intensity (DI) was 22 mg/m(2)/week, and the relative DI was 85%. Median total cisplatin (CDDP) dose/patient was 416 mg/m(2). A total of 31 (27.6%) relapses were recorded, of which 81% were distant. Multivariate analysis showed no significant interaction between overall survival and the following variables: gender, type of surgery, histology, tumor volume, VPI. CONCLUSION: Our results compare favorably with the historical data evaluating the outcome of stage IB patients treated by surgery alone in a customary medical setting. Overall, our data support the use of adjuvant CT in stage IB NSCLC patients.

Calpain inhibition protected spinal cord motoneurons against 1-methyl-4-phenylpyridinium ion and rotenone.

Parkinson's disease (PD), characterized by selective midbrain nigrostriatal dopaminergic degeneration, is consistently associated with moderate systemic mitochondrial dysfunction. Downstream degeneration of spinal cord has also been suggested in PD, although the mechanisms have not been much investigated. In the present study, two mitochondrial toxicants, 1-methyl-4-phenylpyridinium ion (MPP(+)) and rotenone were tested in ventral spinal cord (VSC 4.1) motoneuronal cells. Cell death was assessed by morphological and biochemical means to discern a lower apoptosis-inducing concentration and lethal concentration of 50% cell death (LC(50)), which were subsequently compared in further cytoprotection experiments. Mitochondrial toxicants dose-dependently induced increase in intracellular free Ca(2+) level, which was conducive for increased expression and activities of Ca(2+)-activated neutral protease calpain and downstream caspase-3. Thus, mitochondrial damage triggered apoptotic mechanisms in spinal cord motoneurons. Inhibition of calpain by calpeptin significantly attenuated damaging effects of MPP(+) and rotenone on motoneurons, especially at low apoptosis-inducing concentrations of toxicants and partly at their LC(50), as demonstrated by absence of DNA ladder formation and decrease in terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells. Cytoprotection by calpeptin was observed with marked decreases in Bax: Bcl-2 ratio and activities of calpain and caspase-3, which affirmed the role of mitochondrial dysfunction and involvement of intrinsic pathway in mediation of apoptosis. These findings strongly suggested that parkinsonian toxicants MPP(+) and rotenone at low doses induced cascade of cell-damaging effects in spinal cord motoneurons, thus, highlighting the possibility of induction of apoptotic mechanisms in these cells, when subjected to mitochondrial stress. Cytoprotection rendered by calpeptin further validated the involvement of calpain in apoptosis and suggested calpain inhibition as a potential neuroprotective strategy.

Adjuvant therapy with aromatase inhibitors in postmenopausal, estrogen receptor- positive breast cancer patients: upfront or sequential?

For decades tamoxifen (TAM) has been the mainstay hormonal treatment for estrogen receptor positive (ER+) breast cancer patients. Nevertheless, during the last years, for postmenopausal women particularly, the third generation aromatase inhibitors (AI) became the preferred alternative. The results of the randomized trials showed that AI were superior to TAM in terms of efficacy, and were accompanied by a different but fairly convenient side effects profile. Subsequently, all updated guidelines recommend the use of AI in the adjuvant setting for this category of patients, either upfront, following 2-3 years of TAM or as extended adjuvant therapy, after 5 years of TAM. However, no consensus has been reached regarding the best strategy to be used, and the expert opinion is divided, based on the available evidence. The controversial aspect of whether AI should be used upfront or following 2-3 years of TAM is further detailed in this manuscript, and some useful recommendations are provided in order to facilitate the decision-making process during the current clinical practice.

Controversies around the use of monoclonal antibodies in the treatment of advanced non-small cell lung cancer.

First line combination chemotherapy (CT) using platinum-based doublets is established as a standard of care for advanced non-small cell lung cancer (NSCLC). Nevertheless, no significant advances have been recorded during the last years in this field. Therefore, there is a wide consensus among physicians that a plateau has already been reached with this strategy. Targeted therapy using tyrosine-kinase inhibitors (TKIs) and monoclonal antibodies emerged as a new field of development in the NSCLC therapeutics. Recently, the results of the phase III trials testing antibodies against vascular endothelial growth factor-VEGF (bevacizumab) and epidermal growth factor receptor-EGFR (cetuximab) challenged the paradigm of the platinum doublets as a gold standard in advanced NSCLC. Their appearance was enthusiastically commended both by patients and the oncological community. However, all medical oncologists have the responsibility to carefully analyze the real benefits of these new agents, to balance the advantages against the implicit risks of therapy and to make the decision having in mind the best interest of their patients. Last but not least, the associated health economic burden should also be considered. This paper addresses some issues related to the use of cetuximab and bevacizumab in advanced NSCLC. The main controversial aspects regarding patient selection, the real benefit of therapy, the molecular and clinical predictors, and the impact of other independent variables are carefully examined and presented. Due to many unsolved questions, no definite conclusions can be supported. The final decision about the optimal use of these agents is left to the clinical judgment of each treating physician.

Key amino acids located within the transmembrane domains 5 and 7 account for the pharmacological specificity of the human V1b vasopressin receptor.

In mammals, the vasopressin V(1b) receptor (V(1b)-R) is known to regulate ACTH secretion and, more recently, stress and anxiety. The characterization of the molecular determinant responsible for its pharmacological selectivity was made possible by the recent discovery of the first V(1b) antagonist, SSR149415. Based upon the structure of the crystallized bovine rhodopsin, we established a three-dimensional molecular model of interaction between the human V(1b)-R (hV(1b)-R) and SSR149415. Four amino acids located in distinct transmembrane helices (fourth, fifth, and seventh) were found potentially responsible for the hV(1b)-R selectivity. To validate these assumptions, we selectively replaced the leucine 181, methionine 220, alanine 334, and serine 338 residues of hV(1a)-R by their corresponding amino acids present in the hV(1b)-R (phenylalanine 164, threonine 203, methionine 324, and asparagine 328, respectively). Four mutants, which all exhibited nanomolar affinities for vasopressin and good coupling to phospholipase C pathway, were generated. hV(1a) receptors mutated at position 220 and 334 exhibited striking increase in affinity for SSR149415 both in binding and phospholipase C assays at variance with the hV(1a)-R modified at position 181 or 338. In conclusion, this study provides the first structural features concerning the hV(1b)-R and highlights the role of few specific residues in its pharmacological selectivity.

The discovery of novel vasopressin V1b receptor ligands for pharmacological, functional and structural investigations.

Until recently, pharmacological studies dealing with vasopressin receptor isoforms were severely hampered by the lack of selective agonists or antagonists that recognize the pituitary V(1b) vasopressin receptor. By contrast, many selective vasopressin-related compounds are available for characterization of the vasopressor (V(1a)) or antidiuretic (V(2)) vasopressin receptor subtypes. Recently, SSR149415, a selective nonpeptide molecule, was discovered with nanomolar affinity for mammalian V(1b) receptors and good selectivity for the other vasopressin and oxytocin receptor isoforms. This molecule exhibits potent antagonist properties both in vitro and in vivo. We also designed synthetic peptides derived from [deaminocysteine(1),arginine(8)]vasopressin (dAVP), modified in position 4 by various amino acid residues. Some of these, d[cyclohexylalanine(4)]AVP or d[lysine(4)]AVP, have a high affinity and an excellent selectivity for the human V(1b) receptor subtype. However, they exhibit a mixed V(1b)/V(2) pharmacological profile for the rat vasopressin receptor isoforms. Whatever the species considered, these peptides behave as agonists both in bioassays performed in vitro and in vivo. The d[cyclohexylalanine(4)]AVP was tritiated and represents the first selective radiolabelled ligand available for studying the human V(1b) receptors. The discovery of these new selective V(1b) agonists and V(1b) antagonist allows an accurate pharmacological characterization of all the vasopressin receptor isoforms. As emphasized in this review, attention to the vasopressin and oxytocin receptor species differences is of critical importance in studies with all vasopressin and oxytocin ligands.

Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands.

The involvement of vasopressin (AVP) in several pathological states has been reported recently and the selective blockade of the different AVP receptors could offer new clinical perspectives. During the past few years, various selective, orally active AVP V1a (OPC-21268, SR49059 (Relcovaptan)), V2 (OPC-31260, OPC-41061 (Tolvaptan), VPA-985 (Lixivaptan), SR121463, VP-343, FR-161282) and mixed V1a/V2 (YM-087 (Conivaptan), JTV-605, CL-385004) receptor antagonists have been intensively studied in various animal models and have reached, Phase IIb clinical trials for some of them. For many years now, our laboratory has focused on the identification of nonpeptide vasopressin antagonists with suitable oral bioavailability. Using random screening on small molecule libraries, followed by rational SAR and modelization, we identified a chemical series of 1-phenylsulfonylindolines which first yielded SR49059, a V1a receptor antagonist prototype. This compound displayed high affinity for animal and human V1a receptors and antagonized various V1a AVP-induced effects in vitro and in vivo (intracellular [Ca2+] increase, platelet aggregation, vascular smooth muscle cell proliferation, hypertension and coronary vasospasm). We and others have used this compound to study the role of AVP in various animal models. Recent findings from clinical trials show a potential interest for SR49059 in the treatment of dysmenorrhea and in Raynaud's disease. Structural modifications and simplifications performed in the SR49059 chemical series yielded highly specific V2 receptor antagonists (N-arylsulfonyl-oxindoles), amongst them SR121463 which possesses powerful oral aquaretic properties in various animal species and in man. SR121463 is well-tolerated and dose-dependently increases urine output and decreases urine osmolality. It induces free water-excretion without affecting electrolyte balance in contrast to classical diuretics (e.g. furosemide and hydrochlorothiazide). Notably, in cirrhotic rats with ascites and impaired renal function, a 10-day oral treatment with SR121463 (0.5 mg/kg) totally corrected hyponatremia and restored normal urine excretion. This compound also displayed interesting new properties in a rabbit model of ocular hypertension, decreasing intraocular pressure after single or repeated instillation. Thus, V2 receptor blockade could be of interest in several water-retaining diseases such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), liver cirrhosis and congestive heart failure and deserves to be widely explored. Finally, further chemical developments in the oxindole family have led to the first specific and orally active V1b receptor antagonists (with SSR149415 as a representative), an awaited class of drugs with expected therapeutic interest mainly in ACTH-secreting tumors and various emotional diseases such as stress-related disorders, anxiety and depression. However, from the recently described tissue localization for this receptor, we could also speculate on other unexpected uses. In conclusion, the development of AVP receptor antagonists is a field of intensive pharmacological and clinical investigation. Selective and orally active compounds are now available to give new insight into the pathophysiological role of AVP and to provide promising drugs.

An overview of SR121463, a selective non-peptide vasopressin V(2) receptor antagonist.

SR121463 is a selective, orally active, non-peptide antagonist of vasopressin (AVP) V(2) receptors with powerful aquaretic properties in various animal species and humans. SR121463 belongs to a new class of drugs, called aquaretics, which are capable of inducing free-water excretion without affecting electrolyte balance. SR121463 displays high affinity for animal and human V(2) receptors and exhibits a remarkably selective V(2) receptor profile. SR121463 and [(3)H]SR121463 are used, therefore, as selective probes for characterization and labeling of V(2) receptors. In various functional studies in vitro, SR121463 behaves as a potent antagonist. It inhibits AVP-stimulated human renal adenylyl cyclase and dDAVP (1-desamino, 8-D arginine-vasopressin)-induced relaxation of rat aorta. SR121463 also behaves as an inverse agonist in cells expressing a constitutively activated human V(2) receptor mutant. In vitro, SR121463 rescued misfolded V(2) AVP receptor mutants by increasing cell surface expression and restoring V(2) function. In normally hydrated conscious rats, dogs and monkeys, SR121463, by either i.v. or p.o. administration, induced a dose-dependent aquaresis with no major changes in urinary Na+ and K+ excretion (unlike classical diuretics). In cirrhotic rats with ascites and impaired renal function, a 10-day treatment with SR121463 totally corrected hyponatremia and restored normal urine excretion. In a model of diabetic nephropathy in rats, SR121463 strongly reduced albumin excretion. SR121463 was also effective at extrarenal V(2) (or V(2)-like) receptors involved in vascular relaxation or clotting factor release in vitro and in vivo. In the rabbit model of ocular hypertension, SR121463 by either single or repeated instillation, decreased intraocular pressure. After acute and chronic administration to rats, dogs or healthy human volunteers, SR121463 was well absorbed and well tolerated. In all species studied the drug produced pronounced aquaresis without any agonist effect. Thus, SR121463 is a potent, orally active and selective antagonist at V(2) receptors with powerful aquaretic properties. It is a useful tool for further exploration of function of renal or extrarenal V(2) receptors. Pure V(2) receptor antagonists are likely to be therapeutically useful in several water-retaining diseases such as hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), congestive heart failure, liver cirrhosis, and other disorders possibly mediated by V(2) receptors (e.g., glaucoma).

A nonpeptide vasopressin V(1a) receptor antagonist, SR 49059, does not prevent cisplatin-induced emesis in piglets.

We determined the pharmacological and the antiemetic properties of SR 49059, a selective nonpeptide V(1a) receptor antagonist, on cisplatin-induced emesis in the piglet. Firstly, we clearly demonstrate that SR 49059 is a potent V(1a) receptor antagonist in vitro and in vivo in the piglet. In binding studies, [3H]-SR 49059 exhibited high affinity for V(1a) receptors in piglet liver membranes (K(d) of 0.76 +/- 0.12 nM and B(max) of 138 +/- 22 fmol/mg prot.). In vivo, in decerebrate piglets, SR 49059 (1 mg/kg iv) antagonized AVP (500 ng/kg iv)-induced hypertension for at least 150 min and also blocked, for at least 270 min at 3 mg/kg iv, the pressor responses to exogenous LVP. After single and repeated iv or icv administration, we studied the antiemetic properties of SR 49059 on cisplatin-induced emesis in piglets. Animals receiving an emetic dose of cisplatin (5.5 mg/kg, iv) were observed continuously for 60 h. Piglets acting as controls were iv administered with vehicle 15 min prior to cisplatin infusion (T0(-15min)), while experimental animals received a single iv administration of SR 49059 at the dose of 1 or 3 mg/kg. In additional piglets, we administered SR 49059 (3 mg/kg) every 12 h from T0(-15min) to T48(-15min) (cumulative dose, 15 mg/kg). Another set of animals - observed only during the acute phase - was administered with SR 49059 (10 mg/kg) every 3 h from T0(-15min) to T15(-15min) (cumulative dose, 60 mg/kg). Lastly, 10 piglets were given a bilateral icv injection of SR 49059 (500 microg and 1500 microg/side) 1 h prior to cisplatin infusion. In all groups treated with SR 49059, the latency of the first emetic episode and the incidence of vomiting during the acute, the delayed and the cumulative phases remained statistically similar to that observed in controls, suggesting that V(1a) receptors are not involved in the onset and completion of nausea and vomiting.