Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs?

The management of premature birth still remains unsatisfactory. Since the relative lack of efficiency and/or safety of current tocolytic agents have been highlighted, it is necessary to develop new uterorelaxant drugs deprived of important maternal and foetal side effects. Our work reported in this review focuses on a potential new target for tocolytic drugs, the β3-adrenoceptor (ADRB3). This third type of ADRB is shown to be present and functional in human myometrium. We demonstrated that ADRB3 agonists are able to inhibit in-vitro spontaneous contractions of myometrial strips, via a cyclic AMP-mediated pathway. Furthermore, we established that ADRB3 is the predominant subtype over the ADRB2 in human myometrium and that its expression is increased in near-term myometrium, compared to non-pregnant myometrium. Finally, we reported that contrary to ADRB2, the human myometrial ADRB3 is resistant to long-term agonist-induced desensitisation. These compelling data confirm the clinical potential interest of ADRB3 agonists in the pharmacological management of preterm labour

Le récepteur b3-adrénergique du muscle lisse utérin humain (une cible potentielle d'agents tocolytiques)

PARIS-BIUP (751062107) / SudocSudocFranceF

Ketanserin and Naftopidil Enhance the Potentiating Effect of Alpha-Methyl-Serotonin on the Neurally-Induced Contraction of Human Isolated Urinary Bladder Muscle Strips

Purpose The aim of this study was to assess the potential involvement of a specific subtype of 5-hydroxytryptamine (5-HT), 5HT2 receptors in neurally-induced contractions of the human detrusor. Methods Contractile responses to electrical field stimulation (EFS) were examined in human isolated urinary bladder muscle strips. The potentiation of EFS-induced detrusor contraction was examined by adding cumulative concentrations of a 5-HT and 5-HT2 receptor agonist, α-methyl-serotonin (α-Me-5-HT) (1nM–100μM) in the presence or absence of a 5-HT2 antagonist, ketanserin (5-HT2A>5-HT2C) or naftopidil (5-HT2B>5-HT2A) (0.3–3μM). Results 5-HT and α-Me-5-HT potentiated EFS-induced contraction with a maximal effect (Emax) of 37.6% and 38.6%, respectively, and with pEC50 (negative logarithm of the concentration required for a half-maximal response to an agonist) values of 8.3 and 6.8, respectively. Neither ketanserin nor naftopidil at any concentration produced a rightward displacement of the α-Me-5-HT concentration response curve. Instead, the Emax of α-Me-5-HT increased in the presence of ketanserin at 0.3–1μM and in the presence of naftopidil at 1μM to 51% and 56%, respectively, while the Emax in the presence of vehicle alone was 36%. The highest concentration (3μM) of either drug, however, fully reversed the enhancement. Conclusions The potentiating effect of α-Me-5-HT on neurally-induced contraction of human urinary bladder muscle strips was not found to be mediated via any 5-HT2 receptor subtypes. The underlying mechanism for the enhancement of the α-Me-5-HT potentiating effect on detrusor contractility by ketanserin and naftopidil remains unknown; however, our results suggest that these drugs may be useful for treating contractile dysfunction of the detrusor, as manifested in conditions such as underactive bladder

Stream chemical dynamic and metal accumulation in a temperate watershed affected by agricultural practices (Penzé, NW France)

RationaleUnderstanding the fate of metals in agricultural land is an important issue for agronomic sustainability. This study aimed at quantifying the export/retention of metals in a temperate watershed subject to important manuring activities. MethodsThe chemical composition of the Penze stream was examined at high resolution during a 1-year study in 2012. After immediate on-site filtration, here demonstrated as necessary to avoid modification of the dissolved-particulate partition, the concentrations of 21 elements were determined using inductively coupled plasma (ICP) optical emission spectrometry and ICP mass spectrometry. This dataset was extended with the local atmospheric deposition of several metals (Cd, Cr, Cu, Pb, Ni and Zn) monitored on a monthly basis. ResultsTwo groups were distinguished according to the evolution of the concentrations during floods. Some major cations (Na, Ca, Mg, Sr, K, Ba) and nitrate followed counter-clockwise hysteresis patterns originating from the dilution of the enriched groundwaters by surface waters. Conversely, Al, Fe, Mn, Ti, V, Cr, Co, Ni, Cu, Zn, Cd, Pb and U displayed high dissolved concentration increases at the early stage of floods due to washing out of the enriched soils. ConclusionsThe comparison of stream output fluxes for the two main inputs for the watershed, i.e. atmospheric deposition and manure spreading, indicates that the vast majority of the Cu and Zn (>99 and 96%, respectively), mainly originating from pig manure, is accumulated in the watershed. The accumulation rates for other metals were >60% for Ni and Cr, >75% for As and >90% for Pb and Cd

Partial melting of a C-rich asteroid: Lithophile trace elements in ureilites

International audienceUreilites are among the most common achondrites and are widely believed to sample the mantle of a single, now-disrupted, C-rich body. We analyzed 17 ureilite samples, mostly Antarctic finds, and determined their incompatible trace element abundances. In order to remove or reduce the terrestrial contamination, which is marked among Antarctic ureilites by light-REE enrichment, we leached the powdered samples with nitric acid. The residues display consistent abundances, which strongly resemble those of the pristine rocks. All the analyzed samples display light-REE depletions, negative Eu anomalies, low (Sr/Eu∗)n, and (Zr/Eu∗)n ratios which are correlated. Two groups of ureilites (groups A and B) are defined. Compared to group A, group B ureilites, which are the less numerous, tend to be richer in heavy REEs, more light-REE depleted, and display among the deepest Eu anomalies. In addition, olivine cores in group B ureilites tend to be more forsteritic (Mg# = 81.9-95.2) than in group A ureilites (Mg# = 74.7-86.1). Incompatible trace element systematics supports the view that ureilites are mantle restites. REE modelling suggests that their precursors were rather REE-rich (ca. 1.8-2 x CI) and contained a phosphate phase, possibly merrillite. The REE abundances in ureilites can be explained if at least two distinct types of magmas were removed successively from their precursors: aluminous and alkali-rich melts as exemplified by the Almahata Sitta trachyandesite (ALM-A), and Al and alkali-poor melts produced after the exhaustion of plagioclase from the source. Partial melting was near fractional (group B ureilites, which are probably among the least residual samples) to dynamic with melt porosities that did not exceed a couple of percent (group A ureilites). The ureilite parent body (UPB) was almost certainly covered by a crust formed chiefly from the extrusion products of the aluminous and alkali-rich magmas. It is currently uncertain whether the Al and alkali-poor melts produced during the second phase of melting reached the surface of the body. The fact that initial silicate melting of ureilitic precursors would have produced relatively low density liquids capable of forming an external crust to the UPB casts doubt on models that invoke chondritic outer layers to achondritic asteroids

Impact of Saharan Dust on Severe Small for Gestational Births in the Caribbean

International audienceDesert dust transported from the Sahara to the Caribbean generates peak exposures to particulate matter ≤ 10 μm (PM). We investigated the impact of dust episodes on severe small for gestational-age births in Guadeloupe. The study sample consisted of 911 pregnant women enrolled in the Timoun mother-child cohort. Desert dust exposure was assessed through the mean daily PM concentrations averaged over the entire pregnancy. Numerous sociodemographic and medical risk factors were considered as covariates and introduced into multinomial logistic regression models. Odds ratios (ORs) were calculated per SD change (3.08 μg/m). Among various outcomes, symmetrically growth-retarded births showed the highest OR (3.28, 95% CI 1.08-10.02). Saharan dust seems to influence weight but not length or head circumference at birth. Given the high OR observed in this study, it is conceivable that Saharan dust plays a role through severe placental insufficiency early in pregnancy

Consultation infirmière pour le maintien des capacités au travail

International audienc

G protein-coupled receptors, an unexploited animal toxin targets: Exploration of green mamba venom for novel drug candidates active against adrenoceptors.

International audienceAt a time when pharmaceutical companies are having trouble finding new low MW drugs and when biologics are becoming more common, animal venoms could constitute an underexploited source of novel drug candidates. We looked for identifying novel animal toxins active against G protein-coupled receptors (GPCR), the most frequently exploited class of treatment targets, with the aim to develop novel research tools and drug candidates. Screening of green mamba (Dendroaspis angusticeps) venom against adrenoceptors identified two novel venom peptides. ρ-Da1a shown an affinity of 0.35 nM for the α1a-AR while ρ-Da1b displayed affinities between 14 and 73 nM for the three α2-ARs. These two venom peptides have sequences similar to those of muscarinic toxins and belong to the three-finger-fold protein family. α1a-AR is the primary target for the treatment of prostate hypertrophy. In vitro and in vivo tests demonstrated that ρ-Da1a reduced prostatic muscle tone as efficiently as tamsulosin (an antagonist presently used), but with fewer cardiovascular side effects. α2-ARs are the prototype of GPCRs not currently used as treatment targets due to a lack of specific ligands. Blockage of these receptors increases intestinal motility, which may be compromised by abdominal surgery and reduces orthosteric hypotension. In vitro and in vivo tests demonstrated that ρ-Da1b antagonizes α2-ARs in smooth muscles and increased heart rate and blood catecholamine concentrations. These results highlight possible exploitation of ρ-Da1a and ρ-Da1b in important pathologies

Two distinct dopamine D2 receptor genes in the European eel: molecular characterization, tissue-specific transcription, and regulation by sex steroids.

International audienceTwo full-length cDNA encoding putative dopamine D2-like receptors were cloned from the brain of female European eel. The deduced protein sequences, termed D2A- and D2B-R, exhibit closer phylogenetic relationships to vertebrate D2 receptors compared with D3 and D4 or D1 receptors. The two protein sequences share 100% identity within the transmembrane domains containing the highly conserved amino acids involved in dopamine binding. Accordingly, an apparent single population of sites on eel brain membranes bound [(3)H]spiperone, a D2-R-specific antagonist, with a K(d) of 0.2 +/- 0.04 nM. However, D2A- and D2B-R significantly differ within the amino terminus and the third intracellular loop. As analyzed by quantitative PCR and in situ hybridization, both receptor transcripts were found, with different relative abundance, in the majority of brain areas and in the pituitary, whereas in the retina, olfactory epithelium, spinal cord, and adipose tissue, only D2A-R gene was expressed. Because sex steroid hormones recently have been shown to regulate eel brain dopamine systems, we analyzed the effect of steroids on the amount of D2-R transcripts by quantitative PCR and in situ hybridization. In eels treated with testosterone, the gene expression of the D2B-R, but not D2A-R, was increased in a region-dependent manner. The effect of testosterone on D2B-R transcript levels was mimicked by dihydrotestosterone, a nonaromatizable androgen, whereas estradiol had no stimulatory action, evidencing an androgen receptor-dependent mechanism. Although functionality of the two receptors awaits determination of D2-R proteins, we hypothesize that differences in the tissue expression pattern and hormonal regulation of eel D2A- and D2B-R gene expression could represent selective forces that have contributed to the conservation of the duplicated D2-R