Role of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in Modulating Vascular Smooth Muscle Cells by Activating Large-Conductance Potassium Ion Channels

International audienceIn this chapter we propose to discuss the role of K+ ion channels in stimulating vasodilatation by altering the membrane potential of vascular smooth muscle cells. We present evidence that the K+ channels are modulated by a direct action of non-steroidal antiinflammatory drugs (NSAIDs) to activate the K+ ion channels

Kynurenine pathway metabolism following prenatal KMO inhibition and in Mecp2+/- mice, using liquid chromatography-tandem mass spectrometry

To quantify the full range of tryptophan metabolites along the kynurenine pathway, a liquid chromatography – tandem mass spectrometry method was developed and used to analyse brain extracts of rodents treated with the kynurenine-3-mono-oxygenase (KMO) inhibitor Ro61-8048 during pregnancy. There were significant increases in the levels of kynurenine, kynurenic acid, anthranilic acid and 3-hydroxy-kynurenine (3-HK) in the maternal brain after 5 h but not 24 h, while the embryos exhibited high levels of kynurenine, kynurenic acid and anthranilic acid after 5 h which were maintained at 24 h post-treatment. At 24 h there was also a strong trend to an increase in quinolinic acid levels (P = 0.055). No significant changes were observed in any of the other kynurenine metabolites. The results confirm the marked increase in the accumulation of some neuroactive kynurenines when KMO is inhibited, and re-emphasise the potential importance of changes in anthranilic acid. The prolonged duration of metabolite accumulation in the embryo brains indicates a trapping of compounds within the embryonic CNS independently of maternal levels. When brains were examined from young mice heterozygous for the meCP2 gene – a potential model for Rett syndrome - no differences were noted from control mice, suggesting that the proposed roles for kynurenines in autism spectrum disorder are not relevant to Rett syndrome, supporting its recognition as a distinct, independent, condition

Global Soil Moisture Patterns Observed by Space Borne Microwave Radiometers and Scatterometers

Within the scope of the upcoming launch of a new water related satellite mission (SMOS) a global evaluation study was performed on two available global soil moisture products. ERS scatterometer surface wetness data was compared to AMSR-E soil moisture data. This study pointed out a strong similarity between both products in sparse to moderate vegetated regions with an average correlation coefficient of 0.83. Low correlations were found in densely vegetated areas and deserts. The low values in the vegetated regions can be explained by the limited soil moisture retrieval capabilities over dense vegetation covers. Soil emission is attenuated by the canopy and tends to saturate the microwave signal with increasing vegetation density, resulting in a decreased sensor sensitivity to soil moisture variations. It is expected that the new low frequency satellite mission (SMOS) will obtain soil moisture products with a higher quality in these regions. The low correlations in the desert regions are likely due to volume scattering or to the dielectric dynamics within the soil. The volume scattering in dry soils causes a higher backscatter under very dry conditions than under conditions when the sub-surface soil layers are somewhat wet. In addition, at low moisture levels the dielectric constant has a reduced sensitivity in response to changes in the soil moisture content. At a global scale the spatial correspondence of both products is high and both products clearly distinguish similar regions with high seasonal and inter annual variations. Based on the global analyses we concluded that the quality of both products was comparable and in the sparse to moderate vegetated regions both products may be beneficial for large scale validation of SMOS soil moisture. Some limitations of the studied products are different, pointing to significant potential for combining both products into one superior soil moisture data set. © The Author(s) 2008

Kynurenine pathway metabolism in human blood-brain-barrier cells: implications for immune tolerance & neurotoxicity

C1 - Journal Articles RefereedThe catabolic pathway of l-tryptophan (l-trp), known as the kynurenine pathway (KP), has been implicated in the pathogenesis of a wide range of brain diseases through its ability to lead to immune tolerance and neurotoxicity. As endothelial cells (ECs) and pericytes of the blood-brain-barrier (BBB) are among the first brain-associated cells that a blood-borne pathogen would encounter, we sought to determine their expression of the KP. Using RT-PCR and HPLC/GC-MS, we show that BBB ECs and pericytes constitutively express components of the KP. BBB ECs constitutively synthesized kynurenic acid, and after immune activation, kynurenine (KYN), which is secreted basolaterally. BBB pericytes produced small amounts of picolinic acid and after immune activation, KYN. These results have significant implications for the pathogenesis of inflammatory brain diseases in general, particularly human immunodeficiency virus (HIV)-related brain disease. Kynurenine pathway activation at the BBB results in local immune tolerance and neurotoxicity: the basolateral secretion of excess KYN can be further metabolized by perivascular macrophages and microglia with synthesis of quinolinic acid. The results point to a mechanism whereby a systemic inflammatory signal can be transduced across an intact BBB to cause local neurotoxicity

Characterization of the P(2) receptors in rabbit pulmonary artery

1. We have identified the P(2) receptors mediating vasomotor responses in the rabbit pulmonary artery. 2. Neither ATP nor UTP contracted intact or endothelium-denuded rings. However, both relaxed intact rings of rabbit pulmonary artery that had been preconstricted with phenylephrine (pD(2) 5.2 and 5.6, respectively). 3. The vasodilator effect of UTP was endothelium-dependent and abolished by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine (L-NOARG). 4. The vasodilator effect of ATP was only partially inhibited by removal of endothelium or addition of L-NOARG, suggesting an additional direct effect on vascular smooth muscle. 5. The endothelium-dependent vasodilator responses to UTP and ATP were competitively antagonized by suramin. 6. Preconstricted, endothelium-denuded rings were also relaxed by 2-methylthio ATP (pD(2) 6.6), a P(2Y) receptor agonist. 7. Ca(2+)-mobilizing P(2U) receptors were identified on smooth muscle cells on the basis of single cell responses to ATP (pD(2) 7.8) and UTP (pD(2) 7.9; 6.7 in the presence of 100 μM suramin). 8. There was no evidence of a Ca(2+)-mobilizing P(2Y) receptor in these cultured cells. 9. The data suggest the presence of (i) a suramin-sensitive P(2U) receptor on endothelial cells that induces vasorelaxation through NO release, (ii) a suramin-sensitive P(2U) receptor on cultured smooth muscle cells that mobilizes Ca(2+) but is not coupled to vasomotor responses and (iii) a putative P(2Y) receptor on vascular smooth muscle cells that induces relaxation via a Ca(2+)-independent signal transduction pathway