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Mechanism Sensitive (mechanism + sensitive)
Selected AbstractsMolecular physiology of SLC4 anion exchangersEXPERIMENTAL PHYSIOLOGY, Issue 1 2006Seth L. Alper Plasmalemmal Cl,,HCO3, exchangers regulate intracellular pH and [Cl,] and cell volume. In polarized epithelial cells, they contribute also to transepithelial secretion and reabsorption of acid,base equivalents and of Cl,. Members of both the SLC4 and SLC26 mammalian gene families encode Na+ -independent Cl,,HCO3, exchangers. Human SLC4A1/AE1 mutations cause either the erythroid disorders spherocytic haemolytic anaemia or ovalocytosis, or distal renal tubular acidosis. SLC4A2/AE2 knockout mice die at weaning. Human SLC4A3/AE3 polymorphisms have been associated with seizure disorder. Although mammalian SLC4/AE polypeptides mediate only electroneutral Cl,,anion exchange, trout erythroid AE1 also promotes osmolyte transport and increased anion conductance. Mouse AE1 is required for DIDS-sensitive erythroid Cl, conductance, but definitive evidence for mediation of Cl, conductance is lacking. However, a single missense mutation allows AE1 to mediate both electrogenic SO42,,Cl, exchange or electroneutral, H+ -independent SO42,,SO42, exchange. In the Xenopus oocyte, the AE1 C-terminal cytoplasmic tail residues reported to bind carbonic anhydrase II are dispensable for Cl,,Cl, exchange, but required for Cl,,HCO3, exchange. AE2 is acutely and independently inhibited by intracellular and extracellular H+, and this regulation requires integrity of the most highly conserved sequence of the AE2 N-terminal cytoplasmic domain. Individual missense mutations within this and adjacent regions identify additional residues which acid-shift pHo sensitivity. These regions together are modelled to form contiguous surface patches on the AE2 cytoplasmic domain. In contrast, the N-terminal variant AE2c polypeptide exhibits an alkaline-shifted pHo sensitivity, as do certain transmembrane domain His mutants. AE2-mediated anion exchange is also stimulated by ammonium and by hypertonicity by a mechanism sensitive to inhibition by chelation of intracellular Ca2+ and by calmidazolium. This growing body of structure,function data, together with increased structural information, will advance mechanistic understanding of SLC4 anion exchangers. [source] Improvement of age-related endothelial dysfunction by simvastatin: effect on NO and COX pathwaysBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2005Maria Álvarez De Sotomayor The effects of oral administration of the HMG-CoA reductase inhibitor, simvastatin (SV), on age-related endothelial dysfunction were investigated in the aorta of male Wistar rats. Adult (12,14 weeks) and old (60,80 weeks) rats were treated daily for 12 weeks with either vehicle or SV (1 mg kg,1). In old rats, SV treatment did not significantly affect systolic blood pressure and LDL-cholesterol, but it reduced plasma cholesterol, triglycerides and oxidised LDL though it did not affect total antioxidant status. SV improved endothelium-dependent relaxation to acetylcholine and A-23187 in vessels from aged, but not adult, rats. This effect was linked to a greater NO vasodilatation via an increased expression of endothelial NO-synthase. A mechanism sensitive to superoxide dismutase and catalase also accounts for enhanced endothelial vasodilatation. Finally, SV did not affect the release of prostacyclin, but it inhibited the generation of thromboxane (TX) A2 from COX-2 isoform. The effect of the latter was sensitive to the Tp receptor antagonist, ICI-192,605. The present study provides evidence that oral administration of SV improves endothelial dysfunction in the aorta from aged rats by mechanisms associated with enhanced NO vasodilatation, reduced release of TXA2 from cyclo-oxygenase, and increased antioxidant properties of the vessel wall. These data underscore a new therapeutic perspective for SV in age-related endothelial dysfunction. British Journal of Pharmacology (2005) 146, 1130,1138. doi:10.1038/sj.bjp.0706420 [source] Characterization of endothelial factors involved in the vasodilatory effect of simvastatin in aorta and small mesenteric artery of the ratBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2000Maria Álvarez De Sotomayor Vascular effects of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, were studied in conductance (aorta) and resistance vessels (branch II or III of superior mesenteric artery, SMA) of the rat (12,14 weeks old). Simvastatin produced relaxation of both aorta and SMA, with and without functional endothelium. These responses were inhibited by the product of HMG-CoA reductase, mevalonate (1 mmol l,1). In vessels with functional endothelium, the NO-synthase inhibitor, L -NG -nitroarginine (L -NOARG, 30 ,mol l,1), inhibited simvastatin-induced relaxation. In the presence of L -NOARG, relaxation to simvastatin was lower in vessels with endothelium than in endothelium-denuded arteries without L -NOARG. The cyclo-oxygenase inhibitor, indomethacin (10 ,mol l,1), abolished endothelium-dependent component of the response to simvastatin in both arteries. The combination of L -NOARG plus indomethacin did not produce further inhibition. The Tp receptor antagonist, GR 32191B (3 ,mol l,1), did not affect relaxation in aorta but it reduced response to low concentrations of simvastatin in SMA. However, the inhibitory effect of L -NOARG was less marked in the presence of GR 32191B in aorta but not in SMA. The endothelium-dependent relaxation to simvastatin was inhibited by the superoxide dismutase (SOD, 100 u ml,1) or by the tyrosine kinase inhibitor, genistein (30 ,mol l,1) in the two arteries. The present study shows that simvastatin produces relaxation of conductance and small arteries through mevalonate-sensitive pathway. The endothelium-dependent relaxation to simvastatin involves both NO and vasodilator eicosanoids by a mechanism sensitive to SOD, and to genistein. Also, the results highlighted participation in the aorta of endothelial vasoconstrictor eicosanoids acting on the Tp receptor after blockage of NO synthase only. British Journal of Pharmacology (2000) 131, 1179,1187; doi:10.1038/sj.bjp.0703668 [source] Mechanisms of time-based figure,ground segregationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2003Farid I. Kandil Abstract Figure,ground segregation can rely on purely temporal information, that is, on short temporal delays between positional changes of elements in figure and ground (Kandil, F.I. & Fahle, M. (2001) Eur. J. Neurosci., 13, 2004,2008). Here, we investigate the underlying mechanisms by measuring temporal segregation thresholds for various kinds of motion cues. Segregation can rely on monocular first-order motion (based on luminance modulation) and second-order motion cues (contrast modulation) with a high temporal resolution of ,,20 ms. The mechanism can also use isoluminant motion with a reduced temporal resolution of 60 ms. Figure,ground segregation can be achieved even at presentation frequencies too high for human subjects to inspect successive frames individually. In contrast, when stimuli are presented dichoptically, i.e. separately to both eyes, subjects are unable to perceive any segregation, irrespective of temporal frequency. We propose that segregation in these displays is detected by a mechanism consisting of at least two stages. On the first level, standard motion or flicker detectors signal local positional changes (flips). On the second level, a segregation mechanism combines the local activities of the low-level detectors with high temporal precision. Our findings suggest that the segregation mechanism can rely on monocular detectors but not on binocular mechanisms. Moreover, the results oppose the idea that segregation in these displays is achieved by motion detectors of a higher order (motion-from-motion), but favour mechanisms sensitive to short temporal delays even without activation of higher-order motion detectors. [source] Redox-sensitive modulation of CD45 expression in pancreatic acinar cells during acute pancreatitisTHE JOURNAL OF PATHOLOGY, Issue 2 2006I de Dios Abstract CD45, a transmembrane protein tyrosine phosphatase required for signal transduction in leukocytes, has recently been found in pancreatic acinar cells. We have investigated the relationship between kinetic expression of CD45 on acinar cells during acute pancreatitis (AP) and the ability of these cells to produce tumour necrosis factor-, (TNF-,) through mechanisms sensitive to the cellular redox state. Flow cytometric analysis showed a significant decrease in the constitutive expression of CD45 in acinar cells from six hours onwards after inducing AP by bile-pancreatic duct obstruction (BPDO) in parallel with a significant increase in acinar TNF-, production. Changes in protein expression on the acinar cell surface preceded CD45 mRNA down-regulation, which was not found until 12 hours after BPDO. N -Acetylcysteine treatment delayed and reduced the down-regulation of CD45 expression induced by AP and prevented acinar cells from producing TNF-,. Our results show that CD45 expression is down-regulated in acinar cells during acute pancreatitis by redox-sensitive mechanisms, and they support the notion that CD45 negatively controls the production of cytokines in pancreatic acinar cells. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] | |||||||||||||