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Respective Inhibitors (respective + inhibitor)
Selected AbstractsInduction of hypoxia inducible factor-1 attenuates metabolic insults induced by 3-nitropropionic acid in rat C6 glioma cellsJOURNAL OF NEUROCHEMISTRY, Issue 3 2005Ya-Ting Yang Abstract Compromised mitochondrial function in neurons and glia has been observed in several neurodegenerative disorders, including Huntington's disease and Alzheimer's disease. Chemical/hypoxic preconditioning may afford protection against subsequently more severe oxidative damages. In this study, we tested whether induction of hypoxia inducible factor-1 (HIF-1) may exert cytoprotective effects against mitochondrial dysfunction caused by 3-nitropropionic acid (3-NP) in glial cells. Preconditioning of C6 astroglial cells with cobalt chloride, mimosine (MIM), and desferrioxamine (DFO), all of which known to activate HIF-1, significantly attenuated cytotoxicity induced by 3-NP, an irreversible inhibitor of mitochondrial complex II, and antimycin A, a mitochondrial complex III inhibitor. Application of cadmium chloride capable of neutralizing cobalt-induced HIF-1 activation, HIF-specific oligodeoxynucleotide (ODN) decoy, and antisense phosphorothioate ODN against HIF-1, abolished the protective effect mediated by preconditioning with cobalt chloride. Preloading of C6 cells with SN50, PD98059, or SB202190, the respective inhibitor of nuclear factor-,B (NF-,B), p44/p42 extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (MAPK), failed to affect the protection afforded by cobalt preconditioning. Taken together, these results suggest that HIF-1 induction secondary to preconditioning with cobalt chloride or iron chelators may mediate the protective effects against metabolic insult induced by the mitochondrial inhibitor 3-NP in C6 astroglial cells. [source] Calcium in the mechanism of ammonia-induced astrocyte swellingJOURNAL OF NEUROCHEMISTRY, Issue 2009Arumugam R. Jayakumar Abstract Brain edema, due largely to astrocyte swelling, is an important clinical problem in patients with acute liver failure. While mechanisms underlying astrocyte swelling in this condition are not fully understood, ammonia and associated oxidative/nitrosative stress appear to be involved. Mechanisms responsible for the increase in reactive oxygen/nitrogen species (RONS) and their role in ammonia-induced astrocyte swelling, however, are poorly understood. Recent studies have demonstrated a transient increase in intracellular Ca2+ in cultured astrocytes exposed to ammonia. As Ca2+ is a known inducer of RONS, we investigated potential mechanisms by which Ca2+ may be responsible for the production of RONS and cell swelling in cultured astrocytes after treatment with ammonia. Exposure of cultured astrocytes to ammonia (5 mM) increased the formation of free radicals, including nitric oxide, and such increase was significantly diminished by treatment with the Ca2+ chelator 1,2-bis-(o -aminophenoxy)-ethane- N,N,- N,,N, -tetraacetic acid tetraacetoxy-methyl ester (BAPTA). We then examined the activity of Ca2+ -dependent enzymes that are known to generate RONS and found that ammonia significantly increased the activities of NADPH oxidase (NOX), constitutive nitric oxide synthase (cNOS), and phospholipase A2 (PLA2) and such increases in activity were significantly diminished by BAPTA. Pre-treatment of cultures with 7-nitroindazole, apocyanin, and quinacrine, respective inhibitors of cNOS, NOX, and PLA2, all significantly diminished RONS production. Additionally, treatment of cultures with BAPTA or with inhibitors of cNOS, NOX, and PLA2 reduced ammonia-induced astrocyte swelling. These studies suggest that the ammonia-induced rise in intracellular Ca2+ activates free radical producing enzymes that ultimately contribute to the mechanism of astrocyte swelling. [source] Different sensitivity of isoprenaline-induced responses in ventricular muscle to sodium nitroprusside in normotensive and spontaneously hypertensive rats 1AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2000A. M. Manso 1 The aim of the present work was to study the possible modulatory role of nitric oxide (NO) on the positive inotropic effect induced by the ,-adrenoceptor agonist isoprenaline in myocardial contractility, and whether this modulation is altered by hypertension. 2 The study was performed using right ventricular strips from the hearts of 6-month-old male Wistar,Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The contractile force of electrically-stimulated ventricular strips was measured by a force-displacement transducer. 3 Isoprenaline (from 10 nmol l,1 to 10 ,mol l,1) induced a concentration-dependent increase in cardiac contractility in strips from both rat strains. This positive inotropic effect to isoprenaline was reduced by the NO donor sodium nitroprusside (SNP, 0.1 mmol l,1) in muscles from WKY rats and slightly increased in those from SHR. The SNP-induced increase in strips from SHR was abolished by superoxide dismutase (100 U ml,1). 4 NG-nitro-arginine-methyl ester (L-NAME, 0.1 mmol l,1) and 1H-[1,2,4]oxadiazolo[4,3]quinoxalin-1-one (ODQ, 10 ,mol l,1), respective inhibitors of NO synthase and guanylate cyclase, increased the response to isoprenaline in muscles from WKY rats, whereas it was unaltered in strips from SHR. 5 In strips from WKY rats, the combination of ODQ and SNP produced an increase in the response elicited by isoprenaline, which was similar to that observed with ODQ or L-NAME. 8-Br-cyclicGMP (8-Br-cGMP, 0.1 mmol l,1), a permeable and structural cGMP analogue, decreased the effect induced by isoprenaline only in muscles from WKY rats. 6 These results suggest that the positive inotropic response to isoprenaline in ventricular strips from WKY rats is negatively modulated by NO, and positively by superoxide anions in those from SHR. The lack of a modulatory response to NO in ventricular strips from SHR is probably a result of an alteration of mechanisms in NO-signalling pathway downstream of cGMP formation in SHR hearts. [source] Mechanisms involved in the early increase of serotonin contraction evoked by endotoxin in rat middle cerebral arteriesBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003Raquel Hernanz The present study investigated the mechanisms involved in the increased 5-hydroxytryptamine (5-HT) vasoconstriction observed in rat middle cerebral arteries exposed in vitro to lipopolysaccharide (LPS, 10 ,g ml,1) for 1,5 h. Functional, immunohistochemical and Western blot analysis and superoxide anion measurements by ethidium fluorescence were performed. LPS exposure increased 5-HT (10 ,M) vasoconstriction only during the first 4 h. In contrast to control tissue, indomethacin (10 ,M), the COX-2 inhibitor NS 398 (10 ,M), the TXA2/PGH2 receptor antagonist SQ 29,548 (1 ,M) and the TXA2 synthase inhibitor furegrelate (1 ,M) reduced 5-HT contraction of LPS-treated arteries from hour one. The iNOS inhibitor aminoguanidine (0.1 mM) increased 5-HT contraction from hour three of LPS incubation. The superoxide anion scavenger superoxide dismutase (SOD, 100 U ml,1) and the H2O2 scavenger catalase (1000 U ml,1), as well as the respective inhibitors of NAD(P)H oxidase and xanthine oxidase, apocynin (0.3 mM) and allopurinol (0.3 mM), reduced 5-HT contraction after LPS incubation. LPS induced an increase in superoxide anion levels that was abolished by PEG-SOD. Subthreshold concentrations of the TXA2 analogue U 46619, xanthine/xanthine oxidase and H2O2 potentiated, whereas those of sodium nitroprusside inhibited, the 5-HT contraction. COX-2 expression was increased at 1 and 5 h of LPS incubation, while that of iNOS, Cu/Zn-SOD and Mn-SOD was only increased after 5 h. All the three vascular layers expressed COX-2 and Cu/Zn-SOD. iNOS expression was detected in the endothelium and adventitia after LPS. In conclusion, increased production of TXA2 from COX-2, superoxide anion and H2O2 enhanced vasoconstriction to 5-HT during the first few hours of LPS exposure; iNOS and SOD expression counteracted that increase at 5 h. These changes can contribute to the disturbance of cerebral blood flow in endotoxic shock. British Journal of Pharmacology (2003) 140, 671,680. doi:10.1038/sj.bjp.0705501 [source] | ||||||||||