Prevention of the expression of inducible nitric oxide synthase by aminoguanidine or aminoethyl-isothiourea in macrophages and in the rat.
An enhanced formation of nitric oxide (NO) following the induction of the inducible isoform of NOS (iNOS) has been implicated in the pathogenesis of circulatory shock and inflammation. This study elucidates the effects of the NOS inhibitors aminoethyl-isothiourea (AE-ITU), aminoguanidine (AG), NG-methyl-L-arginine (L-NMMA) or N omega-Nitro-L-arginine methyl ester (L-NAME) on the expression of iNOS protein lipopolysaccharide (LPS) in macrophages and the rat (lung homogenates). The expression of iNOS protein was detected by Western blot analysis using a specific iNOS antibody. In the absence of LPS, the iNOS protein was expressed neither in macrophages nor in the lung. LPS (1 microgram.ml-1) resulted in the expression of iNOS protein in macrophages, which was significantly inhibited by pretreatment of cells with AE-ITU or AG, but not by L-NMMA or L-NAME. In addition, LPS (10 mg.kg-1, i.v.) also caused an increase in the expression of iNOS protein in lungs obtained from rats at 6 h after LPS, which was significantly reduced by treatment of LPS-rats with AE-ITU or AG, but not with L-NMMA or L-NAME. Thus, AE-ITU or AG inhibit not only iNOS activity, but also the induction of iNOS protein in vitro and in vivo caused by endotoxin.
Ruetten
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H
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, United Kingdom.
Thiemermann
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C
D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; C004479:pimagedine