Effect of nitric oxide synthase inhibitors on lipid peroxide formation in liver caused by endotoxin challenge.
This study investigated the effect of nitric oxide on lipid peroxide formation during endotoxaemia. Nitric oxide synthase inhibitors N(G)-monomethyl-L-arginine acetate (L-NMMA, 20 mg/kg, intravenously), N(G)-nitro-L-arginine-methyl ester (L-NAME, 10 mg/kg, intravenously), and N(G)-nitro-L-arginine (L-NA, 10 mg/kg, intravenously), and a relatively selective inducible nitric oxide synthase inhibitor aminoguanidine (10 mg/kg, intravenously), did not protect against endotoxin-induced death of mice. Superoxide dismutase activity in liver 18 hr after administration of endotoxin (6 mg/kg, intraperitoneally) to L-arginine analogues (L-NMMA, L-NAME, L-NA)-treated mice was lower than in mice treated with endotoxin alone, whereas the administration of L-arginine analogues increased xanthine oxidase activity in the livers of endotoxin-injected mice compared with mice treated with endotoxin alone. In mice treated with L-arginine analogues and aminoguanidine, the levels of non-protein sulfhydryl and lipid peroxide in liver 18 hr after endotoxin injection did not show significant differences from mice treated with endotoxin alone. L-Arginine analogues and aminoguanidine had little effect on lipid peroxide formation in liver caused by endotoxin. Treatment with aminoguanidine (300 microM) significantly inhibited endotoxin-induced intracellular peroxide in J774A.1 cells, however, aminoguanidine did not affect endotoxin-induced cytotoxicity in J774A.1 cells. Our results clearly demonstrate that treatment with catalase (10 microg/ml), D-mannitol (10 mM), or superoxide dismutase (100 U/ml), has little or no effect on nitric oxide production by endotoxin (1 microg/ml)-activated J774A.1 cells. These findings suggest that nitric oxide is not crucial for lipid peroxide formation during endotoxaemia. Therefore, it is unlikely that nitric oxide plays a significant role in liver injury caused by free radical generation in endotoxaemia.
Sakaguchi
S
S
First Department of Hygienic Chemistry, Tohoku Pharmaceutical University, Sendai, Japan.
Furusawa
S
S
Yokota
K
K
Sasaki
K
K
Takayanagi
M
M
Takayanagi
Y
Y
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002452:Cell Count / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004731:Endotoxins / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D008054:Lipid Peroxides / Q000096:biosynthesis* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D015996:Survival Rate; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000975:Antioxidants; D004731:Endotoxins; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006146:Guanidines; D008054:Lipid Peroxides; D008070:Lipopolysaccharides; D013438:Sulfhydryl Compounds; D013481:Superoxides; D019335:Nitroarginine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester