Role of nitric oxide during carrageenan-sensitized endotoxin shock in mice.
We have previously clarified that sensitization with a sulfated polygalactose, carrageenan (CAR), enhances endotoxin-induced tumor necrosis factor (TNF) production and lethality in mice. The present study was performed to examine the role of nitric oxide (NO) in CAR-sensitized septic mice with two different types of NO synthase (NOS) inhibitors, a non-selective inhibitor to NOS subtypes, N omega-nitro-L-arginine methyl ester (L-NAME), and a selective inhibitor to inducible NOS, aminoguanidine. Seven or eight-week-old male ddY mice were given 5 mg of CAR intraperitoneally as a primer. Then, 5 micrograms of lipopolysaccharide (LPS) was injected into the tail vein 16 hours later the pretreatment. Marked synthesis of NO was induced in CAR-sensitized mice, as indicated by the high plasma levels of the stable endproducts, NO2-/NO3- peaking at 12 hr after the LPS challenge. The peak values at 12 hr after the LPS challenge were dependent on the dose of CAR with 1 to 5 mg, although the injection with 10 mg of CAR was adversely inhibited NO production compared with 5 mg of CAR. The LPS challenge was followed by either L-NAME (0.25, 0.5 or 1 mg) or aminoguanidine (1, 2 or 4 mg) in the septic mice sensitized with 5 mg of CAR. L-NAME reduced the plasma NO2-/NO3- level in a dose-dependent fashion, although it augmented liver injury, as measured by plasma levels of ornithine carbamyltransferase (OCT) and the LPS-induced lethality in a dose-dependent fashion. In contrast, aminoguanidine did not significantly deteriorate either liver injury or lethality in spite of the decrease of NO endproducts in a similar fashion to L-NAME. These findings suggest that the inhibition of constitutive NOS is detrimental and augments LPS-induced liver injury and subsequent lethality.
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002351:Carrageenan / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*; D009954:Ornithine Carbamoyltransferase / Q000097:blood; D012772:Shock, Septic / Q000503:physiopathology*
D006146:Guanidines; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D002351:Carrageenan; D001120:Arginine; D009954:Ornithine Carbamoyltransferase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester