Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors.
The benefits of nitric oxide synthase (NOS) inhibitors in the treatment of endotoxemia or sepsis presumably arise from inhibition of the type II (inducible) NOS. However, inasmuch as the effect of these inhibitors on NOS function in vivo is rarely assessed, NOS activity was evaluated in rats and mice by measuring changes in plasma nitrite and nitrate concentrations ([NOx]) after administration of lipopolysaccharide (LPS). In both species, [NOx] peaked at 20 hr, returning to base line by 48 to 72 hr. The ED50 values (dose that elicited a 50% inhibition of the LPS-dependent increase in [NOx] 6 hr after LPS administration) for L-NG-monomethylarginine acetate, L-NG-nitroarginine methyl ester and aminoguanidine (administered 3 hr after LPS) were 34, 21 and 19 mg/kg in the rat and 32, 5 and 4 mg/kg in the mouse. These compounds also decreased the survival of LPS-challenged animals, which in the case of L-NG-nitroarginine methyl ester was reversed by L-arginine. Dexamethasone (which prevents the induction of type II NOS) also inhibited the LPS-dependent increase in [NOx] with ED50 values of 0.05 mg/kg (rat) and 1 mg/kg (mouse), but did not lead to decreased survival. Thus, inhibition of the type I (neuronal) or type III (endothelial) NOS, rather than the type II isoform, may be a possible mechanism for the animal mortality. These models provide a simple and reproducible means for assessing the in vivo inhibition of type II NOS by various compounds.
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Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois.
Tse
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Carter
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D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019331:NG-Nitroarginine Methyl Ester; D009566:Nitrates / Q000097:blood*; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D019323:omega-N-Methylarginine
D006146:Guanidines; D008070:Lipopolysaccharides; C092506:N(G)-monomethylarginine acetate; D009566:Nitrates; D009573:Nitrites; D019323:omega-N-Methylarginine; D003907:Dexamethasone; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester