The timing of endothelin and nitric oxide inhibition affects survival in a mice model of septic shock.
The effect of endothelin and nitric oxide (NO) inhibition on survival from septic shock was investigated in male Swiss albino mice (20-40 g), with particular emphasis on the timing of the administration of their blockers after Escherichia coli endotoxin (lipopolysaccharide, O55:B5, 60 mg kg(-1), i.p.) challenge. Mice were injected with the endothelin receptor antagonist bosentan (30 mg kg(-1), i.p., either 2 or 12 h after endotoxin) alone or in addition to the NO synthase blockers L-canavanine (100 mg kg(-1), i.p.), N(G)-nitro-L-arginine methyl ester (L-NAME, 3 mg kg(-1), i.p.) or aminoguanidine (15 mg kg(-1), i.p.), which were also given twice at 2 and 6 h after endotoxin. Control animals received saline, and survival rates in each group (n=10) were recorded over 24 h at 6-h intervals. At 24 h, the survival rate was 10% in controls, but 30% (n.s.) and 70% (P<0.05) in animals that received only bosentan at 2 and 12 h, respectively, indicating a relatively late involvement of endothelin in comparison to NO. In contrast, these figures were 70% (P<0.05) and 80% (P<0.05) at 12 h for L-NAME and L-canavanine, respectively, and 10% (n.s.) at 24 h, implying a relatively early involvement of NO compared to endothelin. Interestingly, survival in the aminoguanidine group (75% at 24 h, P<0.05 vs. controls) was markedly higher than that in the L-NAME and L-canavanine groups, an effect that was attributed to mechanisms other than NO inhibition. Survival was better (60%, P<0.05 vs. endotoxin alone) when bosentan was given at 2 h in combination with L-NAME, but the best outcome (90% survival, P<0.05) was observed in animals when bosentan was given at 12 h and L-NAME was injected twice at 2 and 6 h. However, the statistical analysis revealed no significant additional beneficial effect of L-NAME coadministered with bosentan. Therefore, we conclude that NO is involved during the earlier phases of septic shock in comparison to a relatively late involvement of endothelin peptides, and that bosentan alone appears to be beneficial when administered at least 12 h after the endotoxin challenge in our mice model of septic shock.
Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
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D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000077300:Bosentan; D002172:Canavanine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D004731:Endotoxins; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology* / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy / Q000401:mortality*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D015996:Survival Rate
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D004731:Endotoxins; D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D013449:Sulfonamides; D002172:Canavanine; D019001:Nitric Oxide Synthase; D000077300:Bosentan; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester