The timing of endothelin and nitric oxide inhibition affects survival in amice 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 par ticular emphasis on the timing of the administration of their blockers afte r Escherichia coli endotoxin (lipopolysaccharide, O55:B5, 60 mg kg(-1), i.p .) challenge. Mice were injected with the endothelin receptor antagonist bo sentan (30 mg kg(-1), i.p., either 2 or 12 h after endotoxin) alone or in a ddition 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 aminoguanidin e(15 mg kg(-1), i.p.), which were also given twice at 2 and 6 h after endot oxin. 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 w as 10% in controls, but 30% (n.s.) and 70% (P < 0.05) in animals that recei ved 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 involvem ent of NO compared to endothelin. Interestingly, survival in the aminoguani dine group (75% at 24 h, P < 0.05 vs. controls) was markedly higher than th at 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 whe n bosentan was given at 12 h and L-NAME was injected twice at 2 and 6 h. Ho wever, the statistical analysis revealed no significant additional benefici al effect of L-NAME coadministered with bosentan. Therefore, we conclude th at NO is involved during the earlier phases of septic shock in comparison t o a relatively late involvement of endothelin peptides, and that bosentan a lone appears to be beneficial when administered at least 12 h after the end otoxin challenge in our mice model of septic shock. (C) 2001 Published by E lsevier Science B.V.