Ab. Iskit et Mo. Guc, The timing of endothelin and nitric oxide inhibition affects survival in amice model of septic shock, EUR J PHARM, 414(2-3), 2001, pp. 281-287
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.