Timing of endothelin and nitric oxide inhibition is crucial for survival in septic shock

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Abstract
Background: The effect of endothelin and nitric oxide inhibition on survival from septic shock was investigated in mice, with particular emphasis on the timing of the administration of their blockers after an endotoxin (lipopolysaccharide; LPS) challenge. Methods: Male Swiss albino mice (20–40 g) received LPS (Escherichia coli 055: B5; 60 mg kg−1 intraperitoneally) followed by intraperitoneal injection of the endothelin receptor antagonist bosentan 30 mg kg−1, either 2 or 12 h after LPS, alone or in addition to intraperitoneal nitric oxide synthase blockers l-canavanine 20 or 100 mg kg−1, L-NAME 3 mg kg−1 or aminoguanidine 15 mg kg−1, which were given twice, at 2 and 6 h after LPS. Control animals received saline and survival rates in each group (n = 10) were recorded over 24 h at 6-h intervals. Results: At 24 h, the survival rate was 10 per cent in controls, but 30 per cent (P not significant) and 70 per cent (P < 0·05) in animals that received bosentan only at 2 and 12 h respectively, indicating a relatively ‘late’ involvement of endothelin. In contrast, these values were 70 per cent (P < 0·05) and 80 per cent (P < 0·05) at 12 h for L-NAME and l-canavanine, which both decreased to 10 per cent (P not significant) at 24 h implying a relatively ‘early’ involvement of nitric oxide. A higher value (60 per cent; P < 0·05) was obtained when bosentan given at 2 h was combined with L-NAME. The best outcome (90 per cent survival rate; P < 0·05) was observed when bosentan was given at 12 h in combination with L-NAME at 2 and 6 h. Interestingly, the survival rate was 70 per cent (P < 0·05) in the aminoguanidine group, which can be explained by other pharmacological effects of this drug in addition to nitric oxide blockade. Conclusion: Nitric oxide plays a significantly deleterious role during the early phases of septic shock, in contrast to a relatively late involvement of endothelin peptides. This should be taken into consideration when devising treatment strategies.

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