Elsevier

Pharmacological Research

Volume 38, Issue 5, November 1998, Pages 405-411
Pharmacological Research

Regular Article
EFFECTS OF NITRIC OXIDE SYNTHASE INHIBITION IN LIPOPOLYSACCHARIDE-INDUCED SEPSIS IN MICE

https://doi.org/10.1006/phrs.1998.0381Get rights and content

Abstract

In the present study, we have investigated the effects of nitric oxide (NO) synthase inhibition on mortality in lipopolysaccharide (LPS)-induced sepsis in mice. Serum nitrite levels peaked at 15 h after an injection of LPS (10 mg kg−1, i.p.). Aminoguanidine, a selective inducible NO synthase (iNOS) inhibitor, at a dose of 100 mg kg−1significantly reduced the LPS-induced increase in nitrite levels and improved mortality. Econazole, iNOS inhibitor, calmodulin antagonist, 5-lipoxygenase and a specific thromboxane synthase inhibitor, at a 1 mg kg−1dose significantly decreased the LPS-induced increase in nitrite levels, but increased mortality 4.9-fold when compared to the LPS group (control). Indomethacin, a putative iNOS and non-selective cyclo-oxygenase (COX) inhibitor, of 1, 10 and 100 mg kg−1, dose dependently decreased the LPS-induced increase in nitrite levels. This decrease was significantly different from the control at 10 and 100 mg kg−1dose levels. When indomethacin (100 mg kg−1) was combined with aminoguanidine (100 mg kg−1), LPS-induced nitrite levels were significantly attenuated. NO precursor,L-arginine, was added to this combination in order to test the inhibition of iNOS activity which resulted in no change in nitrite levels. An indomethacin and aminoguanidine combination increased mortality twofold when compared to the control. The addition ofL-arginine to the combination enhanced the mortality rate to 1.5-fold. These results suggest that NO appears to play a role in the LPS-induced septic shock model in mice. The improvement in sepsis-induced mortality enhanced by aminoguanidine by the inhibition of iNOS but not with the other agents or combinations should be re-evaluated in order to make an appropriate choice of the therapeutic target. In addition, it may also suggest that other mediators, such as arachidonic acid products and cytokines play a role in septic shock pathogenesis as well.

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