Effects of nitric oxide synthase inhibition in lipopolysaccharide-induced sepsis in mice.
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-1 significantly 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-1 dose 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-1 dose 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 of L-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. (c) 1998 The Italian Pharmacological Society.
Tunçtan
B
B
Department of Pharmacology, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
Uludag
O
O
Altug
S
S
Abacioglu
N
N
D000818:Animals; D004464:Econazole / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006146:Guanidines / Q000627:therapeutic use; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000209:etiology
D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D009573:Nitrites; D009569:Nitric Oxide; D004464:Econazole; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C004479:pimagedine