INCREASED NITRIC OXIDE SYNTHESIS DURING THE DEVELOPMENT OF ENDOTOXIN TOLERANCE

Abstract

The role of nitric oxide (NO) synthesis was investigated in endotoxin (LPS) tolerance induced in rats by intraperitoneal injection of a sublethal dose of Salmonella enteritidis LPS (100 micrograms/kg intraperitoneally). Peritoneal macrophages were harvested 6 and 24 h after LPS injection and stimulated in vitro with LPS. LPS significantly stimulated arachidonic acid metabolism, as assessed by 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) levels, and NO production, as assessed by nitrite, in macrophages collected from control rats. In macrophages from tolerant rats LPS-stimulated 6-keto-PGF1 alpha production was significantly reduced, while nitrite production was increased compared to control macrophages (p < .001). In in vivo mortality studies, rats that were pretreated 24 h earlier with sublethal LPS were resistant to the lethal effect of a subsequent dose of LPS (15 mg/kg intravenously) in comparison to control rats (p < .001). NG-Nitro-L-arginine-methyl ester, an inhibitor of NO synthase, decreased mean survival time in control rats and abrogated the resistance to the lethal effect of LPS in tolerant rats. In contrast, molsidomine, a NO donor, improved survival in control rats but did not modify the resistance to the lethal dose of LPS in tolerant rats. The results suggest that sustained NO synthesis may be a beneficial mechanism for the induction of LPS tolerance.