Dose-dependent attenuation of lipopolysaccharide-fever by inhibitors of inducible nitric oxide-synthase in guinea pigs.
Different doses of aminoguanidine or S-methylisothiourea, both predominantly inhibitors of the inducible form of nitric oxide (NO)-synthase, were injected into the arterial circulation of guinea pigs alone or along with 10 microg/kg bacterial lipopolysaccharide. Doses of 10 mg/kg, 50 mg/kg or 250 mg/kg aminoguanidine per se had no influence on abdominal temperature of guinea pigs. Only the highest dose of aminoguanidine (250 mg/kg) completely suppressed the first phase of the biphasic febrile response to lipopolysaccharide-injections. Lipopolysaccharide-fever was not modulated by administration of 10 mg/kg or 50 mg/kg aminoguanidine, when compared to fever in response to injections of lipopolysaccharide along with solvent. Doses of 10 mg/kg or 50 mg/kg S-methylisothiourea did not alter abdominal temperature while a dose of 250 mg/kg S-methylisothiourea had a lethal effect in guinea pigs. The febrile response to lipopolysaccharide was unimpaired by administration of 10 mg/kg S-methylisothiourea, while a dose of 50 mg/kg again attenuated fever predominantly by a suppression of the first fever phase. None of the applied doses of aminoguanidine or S-methylisothiourea resulted in a significant attenuation of the lipopolysaccharide-induced circulating cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6. The drugs themselves, without lipopolysaccharide-injections, did not enhance or reduce circulating levels of the investigated cytokines. The results indicate that endogenous NO may participate in the induction of lipopolysaccharide-fever and that fever suppression by systemic administration of NO-synthase inhibitors occurs independently from the lipopolysaccharide-induced circulating cytokines.