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.
Roth
J
J
Institut für Normale und Pathologische Physiologie, Klinikum der Philipps-Universität, Deutschhausstrasse 2, 35033, Marburg, Germany.
Störr
B
B
Goldbach
J
J
Voigt
K
K
Zeisberger
E
E
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000378:metabolism*; D005246:Feedback / Q000502:physiology; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006146:Guanidines / Q000627:therapeutic use; D006168:Guinea Pigs; D015850:Interleukin-6 / Q000378:metabolism; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D004731:Endotoxins; D004791:Enzyme Inhibitors; D006146:Guanidines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007550:Isothiuronium; C044101:endotoxin, Escherichia coli; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C027744:S-methylisothiopseudouronium; C004479:pimagedine