Inhibitors of alternative pathways of arachidonate metabolism differentially affect fever in mice.
Inhibitors of cyclooxygenases prevent fever. The purpose of this study was to test the hypothesis that selective and dual inhibitors of the other enzyme systems of arachidonic acid oxygenation (i.e., lipoxygenase and epoxygenase) affect the time course or magnitude of fever in mice. Swiss Webster mice kept at 30 degreesC ambient temperature were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide at doses from 10 micrograms/kg to 2.5 mg/kg. Phenidone (20-30 mg/kg ip), a dual lipoxygenase and cyclooxygenase inhibitor, prevented fever in these mice, but esculetin (1-10 mg/kg ip), a selective inhibitor of lipoxygenases, did not affect fever. Intramuscular injection of nordihydroguaiaretic acid (10-20 mg/kg), a dual lipoxygenase and epoxygenase inhibitor, as well as SKF-525A (5 mg/kg ip) and clotrimazole (20 mg/kg im), inhibitors of the cytochrome P-450/epoxygenase pathway, augmented fever in mice. Indomethacin (5 mg/kg ip), an inhibitor of cyclooxygenase, suppressed the exacerbation of fever due to clotrimazole, suggesting that the epoxygenase inhibitor-induced potentiation of fever in mice is a prostaglandin-mediated effect. From this study, we hypothesize that the cytochrome P-450/epoxygenase branch of the arachidonate cascade is involved in antipyresis and in controlling the upper limit of fever.
Kozak
W
W
Lovelace Respiratory Research Institute, Inhalation Toxicology Laboratory, Albuquerque, New Mexico 87185, USA.
Archuleta
I
I
Mayfield
K P
KP
Kozak
A
A
Rudolph
K
K
Kluger
M J
MJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism*; D001831:Body Temperature; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology*; D003022:Clotrimazole / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice; D011335:Proadifen / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D013997:Time Factors; D014468:Umbelliferones / Q000494:pharmacology
D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D014468:Umbelliferones; D016718:Arachidonic Acid; D009637:Masoprocol; D011335:Proadifen; D003022:Clotrimazole; C015429:phenidone; C007628:esculetin; D007213:Indomethacin