The prevention of fatalities in cycloheximide challenged mice pretreated with a submicrogram dose of lipopolysaccharide or with a small volume of cell-free Ehrlich ascites tumour fluid.
OBJECTIVE
Therapeutic strategies were employed to better understand the pathogenesis of fatal cycloheximide (CX) intolerance in mice pretreated with a submicrogram dose of lipopolysaccharide (LPS) or with a small volume of cell-free Ehrlich ascites tumour fluid (EAF).


METHODS
Inbred, male CBA-strain mice.


METHODS
Aminoguanidine (AMG), a selective inhibitor of inducible nitric oxide synthase (iNOS) was used to determine the role of nitric oxide (NO) in the fatalities. Dexamethasone (DEX) or nordihydroguaiaretic acid (NDGA) were used to assess possible involvement of tumour necrosis factor-alpha (TNF) in sensitisation to CX.


RESULTS
AMG protected CX challenged mice pretreated with LPS or with EAF. DEX, but not NDGA, protected the former animals; both DEX and NDGA protected the latter.


CONCLUSIONS
AMG protection indicates the essential role of iNOS in CX-precipitated fatalities. It is suggested that the pretreatments either directly or indirectly place iNOS expression under control of a labile protein repressor. In the case of EAF pretreated mice, a role for TNF could not be excluded, whereas in LPS pretreated animals TNF plays no part in sensitising to CX.
Parry
E W
EW
The University of Liverpool, Department of Human Anatomy and Cell Biology, New Medical School, UK.
D000818:Animals; D001202:Ascitic Fluid / Q000503:physiopathology*; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism*; D003513:Cycloheximide / Q000008:administration & dosage / Q000633:toxicity*; D003907:Dexamethasone / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology
D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D009637:Masoprocol; D003907:Dexamethasone; D003513:Cycloheximide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C004479:pimagedine