Modification of septic shock in mice by the antiglucocorticoid RU 38486

The survival rate in murine septic peritonitis was inversely proportional to the size of the needle used for cecal puncture following ligation below the ileocecal valve. The smaller, 20-gauge needle permitted 20% survival. Only 20% of the animals survived 24 hr after cecal puncture with a 20-gauge needle compared to 90% survival after 5 days if mice had been rendered tolerant to lipopolysaccharide (LPS) prior to the induction of peritonitis. A single intravenous injection of 1 mg RU 38486, concurrent with puncture with a 21-gauge needle, lowered survival to only 15% from the control level of 71%. This same dose of the antiglucocorticoid decreased the survival rate to only 35% from 90% in the tolerant group. Tolerance to the lethal effects of endotoxins, possibly responsible for resistance to septic peritonitis, was also abolished by the antiglucocorticoid. Just 1 mg RU 38486 lowered the survival rate to 5% if it was given with 600 micrograms LPS, which permitted 95% survival in LPS-tolerant mice and 60% survival in normal controls. Whereas both 1 mg RU 38486 and 100 micrograms dexamethasone, given alone, sensitized mice to septic peritonitis (15% and 30% survival, respectively), their combined effects neutralized each other, leading to 80% survival vs. 71% in the control group. Thus receptor-mediated glucocorticoid-dependent mechanisms appear important in the pathogenesis of both endotoxin and septic shock, albeit to varying degrees and in a seemingly contradictory manner.