The influence of a novel glucocorticoid antagonist on endotoxin lethality in mice strains

Ru 38486 is a recently synthesized molecule which has little intrinsic agonist or antagonist activity but which is specifically capable of antagonizing selected glucocorticoid-induced processes such as liver enzyme induction and gluconeogenesis. This material sensitized both the Swiss albino OF1 and the refractory C3H/HeJ strain of mice to endotoxin lethality and impaired the protective effect of dexamethasone under these conditions. The effect of Ru 38486 and endotoxin was not additive on liver tryptophan pyrrolase and tyrosine transaminase but hepatic glycogen depletion was significantly greater than both agents were given as compared to either of them alone. Ru 38486 was without effect on the activity of the reticuloendothelial system as evidenced by both the clearance of carbon and the distribution of foreign red blood cells. In doses that protected OF1 mice against Ru 38486-mediated sensitization to endotoxin lethality, liver enzyme and glycogen levels were still below normal, albeit significantly greater than in animals succumbing to the toxin. These results constitute the first evidence that a drug acting specifically at the level of the glucocorticoid receptor can modulate the course of endotoxicosis.