Glucocorticoids are the most potent antiinflammatory drugs. Large doses of dexamethasone and other glucocorticoids are widely used in the clinic but the mechanism of the beneficial effects of megadoses still remains to be explained. We tested the effects of a dexamethasone (DEX) megadose therapy in a rat model of anaphylactic shock. By combining DEX with the potent glucocorticoid receptor antagonist RU 486 we looked for evidence of a non-specific action of the glucocorticoid at high doses. A dose of 10 mg/kg DEX given 2 h before challenge protected the heart against the symptoms of cardiac anaphylaxis: heart rate was improved by 22%, ventricular contractility by 13% and coronary flow by 5%. Administration of 20 mg/kg RU 486, 30 min before dexamethasone, reduced the beneficial effect of DEX by about 30%, although this failed to reach statistical significance. We found no dose-response relationship for the high dexamethasone doses of 0.5-10 mg/kg. In experimental allergic encephalomyelitis (EAE) there was a surprising toxic action of DEX after daily doses of 0.25 mg/kg for 5 days, and also following single administration of 2.5 or 10 mg/kg. A single dose of 1.25 mg/kg, given on the day of immunization alone or with additional doses at weekly intervals for 3 weeks, caused a strong inhibition of the EAE. In summary we conclude that the present data of cardiac anaphylaxis hardly point to extra glucocorticoid megadose effects. The present dexamethasone effects in cardiac anaphylaxis and in EAE have to be cleared up by further experiments.