The response of the adrenal cortex to corticotropin during sepsis is variable. We have previously demonstrated a significant decrease of corticosterone production by rat adrenocortical cells in response to corticotropin stimulation after incubation with septic shock plasma (SP) as compared with control plasma (CP). We have studied the mechanisms of this depression. The following defects were demonstrated. (1) Cells bound less radioiodinated corticotropin analog after SP treatment (2.9 +/- 0.4 femtomoles/50 micrograms DNA) than after CP treatment (6.4 +/- 0.3 fmole/50 micrograms DNA). (2) Cyclic adenosine monophosphate (cAMP) production was less after SP treatment (59.3 +/- 4 pmole per 10(5) cells per two hours) compared with CP treatment (110.3 +/- 11.3 pmole per 10(5) cells per two hours). (3) Exogenously added dibutyryl cAMP was unable to correct the defect in corticosterone production after SP treatment (4.96 +/- 0.7 micrograms/24 hr) as compared with CP treatment (6.99 +/- 0.5 micrograms/24 hr). Our studies suggest this defect is located in the synthesis of pregnenolone from cholesterol. These mechanisms may be responsible for the low cortisol levels previously observed in humans during septic shock.