Cortisol-induced inhibition of ACTH secretion in adult sheep

Previous results from this laboratory have demonstrated that in preterm fetal sheep (117-131 days gestation), stimulated ACTH secretion is highly sensitive and that in term fetal sheep (129-143 days), stimulated ACTH secretion is insensitive to the negative feedback effects of cortisol. The purpose of this study was to quantitate cortisol negative feedback inhibition of stimulated ACTH secretion in adult sheep. Adult, conscious, nonpregnant ewes, chronically prepared with carotid arterial loops, were infused intravenously with vehicle or cortisol at 4 different rates (denoted Groups I, II, III, and IV) for 5 hours. These infusions increased total and unbound plasma cortisol concentrations within the range observed after stimulation of the hypothalamus-pituitary-adrenal axis. One hour after termination of the cortisol or vehicle infusions, ACTH secretion was stimulated by intravenous infusion of sodium nitroprusside for 10 min at a rate of 20 micrograms/kg.min. Cortisol infusions suppressed ACTH responses to nitroprusside in a dose-related manner. After vehicle infusion, nitroprusside increased plasma ACTH to 735 +/- 229 pg/ml. After cortisol infusions, nitroprusside increased plasma ACTH to 292 +/- 63, 101 +/- 30, 73 +/- 12, and 67 +/- 24 in Groups I, II, III, and IV, respectively. Overall, there was a significant negative exponential relationship between plateau plasma cortisol concentration during the cortisol or vehicle infusion and the peak plasma ACTH concentration during the response to nitroprusside infusion (r = -0.81). The highest rate of cortisol infusion increased total and unbound plasma cortisol concentrations to 40.1 +/- 5.7 and 19.5 +/- 5.9 ng/ml and completely suppressed the subsequent ACTH response to nitroprusside.