In eight experiments in which a paired crossover design was used, we studied the ability of physiologic levels of cortisol to block adrenocorticotropic hormone (ACTH) and vasopressin responses to hypotension in fetal lambs. On different days, each fetus received a 4-hour infusion of cortisol or ethanol-saline solution vehicle, and then hypotension was induced with nitroprusside. Mean levels of ACTH before manipulation were 20 +/- 10 pg/ml and 18 +/- pg/ml in the saline solution- and cortisol-treated animals, respectively. Mean values of ACTH increased significantly to 70, 88, and 127 pg/ml at 2.5, 5, and 10 minutes of hypotension after pretreatment with saline solution. Cortisol pretreatment abolished the fetal ACTH response to hypotension. Mean levels of vasopressin during the control period were similar in the two groups of animals (5.7 +/- 1.5 pg/ml versus 5.9 +/- 1.3 pg/ml) and rose to comparable levels (69.4 +/- 15.6 pg/ml versus 65.2 +/- 7.7 pg/ml) during hypotension. Thus, increases in plasma cortisol levels within a physiologic range can suppress hypotension-induced ACTH but not vasopressin release in the fetus.