Adrenocorticotrophin (ACTH) administration raises blood pressure in humans, sheep, and the rat. ACTH hypertension can be reproduced in sheep by combined infusion of aldosterone, 17 alpha-OH-progesterone, and 17 alpha,20 alpha-OH-progesterone, and in humans by cortisol. In the rat, ACTH hypertension is probably due to corticosterone. Progesterone treatment can prevent ACTH-induced hypertension in sheep. This study examined the ability of progesterone to antagonize the onset and development of ACTH-induced hypertension in Sprague-Dawley rats (n = 44). We also investigated the relationship of plasma digoxin-like substances (DLS) to ACTH hypertension. ACTH (0.5 mg/kg/day) significantly increased blood pressure (+24 +/- 5 mm Hg, P < .001) in association with an increase of water intake, urine output, and plasma sodium concentration, and a decrease of body weight and plasma potassium concentration. ACTH increased plasma DLS (+132 +/- 18 pg/mL, P < .01), and there was a positive correlation between DLS and blood pressure (r = 0.68, n = 22, P < .001). Progesterone (50 mg/kg/day) did not block the development of ACTH-induced hypertension in the rat. Although progesterone prevented the ACTH-induced rise in plasma sodium and glucose concentration, it did not prevent the decrease in plasma potassium concentration. The failure of progesterone to prevent ACTH-induced hypertension in the rat argues against a common "hypertensinogenic" mechanism for ACTH hypertension in sheep and rat. DLS may play a role in ACTH-induced hypertension in the rat.