Effects of the Antiglucocorticoid RU 486 on Adrenal Function in Dogs*

Abstract

We studied the antiglucocorticoid effects of RU 486 given orally in doses of 5 (low), 20 (intermediate), and 50 mg/kg (high) daily for 10 days to seven female mongrel dogs. No changes in plasma ACTH or cortisol levels were produced by the 5 mg/kg dose. Plasma ACTH levels increased 3-fold with both intermediate and high dosages. Plasma cortisol levels rose 4-fold (P less than 0.05) within 2 days of commencing the high dose schedule and within 3 days with the intermediate dosage. Plasma aldosterone concentrations increased significantly only with the highest dose schedule. Plasma RU 486 levels rose progressively during the 10 days of RU 486 administration and with the highest dose remained elevated for 7 days after it was stopped. Plasma RU 486 levels measured by RIA and high pressure liquid chromatography were comparable. The monodemethylated metabolite of RU 486 changed in parallel to the parent compound. During the high dose of RU 486, there was a 4% increase in body weight, with a reduction in hematocrit and plasma protein concentration. Plasma electrolyte levels and osmolality did not change. We conclude that in dogs a daily RU 486 dose of 5 mg/kg does not alter adrenal function, whereas higher doses (20 and 50 mg/kg) induce increases in plasma ACTH and cortisol concentrations. Despite the blockade of glucocorticoid receptors by RU 486, the presence of isotonic hypervolemia suggests that there was no functional deficiency of cortisol at the renal tubule or it was overshadowed by augmented mineralocorticoid production and action.