Protein breakdown in acute uremia is enhanced, as evidenced by an increment in amino acid release from skeletal muscle and an increased amino acid uptake and urea and glucose production by the liver. To study whether this metabolic pattern is mediated by glucocorticoids, we investigated the effect of the antiglucocorticoid RU 38486 on both muscle protein breakdown and urea and glucose production of isolated hepatocytes in acutely uremic rats. Animals were rendered uremic by bilateral nephrectomy (BNX). Forty-eight hours after BNX, the rats had markedly elevated serum levels of urea nitrogen, creatinine, potassium, and phosphorus. In uremic rats receiving RU 38486 comparable levels of serum creatinine were found, but the serum levels of urea nitrogen (221 +/- 4 vs. 259 +/- 5 mg/dl) and phosphorus (6.5 +/- 0.3 vs. 8.5 +/- 0.4 mmol/liter) were significantly decreased as compared to uremic animals without RU 38486. In comparison to sham operated rats, urea-N appearance (net urea production) was increased by 56% 48 hours after BNX. This increment was almost completely reversed in uremic animals receiving the antiglucocorticoid. In untreated uremic rats, plasma levels of Nt-methylhistidine were 10.3 +/- 0.9 micrograms/dl, whereas the administration of RU 38486 caused a significant decline in the levels of this amino acid (7.6 +/- 0.5 micrograms/dl). Hepatic glucose production in BNX rats was significantly increased from alanine (+174%), glutamine (+158%), and serine (+87%) as compared to sham-operated controls. Concomitantly, hepatic urea formation from amino acid substrates was also enhanced in BNX animals. With the administration of RU 38486 to acutely uremic rats, both hepatic glucose and urea production were normalized.(ABSTRACT TRUNCATED AT 250 WORDS)