The effects of chronic administration of counterregulatory hormones on hepatic glycogenolysis and gluconeogenesis were investigated. We studied 14 20-h fasted conscious dogs prior to (day 0) and after a 70-h stress hormone (SHI, n = 7) or saline (n = 7) infusion (day 3). Glucose production and gluconeogenesis were assessed using tracer and arteriovenous difference techniques. SHI increased plasma glucagon, cortisol, epinephrine, and norepinephrine levels approximately fivefold. SHI increased the arterial plasma glucose and insulin concentrations (110 +/- 2 to 204 +/- 19 mg/dl and 13 +/- 2 to 36 +/- 3 microU/ml on day 3). Tracer-determined glucose appearance and net hepatic glucose output were increased 80 and 60%, respectively. Net hepatic lactate uptake and fractional extraction were increased by 11.2 +/- 3.8 and 0.51 +/- 0.18 mumol.kg-1 x min-1, respectively, as was net hepatic glycerol uptake (1.0 +/- 0.6 mumol.kg-1 x min-1). Net hepatic fractional alanine extraction was also increased by 0.37 +/- 0.03 mumol.kg-1 x min-1; however, net hepatic alanine uptake was not altered. The efficiency of alanine conversion to glucose almost doubled (0.33 +/- 0.05 to 0.59 +/- 0.09). Renal glucose production was also increased, accounting for 33% of the increase in glucose turnover. This increase was paralleled by an increase in renal gluconeogenic precursor uptake. In conclusion, SHI created marked hyperglycemia and hyperinsulinemia and elevated glucose production from both the liver and the kidney, with gluconeogenesis accounting for approximately 70% of the response.