The acute metabolic effects of epinephrine and cortisol, as well as the influence of substrate background on the effects of these two hormones were investigated in normal subjects. While receiving a hypocaloric dextrose feeding (50 ng/kg/h) (DEX), the subjects received a 6-hour continuous intravenous infusion of epinephrine (30 ng/kg-min) (EPI), followed by a 6-hour infusion of a combination of epinephrine (30 mg/kg-min) and cortisol (3.0 microgram/kg-min) (EC). The hormone infusion was repeated 1 week after a continuous intravenous feeding regimen (TPN) was begun with a caloric content of 1.5 times the measured metabolic rate. Under both DEX and TPN, EPI produced increased energy expenditure, hyperglycemia, hyperlactic acidemia, and hypoaminoacidemia. Except for a further increase in circulating glucose levels during the DEX condition, these variables were not altered by the addition of cortisol. Epinephrine under both feeding conditions increased lactate efflux from the extremity without changes in peripheral oxygen or glucose uptake. The hypoaminoacidemic response to EPI in the DEX condition was associated with a decrease in extremity efflux of amino acids (-654 +/- 89 nmol/min/100 cm3 tissue at baseline vs -330 +/- 86 nmol/min/100 cm3 for EPI, p less than 0.05). No change in extremity amino acid flux was noted in response to EPI during total parenteral nutrition. Even with addition of cortisol no significant efflux of amino acids above baseline levels was noted in either feeding condition. We therefore conclude that (1) total parenteral nutrition cannot abolish the hypermetabolic or hyperglycemic response to epinephrine and cortisol; (2) increased extremity lactate efflux and lactic acidosis can occur in response to epinephrine without evidence of diminished oxygen delivery to the extremity; and (3) these two hormones are not primary mediators of acute extremity nitrogen loss.