The effects of increases in plasma epinephrine from 78 +/- 32 to 447 +/- 75, 1,812 +/- 97, or 2,495 +/- 427 pg/ml on glucose production, including gluconeogenesis, were determined in the conscious, overnight-fasted dog, using a combination of tracer [( 3-3H]glucose and [U-14C]alanine) and arteriovenous difference techniques. Insulin and glucagon were fixed at basal levels using a pancreatic clamp. Plasma glucose levels rose during the 180-min epinephrine infusion by 47 +/- 7, 42 +/- 22, and 74 +/- 25 mg/dl, respectively, in association with increases in hepatic glucose output of 1.04 +/- 0.22, 1.87 +/- 0.23, and 3.70 +/- 0.83 mg.kg-1.min-1 (at 15 min). Blood lactate levels rose by 1.52 +/- 0.24, 4.29 +/- 0.49, and 4.60 +/- 0.45 mmol/l, respectively, by 180 min, despite increases in hepatic uptake of lactate of 3.47 +/- 5.73, 12.83 +/- 3.46, and 37.00 +/- 4.20 mumol.kg-1.min-1. The intrahepatic gluconeogenic efficiency with which the liver converted the incoming alanine to glucose had risen by 84 +/- 40, 77 +/- 24, and 136 +/- 34% at 180 min, respectively. The latter effect plus the effect on net hepatic lactate uptake point to an intrahepatic action of high levels of the hormone in vivo. In conclusion, epinephrine produces dose-dependent increments in overall glucose production, which involve a progressive stimulation of both glycogenolysis (as assessed by glucose production at 15 min) and gluconeogenesis (assessed in the last 30 min of the study). The latter involves a peripheral action of the catecholamine to increase gluconeogenic substrate supply to the liver and may also involve a hepatic effect when high epinephrine levels are present.