The role of epinephrine and norepinephrine in contributing to the alterations in hepatic glucose metabolism during a 70-h stress hormone infusion (SHI) was investigated in four groups of chronically catheterized (20-h-fasted) conscious dogs. SHI increased glucagon (approximately 5-fold), epinephrine (approximately 10-fold), norepinephrine (approximately 10-fold), and cortisol (approximately 6-fold) levels. Dogs received either all the hormones (SHI; n = 5), all the hormones except epinephrine (SHI-Epi; n = 6), or all the hormones except norepinephrine (SHI-NE; n = 6). In addition, six dogs received saline only (Sal). Glucose production (Ra) and gluconeogenesis were assessed after a 70-h hormone or saline infusion with the use of tracer ([3-(3)H]glucose and [U-(14)C]alanine) and arteriovenous difference techniques. SHI increased glucose levels (108 +/- 2 vs. 189 +/- 10 mg/dl) and Ra (2.6 +/- 0.2 vs. 4.1 +/- 0.3 mg x kg(-1) x min(-1)) compared with Sal. The absence of an increase in epinephrine markedly attenuated these changes (glucose and Ra were 140 +/- 6 mg/dl and 2.7 +/- 0.4 mg x kg(-1) x min(-1), respectively). Only 25% of the blunted rise in Ra could be accounted for by an attenuation of the rise in net hepatic gluconeogenic precursor uptake (0.9 +/- 0.1, 1.5 +/- 0.1, and 1.1 +/- 0.2 mg x kg(-1) x min(-1) for Sal, SHI, and SHI-Epi, respectively). The absence of an increase in norepinephrine did not blunt the rise in arterial glucose levels, Ra, or net hepatic gluconeogenic precursor uptake (they rose to 195 +/- 21 mg/dl, 3.7 +/- 0.5 mg x kg(-1) x min(-1), and 1.7 +/- 0.2 mg x kg(-1) min(-1), respectively). In summary, during chronic SHI, the rise in epinephrine exerts potent stimulatory effects on glucose production principally by enhancing hepatic glycogenolysis, although the rise in circulating norepinephrine has minimal effects.