To examine the effects of a physiological increase in plasma epinephrine concentration (approximately 800 pg/ml) on muscle glycogenolysis and insulin-stimulated glycogenesis, we infused epinephrine [1.2 micrograms.(m2 body surface)-1.min-1] for 2 h and monitored muscle glycogen and glucose 6-phosphate (G-6-P) concentrations with 13C/31P nuclear magnetic resonance (NMR) spectroscopy. Epinephrine caused an increase in plasma glucose (delta approximately 50 mg/dl), lactate (delta approximately 1.4 mM), free fatty acids (delta approximately 1,200 microM at peak), and whole body glucose oxidation (delta approximately 0.85 mg.kg-1.min-1) compared with levels in a group of control subjects (n = 4) in the presence of slight hyperinsulinemia (approximately 13 microU/ml, n = 8) or basal insulin (approximately 7 microU/ml, n = 7). However, epinephrine did not induce any detectable changes in glycogen or G-6-P concentrations, whereas muscle inorganic phosphate (Pi) decreased by 35%. Epinephrine infusion during a euglycemic-hyperinsulinemic clamp (n = 8) caused a 45% decrease in the glucose infusion rate that could be mostly attributed to a 73% decrease in muscle glycogen synthesis rate. After an initial increase to approximately 160% of basal values, G-6-P levels decreased by approximately 30% with initiation of the epinephrine infusion. We conclude that a physiological increase in plasma epinephrine concentration 1) has a negligible effect on muscle glycogenolysis at rest, 2) decreases muscle Pi, which may maintain phosphorylase activity at a low level, and 3) causes a major impairment in insulin-stimulated muscle glycogen synthesis, possibly due to inhibition of glucose transport-phosphorylation activity.