In view of the increasing frequency of liver transplantation, and the importance of glucagon in the minute-to-minute regulation of glucose production, we assessed the effect of hepatic denervation on the liver's response to a physiological rise in glucagon in 18-h fasted dogs. Before study (2 wk), the dogs underwent liver denervation (DN; n = 6) or sham operation (SH; n = 5). Endogenous insulin and glucagon secretion were inhibited using somatostatin, and the two hormones were replaced intraportally in basal amounts. After the control period the glucagon infusion rate was tripled for 3 h. Glucagon increased from 41 +/- 8 to 128 +/- 8 and 54 +/- 4 to 129 +/- 9 pg/ml in SH and DN, respectively (P < 0.05), causing tracer-determined glucose production to increase from 2.5 +/- 0.1 to 4.9 +/- 0.5 and 2.3 +/- 0.1 to 5.8 +/- 0.8 mg.kg-1.min-1 by 15 min, respectively (P < 0.05). Glucose clearance fell slightly during glucagon infusion in DN, causing a somewhat greater increase in the plasma glucose level (to 175 +/- 15 vs. 207 +/- 20 mg/dl). The changes in gluconeogenic efficiency increased 65-90% in both groups (P < 0.05). In conclusion, denervation of the liver failed to significantly alter the metabolic response of that organ to a half-maximally effective increment in the plasma glucagon level.