The lipolytic and ketogenic effects of norepinephrine (NE) at levels present in the circulation or the synaptic cleft during stress were examined in the overnight-fasted conscious dog. Insulin and glucagon were maintained at basal levels while NE, at a rate of either 0.04 (n = 6) or 0.32 micrograms.kg-1.min-1 (n = 5), or saline (n = 6) was infused for 3 h. NE rose from 129 +/- 17 to 442 +/- 85 pg/ml (P less than 0.05) and 100 +/- 24 to 3,244 +/- 807 pg/ml (P less than 0.05) with the low and high infusion rates, respectively (unchanged with saline infusion). There were no significant changes in lipolysis or ketogenesis with saline infusion. Both low and high NE infusion produced sustained increases in glycerol (from 72 +/- 20 to 119 +/- 24 microM and 59 +/- 19 to 248 +/- 32 microM, respectively, both P less than 0.05), while nonesterified fatty acids (NEFA) rose from 609 +/- 85 to 952 +/- 100 and 767 +/- 140 to 2,054 +/- 199 microM (both P less than 0.05). Ketone levels and net hepatic production rose significantly only with the high NE infusion (from 88 +/- 10 to 266 +/- 46 microM and 1.30 +/- 0.26 to 7.62 +/- 1.48 mumol.kg-1.min-1, respectively, both P less than 0.05). The ratio of net hepatic ketone production to NEFA uptake rose 54% with high NE infusion. In conclusion, at circulating levels seen during stress, NE stimulates lipolysis but does not directly influence ketogenesis. At circulating levels projected to exist in the synaptic cleft during stress, NE has a potent lipolytic effect and stimulates ketogenesis.