Chains of lumbar sympathetic ganglia from 15-day-old chicken embryos were incubated for 4 h at 36 degrees C in a bicarbonate-buffered salt solution equilibrated with 5% CO2-95% O2. Glucose (1-10 mM), lactate (1-10 mM), [U-14C]glucose, [1(-14)C]glucose, [6(-14)C]glucose, and [U-14C]lactate were added as needed. 14CO2 output was measured continuously by counting the radioactivity in gas that had passed through the incubation chamber. Lactate reduced the output of CO2 from [U(-14)C]glucose, and glucose reduced that from [U(-14)C]lactate. When using uniformly labeled substrates in the presence of 5.5 mM glucose, the output of CO2 from lactate exceeded that from glucose when the lactate concentration was > 2 mM. The combined outputs at each concentration tested were greater than those from either substrate alone. The 14CO2 output from [1(-14)C]glucose always exceeded that from [6(-14)C]glucose, indicating activity of the hexose monophosphate shunt. Lactate reduced both of these outputs, with the maximum difference between them during incubation remaining constant as the lactate concentration was increased, suggesting that lactate may not affect the shunt. Modeling revealed many details of lactate metabolism as a function of its concentration. Addition of a blood-brain barrier to the model suggested that lactate can be a significant metabolite for brain during hyperlactemia, especially at the high levels reached physiologically during exercise.