1. Two-day-old rats were exposed at constant temperature to atmospheres containing air and
nitrogen with the air content varied in steps from 100 to 0%. By using this system of graded
hypoxia a comparison was made between rates of gluconeogenesis from
lactate,
serine and
aspartate in the whole animal and the concentrations of several liver metabolites. 2. Gluconeogenesis, expressed as the percentage incorporation of labelled
isotope into
glucose plus
glycogen, proceeds linearly for 30min when the animals are incubated in a normal air atmosphere, but is completely suppressed if the atmosphere is 100%
nitrogen. 3. Preincubation of animals for between 5 and 30min under an atmosphere containing 19% air results in the attainment of a new steady state with respect to gluconeogenesis and hepatic concentrations of
ATP,
ADP,
AMP,
lactate,
pyruvate,
beta-hydroxybutyrate and
acetoacetate. 4. When
lactate (100mumol),
aspartate (20mumol) or
serine (20mumol) was injected, it was shown that the more severe the
hypoxia the greater the depression of gluconeogenesis. Under conditions when gluconeogenesis was markedly inhibited there were no changes in the degree of phosphorylation of hepatic
adenine nucleotides, but free [
NAD(+)]/[
NADH] ratios fell in both cytosol and mitochondrial compartments of the liver cell. 5. Measurements of total liver
NAD(+) and
NADH showed that the concentrations of these
nucleotide coenzymes changed less with
anoxia, in comparison with the concentration ratio of free
coenzymes. 6. Calculations showed that the difference in
NAD(+)-
NADH redox potentials between mitochondrial and cytosol compartments increased with the severity of
hypoxia. 7. From the constancy of the concentrations of
adenine nucleotides it is concluded that liver of hypoxic rats can conserve
ATP by lowering the rate of
ATP utilization for gluconeogenesis. Gluconeogenesis may be regulated in turn by the changes in mitochondrial and cytosol redox state.