1. The effects of varying Pco2 on glucose output and the intracellular concentrations of lactate, pyruvate, phosphoenolpyruvate, 2-phosphoglycerate and 3-phosphoglycerate were studied in the isolated rat liver perfused with differing concentrations of lactate.

2. When the perfusate lactate concentration is above 1.5 mmol/l respiratory acidosis (simulated by high perfusate Pco2) inhibits gluconeogenesis from lactate, whereas respiratory alkalosis stimulates gluconeogenesis.

3. In general there were significant positive correlations between intracellular pH (pHl) and hepatocyte phosphoenolpyruvate, 2-phosphoglycerate and 3-phosphoglycerate concentrations, and negative correlations between pHl and lactate and pyruvate concentrations; there were usually significant correlations in the opposite sense between these metabolites and log Pco2.

4. The results suggest that CO2 exerts an inhibitory effect on gluconeogenesis at a step between pyruvate and phosphoenolpyruvate; however, this is not the only effect of CO2 on the gluconeogenic sequence. CO2 probably acts by changing pHl, but direct effects of CO2 and HCO3 cannot be excluded.

5. Except at low lactate concentrations, non-ionic diffusion probably does not play a major role in the entry of lactate into the hepatocyte.

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