Cellular mechanisms of the antiammoniagenic effect of ketone bodies in the dog.

To investigate the mechanisms of the antiammoniagenic effect of ketone bodies, acidotic dogs (NH4Cl) were infused with either beta-hydroxybutyrate or acetoacetate. Total blood ketones ranged from 2 to 4 mM. Renal ammoniagenesis fell by a mean of 53%, with a proportional decrease in glutamine extraction. Glutamate release in the renal vein rose, renal extraction of lactate fell, and aspartate and alanine production decreased. Study of the metabolite profile of the renal cortex by the freeze-clamp technique before and after ketone infusion showed that tissue glutamine concentration was unchanged, whereas glutamate, alpha-ketoglutarate, malate, and citrate rose. The intermediates of the gluconeogenic pathway, such as phosphoenolypyruvate, 2-phosphoglycerate, 3-phosphoglycerate, and glucose-6-phosphate, fell significantly. The redox state as calculated from the free NAD+/NADH ratios in the cytosolic (lactate dehydrogenase) and the mitochondrial (glutamate dehydrogenase and beta-hydroxybutyrate dehydrogenase) compartments was reduced. The present study suggests that ketone bodies inhibit renal ammoniagenesis through increased generation of alpha-ketoglutarate (metabolic or bicarbonate effect) and a decrease in the mitochondrial and cytosolic redox potentials in the kidney.