Acute acid-base disturbances cause rapid changes in renal ammonia production in the rat. To investigate the regulation of ammonia production in acute acid-base stresses, we examined the effects of such conditions on tissue levels of metabolites such as alpha-ketoglutarate (KG), which inhibits kidney mitochondrial glutamine uptake and deamidation at physiological concentrations. In rats given low (5 mmol/kg) or high (20 mmol/kg) doses of NH4Cl by stomach tube or placed in a 10% CO2 atmosphere, kidney KG levels fell after 1-h by 44, 69, or 73%, respectively. NaHCO3 administration produced no change in KG levels. Renal glutamate and glutamine levels changed little, if at all, in any group, and renal phosphoenolpyruvate levels were not altered except for a decrease in the NH4HCO3 group. In livers of the same rats, treatments produced different patterns of metabolite changes; KG fell only in the NaHCO3 and NH4HCO3 groups. These results support the concept that KG is a specific regulator of renal ammonia production in acute acid-base stresses.