Effects of NH4Cl on oxidative metabolism of cat cerebral cortex slices and mitochondria incubated in vitro were studied. In slices, addition of 10 mm NH4Cl to the incubation medium resulted in significant (16%) reduction of O2 uptake, doubling of lactic acid production and marked increase of glucose utilization compared to control slices. Mitochondria showed a 30–40% decrease of O2 consumption in the presence of 15 mm NH4Cl when pyruvate or α-ketoglutarate were substrates, but little if any difference from controls with succinate, glutamic acid or γ-aminobutyric acid as substrates. Pyruvate utilization by ammonia-treated mitochondria was inhibited to the same degree as O2 consumption and was not increased by supplementing the incubation medium with excess succinate. Additions of α-lipoic acid, thiamine pyrophosphate or DPN to such preparations failed to reverse the NH4Cl effect. Satisfactory P/O ratios were obtained for all mitochondrial preparations. It is concluded that a primary toxic effect of ammonia on the brain may be direct interference with oxidative decarboxylation of pyruvic and α-ketoglutaric acids.
