EFFECTS OF ACUTE HYPERAMMONEMIA IN-VIVO ON OXIDATIVE-METABOLISM IN NONSYNAPTIC RAT-BRAIN MITOCHONDRIA

The effects of hyperammonemia induced in vivo by injecting rats with a mmonium acetate on oxidative phosphorylation, malate-aspartate shuttle , some related enzyme activities and metabolite levels in brain mitoch ondria were studied ex vivo. Rats were found to be either ammonia-sens itive (showing convulsions) or ammonia-resistant (without convulsions) after intraperitoneal injection of ammonium acetate (7 mmol/kg). Ammo nium acetate administration to ammonia-sensitive rats led to inhibitio n of State 3 rates of brain mitochondria utilizing pyruvate, glutamate , isocitrate, and succinate as substrates and to decreased respiratory control index. In brain mitochondria isolated from ammonia-resistant animals, the ammonia-induced effect on such State 3 rates was not obse rved. In brain mitochondria from hyperammonemic rats without convulsio ns, a small increase in the activity of malate dehydrogenase was obser ved; glutamate dehydrogenase, succinate dehydrogenase, and aspartate a minotransferase were not In brain mitochondria from rats with ammonia- induced convulsions, the of malate dehydrogenase and succinate dehydro genase were reduced significantly. Ammonium acetate injection to rats was associated with a 5-fold increase in the brain mitochondrial ammon ium ion content and a decrease (ca. 50%) in brain mitochondrial glutam ate and aspartate; brain mitochondrial malate and 2-oxoglutarate level s remained unchanged. The rate of the malate-aspartate shuttle in brai n mitochondria of hyperammonemic rats was decreased by 20% as compared to corresponding rate in control rats. We conclude that acute adminis tration of ammonium acetate induces serious disturbances in the electr on-transport chain, interferences of the malate-aspartate shuttle, alt erations of the levels of shuttle intermediates and inhibition of the activities of malate and succinate dehydrogenases in brain mitochondri a.