Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts

Abstract

Rats made chronically hyperammonemic by portal systemic shunting were, 8 wk later, subjected to acute ammonia intoxication by i.p. injection of 5.2 mmol/kg of ammonium acetate. In free ranging animals, ammonia treatment induced a brief period of precoma (10-15 min) which progressed into deep, anesthetic coma lasting for several hours and was associated with a high mortality. In paralyzed, artificially ventilated animals which were lightly anesthetized with nitrous oxide, acute ammonia intoxication caused major disturbances of cerebral carbohydrate, amino acid, and energy metabolism which correlated in time with the change in function. At 10 min after injection (precoma), the concentrations of most glycolytic intermediates were increased, as was the lactate/pyruvate ratio. Citrate declined, despite a twofold rise in pyruvate, suggesting that the conversion of pyruvate to citrate had been impaired. Concentrations of phosphocreatine, and of the putative neurotransmitters, glutamate and aspartate, declined during precoma, but the concentrations of the adenine nucleotides in the cerebral hemispheres, cerebellum, and brain stem remained within normal limits. At 60 min after injection (coma), ATP declined in all regions of the brain, the reduction in total high energy phosphates being most notable in the brain stem. The findings indicate that cerebral dysfunction in chronic, relapsing ammonia intoxication is not due to primary energy failure. Rather, it is suggested that ammonia induced depletion of glutamic and aspartic acids, and inhibition of the malate aspartate hydrogen shuttle are the dominant neurochemical lesions.