NITROARGININE, AN INHIBITOR OF NITRIC-OXIDE SYNTHETASE, ATTENUATES AMMONIA TOXICITY AND AMMONIA-INDUCED ALTERATIONS IN BRAIN METABOLISM

We have proposed that acute ammonia toxicity is mediated by activation of the N-methyl-D-aspartate type of glutamate receptors. MK-801; a se lective antagonist of these receptors, prevents death of animals induc ed by acute ammonia intoxication as well as ammonia-induced depletion of ATP. It seems therefore that, following activation of the N-methyl- D-aspartate receptors, the subsequent events in ammonia toxicity shoul d be similar to those involved in glutamate neurotoxicity. As it has b een shown that inhibitors of nitric oxide synthetase such as nitroargi nine prevent glutamate toxicity, we have tested whether nitroarginine prevents ammonia toxicity and ammonia-induced alterations in brain ene rgy and ammonia metabolites. It is shown that nitroarginine prevents p artially (approximate to 50%), but significantly death of mice induced by acute ammonia intoxication. Nitroarginine also prevents partially ammonia-induced depletion of brain ATP. It also prevents completely th e rise in glucose and pyruvate and partially that in lactate. Injectio n of nitroarginine alone, in the absence of ammonia, induces a remarka ble accumulation of glutamine and a decrease in glutamate. The results reported indicate that nitroarginine attenuates acute ammonia toxicit y and ammonia-induced alterations in brain energy metabolites. The eff ects of MK-801 and of nitroarginine are different, suggesting that amm onia can induce nitric oxide synthetase by mechanisms other than activ ation of N-methyl-D-aspartate receptors.