Cerebral ammonia metabolism in normal and hyperammonemic rats

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Abstract
Brain ammonia is generated from many enzymatic reactions, including glutaminase, glutamate dehydrogenase, and the purine nucleotide cycle. In contrast, the brain possesses only one major enzyme for the removal of exogenous ammonia, i.e., glutamine synthetase. Thus, following administration of [13N]ammonia to rats [via either the carotid artery or cerebrospinal fluid (csf)], most metabolized label was in glutamine (amide) and little was in glutamate (plus aspartate). Since blood-and csf-borne ammonia are converted to glutamine largely, if not entirely, in the astrocytes, it is not possible from these types of experiments to predict with certainty the metabolic fate of the bulk of endogenously produced ammonia. By comparing the specific activity ofl-[13N]glutamate to that ofl-[amine-13N]glutamine following intracarotid [13N]ammonia administration it was concluded that metabolic compartmentation is no longer intact in the brains of rats treated with the glutamine synthetase inhibitorl-methionine-SR-sulfoximine (MSO) and that blood and brain ammonia pools mix in such animals. In MSO-treated animals, recovery of label in brain was low (∼20% of controls), and of the label remaining, a prominent portion was in glutamine (amide) (despite an 87% decrease in brain glutamine synthetase activity). These data are consistent with the hypothesis that glutamine synthetase is the major enzyme for metabolism of endogenously—as well as exogenously—produced ammonia. The rate of turnover of blood-derived ammonia to glutamine in normal rat brain is extremely rapid (t 1/2≤3 s), but is slowed in the brains of chronically (12–14-wk portacaval-shunted) or acutely (urease-treated) hyperammonemic rats (t 1/2≤10 s). The slowed turnover rate may be caused by an increased astrocytic ammonia, decreased glutamine synthetase activity, or both. In the hyperammonemic rat brain, glutamine synthetase is still the only important enzyme for the removal of blood-borne ammonia. Hyperammonemia causes an increase in brain lactate/pyruvate ratios and decreases in brain glutamate and brainstem ATP, consistent with an interference with the malate-aspartate shuttle. In vitro, pathological levels of ammonia also inhibit brain α-ketoglutarate dehydrogenase complex and, less strongly, pyruvate dehydrogenase complex. The rat brain does not adapt to prolonged hyperammonemia by increasing its glutamine synthetase activity. Therefore, since the brain only has a limited capacity to buffer against excess ammonia, it is important that diseases in which hyper-ammonemia is a prominent feature be treated to reduce the associated hyperammonemia as much as possible.