CEREBRAL CARBOHYDRATE METABOLISM DURING ACUTE HYPOXIA AND RECOVERY¹

Abstract

Abstract— The levels of ATP, ADP, AMP and phosphocreatine, of four amino acids, and of 11 intermediates of carbohydrate metabolism in mouse brain were determined after: (1) various degrees of hypoxia; (2) hypoxia combined with anaesthesia; and (3) recovery from severe hypoxia. Glycogen decreased and lactate rose markedly in hypoxia, but levels of ATP and phosphocreatine were normal or near normal even when convulsions and respiratory collapse appeared imminent. During 30 s of complete ischaemia (decapitation) the decline in cerebral ATP and phosphocreatine and the increase in AMP was less in mice previously rendered hypoxic than in control mice. From the changes we calculated that the metabolic rate had decreased by 15 per cent or more during 30 min of hypoxia. Hypoxia was also associated with decreases of cerebral 6‐phosphogluconate and aspartate, and increases in alanine, γ‐aminobutyrate, α‐ketoglutarate, malate, pyruvate, and the lactate :pyruvate ratio. Following recovery in air (10 min), increases were observed in glucose (200 per cent), glucose‐6‐phosphate, phosphocreatine and citrate, and there was a fall in fructose‐1, 6‐diphosphale. Similar measurements were made in samples from cerebral cortex, cerebellum, midbrain and medulla. Severe hypoxia produced significant increases in lactate and decreases in glycogen in all areas; γ‐aminobutyrate levels increased in cerebral cortex and brain stem, but not in cerebellum. No significant changes occurred in ATP and only in cerebral cortex was there a significant fall in phosphocreatine. Phosphocreatine, ATP and glycogen were determined by quantitative histochemical methods in four areas of medulla oblongata, including the physiological respiratory centre of the ventromedial portion. After hypoxia, ATP was unchanged throughout and the changes (decreases) in phosphocreatine and glycogen were principally confined to dorsal medulla, notably the lateral zone. Thus there is no evidence that respiratory failure is caused by a ‘power’ failure in the respiratory centre. It is suggested that in extremis a protective mechanism may cause neurons to cease firing before high‐energy phosphate stores have been exhausted.

Cellular Effects of Isoflurane on Bulbar Respiratory Neurons in Decerebrate Cats

“…Brain GABA content increases during a relatively short period of ischemia (38,48) and hypoxia (30,36,49), and this is considered to be due to stimulation of glutamic acid decarboxylase and inhibition of GABA transaminase (38). In contrast, we have shown a marked decrease in cerebral GABA content in microsphere-embolized rats in the present study.…”

“…There are conflicting results with respect to changes in cerebral amino acids following hypoxia and ischemia. For example, cerebral glutamate levels were found to be decreased in hypoxemia (35) and in acute hypoxia (36), but to be increased in ischernia (37,38). Presumably, the difference is due to the different periods and degrees of ischemia or hypoxia induced.…”

Secobarbital Attenuates Excitotoxicity but Potentiates Oxygen—Glucose Deprivation Neuronal Injury in Cortical Cell Culture

“…As discussed above, barbitu rates can inhibit oxidative phosphorylation. Despite other presumably favorable effects on metabolic rate, Oberpichler et al (1990) observed that meth ohexital failed to ameliorate the loss of ATP in chick cerebral cultures exposed to cyanide, and Duffy et al (1972) found no significant effect of pen tobarbital on ATP levels in mouse brains exposed to hypoxia. Furthermore, Dagani and Erecinska (1987) observed that amy tal intensified A TP deple tion in glucose-deprived synaptosomes.…”

Reversible uncoupling of oxidative phosphorylation at low oxygen tension.

“…The horizontal broken lines (----) show, for reference, the average P/ O ratio determined by direct assay in five uninhibited preparations metabolizing 10 (30) were observed at levels of arterial hypoxemia previously characterized by a significant loss of brain phosphocreatine stores (31), levels at which it has also been demonstrated that cerebral energy utilization is, if anything, slightly decreased (32). The apparently universal distribution, among aerobic cells, of the enzyme superoxide dismutase implies that oxygen-dependent organisms are continuously threatened by free radical oxygen (33,34).…”