We have previously shown that activity of the nuclear membrane high-affinity Ca++-ATPase, one of the mechanisms responsible for endonuclear Ca++ homeostasis, is altered in fetal guinea pig brain during hypoxia. The present study tests the hypothesis that nuclear Ca++-ATPase activity in the cerebral cortex of newborn piglets will be differentially altered by hypoxia compared to asphyxia. Following 1 hr of ventilation with normal PaO2 and PaCO2, animals were randomized to 3 groups: control: 1 hr ventilation with normal PaO2 (n=8); hypoxia: 1 hr ventilation with FiO2 0.05-0.08 to achieve PaO2 <20 mmHg(n=6); or asphyxia: 30 min ventilation with FiO2 0.07-0.08 followed by 5-7 min of endotracheal tube occlusion (n=6). ATP and phosphocreatine(PCr)were measured in cerebral cortex to assess the degree of tissue hypoxia. Nuclear membranes were prepared from cerebral cortex and Mg++-dependent high-affinity Ca++-ATPase activity was determined. At the end of hypoxia, pH decreased from control of 7.41 ± 0.05 to 6.96 ± 0.16(p<0.05), PaO2 was 21 ± 4 mmHg (p<0.05 vs control of 102± 10), and PaCO2 was 30 ± 10 mmHg (p=ns vs control of 39± 3). At the end of asphyxia, pH was 6.65 ± 0.10, PaO2 was 13 ± 8 mmHg, and PaCO2 was 95 ± 19 mmHg (p<0.05 vs control and hypoxia for all 3 parameters). Blood lactate concentrations at the end of hypoxia increased significantly to 12.8 ± 2.7 mmol/L (p<0.05 vs control of 1.6 ± 0.4) and were not significantly different from the asphyxia value of 11.4 ± 2.3 mmol/L. ATP decreased from control of 4.4± 1.0 mmoles/g brain to 0.1 ± 0.1in hypoxia (p<0.05) and 0.9± 0.9 in asphyxia (p<0.05). PCr also decreased significantly, from control of 2.5 ± 0.7 mmoles/g brain to 0.4 ± 0.3 in hypoxia and 0.3 ± 0.4 in asphyxia. There was no significant difference in tissue levels of ATP or PCr in hypoxia vs asphyxia. Mg++-dependent activity of the nuclear membrane Ca++-ATPase (nmoles Pi/mg protein/hr) was 412± 95 in control and decreased to 291 ± 25 during hypoxia(p<0.05). In contrast, Mg++-dependent Ca++-ATPase activity in nuclear membranes from piglets exposed to an asphyxic insult was 455 ± 55, not significantly different from control. Thus there was a differential effect of hypoxia and asphyxia on nuclear membrane Ca++-ATPase activity that does not appear to be related to availability of high energy phosphates. We speculate that severe acidosis during asphyxia may decrease Ca++ influx via the NMDA receptor-associated ion channel, decreasing Ca++-mediated alterations in the nuclear membrane and maintaining nuclear Ca++-ATPase activity at control levels.
