Mechanisms of cerebral injury in perinatal asphyxia and strategies for prevention.

We have investigated the mechanisms of hypoxic brain cell injury in the immature animal by examining (1) the role of excitatory amino acid neurotransmitter receptors, (2) the receptor-mediated increase in intracellular Ca2+, and (3) the generation of oxygen free radicals. We examined the effect of brain tissue hypoxia on the NMDA receptor-ion channel complex including the glutamate, Mg2+, spermine, CPP, and the non-NMDA receptor kainate sites. Brain tissue hypoxia resulted in modification of the NMDA receptor ion channel and its modulatory sites. Hypoxia increased the affinity of both the ion channel and the glutamate recognition site. Pretreatment of animals with the glutamate antagonist CPP prevented hypoxia-induced modification of the channel. Similarly, pretreatment of animals with Mg2+, a blocker of the NMDA receptor ion channel, prevented the hypoxia-induced modification of the receptor. In addition, an increased agonist-dependent entry of Ca2+ into synaptosomes was observed in hypoxic animals compared with normoxic animals. Increased free radical generation in the cerebral cortex during hypoxia was demonstrated using spin labeling technique and electron spin resonance spectroscopy. We conclude that hypoxia-induced modification of the NMDA receptor-ion channel complex leads to increased intracellular Ca2+ potentiating free radical generation and resulting in hypoxic cell injury.

Decreased erythrocyte Na+,K(+)-ATPase activity associated with cellular potassium loss in extremely low birth weight infants with nonoliguric hyperkalemia.

To determine whether a shift of potassium ions from the intracellular space to the extracellular space accounts, in part, for the hyperkalemia seen in extremely low birth weight infants, we examined potassium concentration in serum and erythrocytes from extremely low birth weight infants with hyperkalemia (n = 12) or with normokalemia (n = 27). In addition, to determine whether the shift of potassium was associated with low sodium-potassium-adenosinetriphosphatase (Na+,K(+)-ATPase) activity, we studied the activity of ATPase in the last 16 infants enrolled in the study. Fluid intake and output were measured during the first 3 days of life. Infants were considered to have hyperkalemia if the serum potassium concentration was 6.8 mmol/L or greater. Blood was obtained daily for intracellular sodium and potassium levels by means of lysis of erythrocytes. The remaining erythrocyte membranes were frozen and analyzed for Na+,K(+)-ATPase activity. There were significantly lower intracellular potassium/serum potassium ratios in the infants with hyperkalemia for each day of the 3-day study (p < 0.001). In the hyperkalemic group, there was lower Na+,K(+)-ATPase activity than in the infants with normokalemia (p = 0.006). Low Na+,K(+)-ATPase activity was associated with lower intracellular potassium/serum potassium ratios (p = 0.006), higher serum potassium values (p = 0.02), and lower intracellular potassium concentration (p = 0.009). The urinary data demonstrated that there was no difference in glomerulotubular balance between the two groups. We conclude that nonoliguric hyperkalemia in extremely low birth weight infants may be due, in part, to a shift of potassium from the intracellular space to the extracellular space associated with a decrease in Na+,K(+)-ATPase activity.