MODIFICATION OF THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR IN THE BRAINOF NEWBORN PIGLETS FOLLOWING HYPERVENTILATION-INDUCED ISCHEMIA

The present study tests the hypothesis that cerebral ischemia induced by severe hypocapnia modifies the N-methyl-D-aspartate (NMDA) receptor /ion channel complex in the cerebral cortical cell membranes of newbor n piglets. Studies were performed in six newborn piglets subjected to ischemic hypoxia induced by hyperventilation (PaCO2, 9-11 mmHg) for 1 h. Comparisons were made to a normoxic group on room air (n = 6). Foll owing hyperventilation, phosphocreatine decreased 80%, but ATP remaine d unchanged. NMDA receptor activation was determined by measuring [H-3 ]MK-801 binding at concentrations varying from 2.5 to 50 nM. Following hyperventilation, B-max decreased 52% to 0.50 +/- 0.04 pmol/mg protei n (P = 0.001); however, the K-d value was unchanged at 7.45 +/- 0.79 n M. Spermine and magnesium dependent activation of the NMDA receptor wa s determined in the hyperventilated and control groups, With spermine concentrations increasing from 2.5 to 50 mu M the maximal spermine dep endent activation in the normoxic group was 13.7 +/- 7.93% which occur red at a concentration of 3.75 +/- 1.37 mu M. In the hyperventilated g roup maximal activation was 32.4 +/- 23.5% (P = 0.095) at 4.58 +/- 2.4 6 mu M (P = ns). With magnesium concentrations increasing from 2.5 to 100 mu M the maximal magnesium dependent activation in the normoxic gr oup was 17.0 +/- 13.6% which occurred at a concentration of 22.5 +/- 6 .12 mu M. In the hyperventilated group maximal activation was 26.3 +/- 14.9% (P = ns) at 4.58 +/- 2.92 mu M (P < 0.0001). These data show th at with less severe tissue hypoxia, as evidenced by conservation of AT P, there is less modification of the NMDA receptors. Ischemia induced by hyperventilation leads to an increase in spermine activation of the NMDA receptor, and the NMDA receptor is much more sensitive to magnes ium as evidenced by the maximal activation occurring at a significantl y lower magnesium concentration. Ischemia induced by hyperventilation modifies the spermine, magnesium, and MK-801 binding sites of the NMDA receptor and may result in increased NMDA receptor mediated neurotoxi city in the newborn brain.