The present study tests the hypothesis that cerebral ischemia induced by severe hypocapnia results in tissue hypoxia and modifies the N-methyl-D-aspartate (NMDA) receptor/ion channel complex in the cerebral cortex of newborn piglets. Studies were performed in a control(normoxic) group (n=4) and hypocapnic (brain tissue hypoxic) group (n=4) of anesthetized and ventilated newborn piglets. Hypocapnia was induced by hyperventilation (PaCO2 = 9-11 mmHg) for 1 hr. Brain tissue hypoxia was confirmed biochemically in the hypocapnic (ischemic) group by an 80% decrease in [phosphocreatinine]. 3[H]MK-801 binding studies, an index of NMDA receptor activation, was performed at 32°C for 3 hours in an assay medium containing 20mM HEPES (pH 7.0), 75μg protein, glycine (100μM) and glutamate (100μM). Nonspecific binding was measured in the presence of 10μM unlabeled MK-801. Spermine-dependent activation was determined by adding increasing [spermine] from 2.5 to 50μM. Mg++ dependent binding was assayed separately in the presence of [Mg2+] from 2.5 to 100 μM. Maximal spermine-dependent activation in the control and hypocapnic groups was 19.8 ± 4.3% (at 5μM) and 47.6 ± 23.7% (at 6.7μM) above baseline, respectively. Maximal 3[H]MK-801 binding in the control and hypocapnic groups occurred at a [Mg2+] of 25μM and 5.8μM, respectively (p < 0.001). The data show that hypocapnic-induced tissue hypoxia results in increased spermine-dependent maximal activation and increased sensitivity to Mg++, indicating modification of the polyamine and Mg++ sites of the NMDA receptor. We conclude that hypocapnia-induced modification of the spermine and magnesium sites leads to increased activation of the NMDA receptor, resulting in increased NMDA receptor-mediated neurotoxicity in the newborn brain. (NIH-HD20337, MOD-6FY940135, UCP-R50693).
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Graham, E., Apostolou, M., Hoffman, D. et al. EFFECT OF HYPERVENTILATION ON THE SPERMINE AND MAGNESIUM SITES OF THE N-METHYL-D-ASPARTATE RECEPTOR IN THE BRAINS OF NEWBORN PIGLETS. †272. Pediatr Res 39 (Suppl 4), 48 (1996). https://doi.org/10.1203/00006450-199604001-00291
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DOI: https://doi.org/10.1203/00006450-199604001-00291