NMDA receptor-mediated calcium influx in cerebral cortical synaptosomes ofthe hypoxic guinea pig fetus

Calcium influx via the NMDA receptor has been proposed as a mechanism of hy poxia-induced neuronal injury. The present study tests the hypothesis that the increase of [Ca2+](i) observed under hypoxic conditions is the result o f an NMDA-mediated Ca2+ influx. Changes of [Ca2+](i), measured fluorometric ally with Fura-2, were followed after activation of the NMDA receptor with NMDA and glutamate, in the presence of glycine, in cortical synaptosomes pr epared from six normoxic and six hypoxic guinea pig fetuses. [Ca2+](i) was significantly higher in hypoxic vs normoxic synaptosomes, at baseline and i n the presence of glycine as well as following activation of the NMDA recep tor. Increase in [Ca2+](i) was not observed in a Ca2+ free medium and was s ignificantly decreased by MK-801 and thapsigargin. These results demonstrat e that hypoxia-induced modifications of the NMDA receptor ion-channel resul ts in increased [Ca2+](i) in hypoxic vs normoxic synaptosomes. This increas ed accumulation may be due to an initial influx of Ca2+ via the altered NMD A receptor with subsequent release of Ca2+ from intracellular stores. Incre ase in intracellular calcium may initiate several pathways of free radical generation including cyclooxygenase, lipoxygenase, xanthine oxidase and nit ric oxide synthase, and lead to membrane lipid peroxidation resulting in ne uronal cell damage.