Hypoxia modulates nitric oxide-induced regulation of NMDA receptor currents and neuronal cell death

Nitric oxide (NO) released from a new chemical class of donors enhances N-m ethyl-D-aspartate (NMDA) channel activity. Using whole cell and single-chan nel patch-clamp techniques, we have shown that (Z)-1-[N-(3-ammoniopropyl)-N -(n-propyl)amino]-NO -NO (PAPA-NO) and diethylamine NO, commonly termed NON Oates, potentiate the glutamate-mediated response of recombinant rat NMDA r eceptors (NR1/NR2A) expressed in KEK-293 cells. The overall effect is an in crease in both peak and steady-state whole cell currents induced by glutama te. Single-channel studies demonstrate a significant increase in open proba bility but no change in the mean single-channel open time or mean channel c onductance. Reduction in oxygen levels increased and prolonged the PAPA-NO- induced change in both peak and steady-state glutamate currents in transfec ted HEK cells. PAPA-NO also enhanced cell death in primary cultures of rode nt cortical neurons deprived of oxygen and glucose. This potentiation of ne uronal injury was blocked by MK-801, indicating a critical involvement of N MDA receptor activation. The NO-induced increase in NMDA channel activity a s well as NMDA receptor-mediated cell death provide firm evidence that NO m odulates the NMDA channel in a manner consistent with both a physiological role under normoxic conditions and a pathophysiological role under hypoxic conditions.