Nitric oxide modulates NMDA-induced increases in intracellular Ca2+ in cultured rat forebrain neurons.

We studied the effects of nitric oxide (NO) and the NO-releasing agents sodium nitroprusside (SNP), S-nitroso-N-acetylpenicillamine (SNAP) and isosorbide dinitrate (ISDN) on N-methyl-D-aspartate (NMDA)-induced increases in intracellular Ca2+ (Ca2+]i), whole-cell patch-clamp currents and on glutamate-stimulated 3H]dizocilpine binding. NO and agents that release NO partially inhibit increases in Ca2+]i at concentrations between 1 microM and 1 mM. These agents also decrease Ca2+]i changes produced by kainate and potassium, but to a smaller extent. As the effects of NO are still present following alkylation of the redox modulatory site on the NMDA receptor this action of NO is probably not a consequence of oxidation of the redox site. In contrast to SNP, ISDN does not inhibit NMDA-induced whole cell patch-clamp currents suggesting that NO modulates Ca2+]i via perturbation of a Ca2+ homeostatic process. Furthermore, SNP may have a direct action on the NMDA receptor complex in addition to the generation of NO. 8-Bromo-cGMP does not mimic the inhibitory effect of NO suggesting that this effect is not the result of NO stimulation of neuronal cGMP production. As the production of NO in neurons is dependent on increases in Ca2+]i associated with NMDA receptor activation, these data suggest that NO-mediated decreases in Ca2+]i may represent a novel feedback inhibitory mechanism for NO production in the brain.