Nitric Oxide Synthase Activity Endogenously Modulates NMDA Receptors

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Abstract
We tested the possibility that endogenous nitric oxide synthase activity regulated NMDA receptors in primary cultured striatal neurons. We monitored NMDA-induced increase in intra-cellular Ca2+ levels with fura-2 ratio imaging, while nitric oxide synthase activity was either increased with l-arginihe (the natural substrate of nitric oxide synthase) or inhibited using nitro-l-arginine (a specific inhibitor of nitric oxide synthase). We found that the NMDA receptor effect was slowly but strongly diminished after an l-arginine (1 mM, 15 min) treatment (l-arginine preincubation reduced the 100 μM NMDA-induced maximal effect by 30–50%). The l-arginine blockade of NMDA receptors was long-lasting but could be partially reversed by hemoglobin (100 μM, 10 min), which binds nitric oxide. This was not observed when the neurons were treated with l-arginine together with nitro-l-arginine. Our data strongly suggest that physiological nitric oxide synthase activity could regulate NMDA receptors.