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Nitric oxide and arachidonic acid act as inter- and intracellular messengers in the central nervous system. It is well known that the NMDA-mediated generation of nitric oxide and arachidonic acid is dependent on extracellular Ca2+. However, the role of voltage-dependent calcium channels (VDCCs) in this regard is poorly understood. We report here that NMDA-mediated nitric oxide production in striatal neuron cultures is blocked (80%) by the L-type VDCC antagonist nifedipine, but not by omega-conotoxin or omega-agatoxin IVA, antagonists of the N- and P-type VDCCs respectively. By contrast, none of the VDCC antagonists inhibited the NMDA-mediated release of arachidonic acid. These data indicate that permeation through different Ca2+ channels is responsible for the production of arachidonic acid and nitric oxide in striatal neurons.

We have studied the effect of CaM-kinase II inhibition induced by KN-62 on NO synthesis mediated by the activation of NMDA and kainate receptors in striatal neurones. KN-62 partially inhibited NMDA-mediated NO synthesis but the effect of kainate on NO production was unaffected by the specific CaM-kinase II inhibitor. Ionomycin-induced cGMP production and the NMDA-mediated superoxide generation by nNOS were also inhibited by KN-62. Since we determined the NO synthesis via its ability to increase intracellular cGMP, we checked that the kinase inhibitor was unable to block the cGMP production induced by a NO-donor like 3-morpholinosydnonimine (SIN-1). In conclusion, these results indicate that, depending on the glutamatergic receptors involved, CaM-kinase II could participate in the regulation of NO synthesis in striatal neurones.

Nitric oxide (NO) and arachidonic acid (AA) are believed to act as intra- and intercellular messengers in the central nervous system. Using primary cultures of striatal and hippocampal neurons, we have studied the effect of endogenous NO on N-methyl-D-aspartate (NMDA)-mediated AA release. Inhibition of NO synthesis with L-NG-nitroarginine (L-Noarg) produced a dose-dependent increase in NMDA-mediated AA release that was reversed by L-arginine. On the other hand, L-Noarg did not modify AA release produced by joint stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and phospholipase C-coupled metabotropic subtypes of glutamate receptors. Our results indicate that endogenously produced NO could modulate cellular events mediated by NMDA-induced AA release.