Pii: S0304-3940(98)01002-7

We compared the effects of sodium nitroprusside (SNP), and of 8-bromo guanosine 3′,5′-cyclic monophosphate (8-BrcGMP), on the 4-aminopyridine (4-AP)-evoked Ca + -dependent release of glutamate from hippocampal nerve terminals and further investigated the role of protein kinase G (PKG) in this mechanism. SNP and 8-BrcGMP dose-dependently inhibited glutamate release, however SNP concentrations ([SNP]) . 500 mM abolished the 4-AP evoked release, whereas 8-BrcGMP maximally inhibited the release by about 30%. The inhibition of glutamate release at low concentrations of SNP (≤5 mM) was of about 20%, and was reversed by Rp-8(4-chlorophenylthio)guanosine-3′,5′-cyclic-monophosphorotioate) (RpCPTcGMP, 50 nM), but the inhibition at higher concentrations (5 , SNP ≤ 50 mM) was insensitive to the PKG inhibitor, but sensitive to [1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one] (ODQ), which partially prevented the inhibition. [SNP] . 50 mM strongly inhibited glutamate release, and this was not reversed by either inhibitor. Furthermore, [SNP] ≤ 50 mM enhanced cGMP formation, and the observed effects were not related to either decreased Ca + entry or ATP/ADP levels. Our results indicate that NO/PKG is the signaling pathway underlying the inhibition of glutamate release at low concentrations of NO, and imply that other NO-dependent, but PKG-independent, mechanisms are activated and have complementary roles at higher NO concentrations.  1999 Elsevier Science Ireland Ltd. All rights reserved.