NO DONORS STIMULATE NORADRENALINE RELEASE FROM RAT HIPPOCAMPUS IN A CALMODULIN-DEPENDENT MANNER IN THE PRESENCE OF L-CYSTEINE

Nitrogen oxides (NO) such as nitric oxide have been suggested to poten tiate neurotransmitter release in a variety of neuronal cells. In this study, we showed that NO donors stimulate the release of noradrenalin e (NA) from rat hippocampus both in vivo and in vitro. Co-addition of NO donors (sodium nitroprusside [SNP] or S-nitroso-N-acetylpenicillami ne [SNAP]) and thiol compounds (dithiothreitol [DTT] or L-cysteine) st imulated [H-3]NA release from prelabeled hippocampal slices. Microdial ysis in freely moving rats was used to ascertain the role of NO in con trol of NA release from the hippocampus in vivo. Co-addition of SNAP a nd L-cysteine stimulated endogenous NA release within 30 min. The conc entration of NA peaked between 30-60 min to almost 3 times basal level . Another thiol compound, glutathione, had no effect on [H-3]NA releas e in the presence of SNP or SNAP. In the presence of SNAP, the effect of L-cysteine was much higher than that of the D-isomer, although SNAP did not show stereospecificity. The effect of SNAP/L-cysteine was rap id and the maximal increase in [H-3]NA release was attained 0-1 min af ter application, which was similar in time course to the effect of KCl . Unlike the release by KCl, SNAP/L-cysteine-stimulated NA release was independent of extracellular CaCl2. However, pretreatment with the ca lmodulin antagonists W-7 or trifluoperazine significantly reduced the SNAP/L-cysteine-stimulated [H-3]NA release. Formation of nitric oxide and activation of guanylate cyclase by nitric oxide were not responsib le for SNAP/L-cysteine-stimulated NA release. These findings suggest t hat NO donors stimulate NA release from the hippocampus in the presenc e of thiol compounds such as L-cysteine in vivo and in vitro in a calm odulin-dependent, Ca2+- and cyclic GMP-independent manner. The physiol ogical roles of thiol compounds such as L-cysteine or glutathione as i ntermediates of NO are discussed. (C) 1996 Wiley-Liss, Inc.