Nitrogen oxides, such as nitric oxide, have been shown to regulate neuronal functions, including neurotransmitter release. We investigated the effect of S-nitroso-L-cysteine (SNC) on noradrenaline (NA) release in the rat hippocampus in vivo and in vitro. SNC stimulated [3H]NA release from prelabeled hippocampal slices in a dose-dependent manner. SNC stimulated endogenous NA release within 30 min to almost five times the basal level in vivo (microdialysis in freely moving rats). In a Na+-containing Tyrode's buffer, SNC-stimulated [3H]NA release was inhibited 30% by the coaddition of L-leucine. In the Na+-free, choline-containing buffer, SNC-stimulated [3H]NA release, which was similar to that in the Na+-containing buffer, was inhibited markedly by L-leucine, L-alanine, L-methionine, L-phenylalanine, and L-tyrosine. The effects of the other amino acids examined were smaller or very limited. The effect of L-leucine was stronger than that of D-leucine. A specific inhibitor of the L-type amino acid transporter, 2-aminobicyclo[2.2.1]-heptane-2-carboxylate (BCH), inhibited the effects of SNC on [3H]NA release in the Na+-free buffer. Uptake of L-[3H]leucine into the slices in the Na+-free buffer was inhibited by SNC, BCH, and L-phenylalanine, but not by L-lysine. The effect of SNC on cyclic GMP accumulation was not inhibited by L-leucine, although SNC stimulated cyclic GMP accumulation at concentrations up to 25 microM, much less than the concentration that stimulates NA release. These findings suggest that SNC is incorporated into rat hippocampus via the L-type-like amino acid transporter, at least in Na+-free conditions, and that SNC stimulates NA release in vivo and in vitro in a cyclic GMP-independent manner.