Lack of correlation between the observed stability and pharmacological properties of S-nitroso derivatives of glutathione and cysteine-related peptides.

S-Nitrosothiols (RSNOs) have been widely studied as donors of nitric oxide. In general, RSNOs are considered to be somewhat unstable; however, they are both potent vasodilators and inhibitors of platelet aggregation. In order to improve our understanding of the factors that determine the biological activity of RSNOs, the chemical stability and pharmacological activity of a series of RSNOs was determined. Results show that millimolar solutions of S-nitrosocysteine (SNOCys) and S-nitroso-L-cysteinylglycine (SNOCysGly) were the least stable, whereas S-nitroso-3-mercaptopropionic acid (SNOPROPA) and S-nitroso-N-acetyl-L-cysteine (SNONAC) were the most stable of the compounds tested. Recent evidence suggests that RSNOs, such as SNONAC, are as unstable as SNOCys at micromolar concentrations. The decomposition of certain RSNOs is catalysed by trace amounts of copper (II) ions, with this phenomenon being particularly evident for SNOCys and SNOCysGly. The decomposition of the more stable RSNOs, including S-nitroso-L-glutathione (SNOGSH) and L-gamma-glutamyl-L-cysteine (SNOGluCys), were not as sensitive to copper ions. The decomposition of the stable RSNO, SNOGSH, was more rapid in the presence of excess thiol, whereas the decay of the unstable RSNO, SNOCys, was reduced with added thiol. All RSNOs tested inhibited platelet aggregation, relaxed vascular smooth muscle, and inhibited cell growth in the nanomolar range, but their order of potency did not correlate with their chemical stability of millimolar solutions. It is apparent that the potency of an RSNO in a physiological situation will depend on the concentration of the compound present, the presence of trace metal ions such as copper, and the occurrence of transnitrosation reactions.