The peroxynitrite generator, SIN-1, becomes a nitric oxide donor in the presence-of electron acceptors

SIN-1 has been used, in vitro, to simultaneously generate nitric oxide (·NO) and superoxide (O₂/·^-). However, the pharmacological activity of SIN-1 resembles that of a ·NO donor. SIN-1 decays by a three-step mechanism. After initial isomerization to an open ring form, SIN-1A reduces oxygen by a one-electron transfer reaction to give O₂/·^- and the SIN-1 cation radical, which decomposes to form SIN-1C and ·NO. Here we report that one-electron oxidizing agents, in addition to oxygen, can oxidize SIN-1A, resulting in the release of ·NO without the concomitant formation of O₂/·^-. We demonstrate that easily reducible nitroxides, such as the nitronyl and imino nitroxides, are able to oxidize SIN-1. Biological oxidizing agents such as ferricytochrome c also stimulate ·NO production from SIN-1. In addition, decomposition of SIN-1 by human plasma or by the homogenate of rat liver, kidney, and heart tissues results in the formation of ·NO. Our findings suggest that SIN-1 may react with heme proteins and other electron acceptors in biological systems to produce ·NO. Thus, at the relatively low in vivo oxygen concentrations, SIN-1 is likely to behave more like an ·NO donor than a peroxynitrite donor. The relevance of this reaction to myocardial protection afforded by SIN-1 in ischemia/reperfusion-induced injury is discussed.