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)-N-.) and superoxide (O-2(.-)). However, the pharmacological activity of SIN-I resembles that of a (NO)-N-. 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 O-2(.-) and the SIN-1 cation radical, which decomposes to form SIN-1C and (NO)-N-.. Here we report that one-electron oxidizing agents, in addition to oxygen, can oxidize SIN-1A, resulting in the release of (NO)-N-. without the concomitant formation of O-2(.-). We demonstrate that easily reducible nitroxides, such as the nitronyl and imino nitroxides, are able to oxidize SIN-I. Biological oxidizing agents such as ferricytochrome c also stimulate (NO)-N-. production from SIN-I. 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)-N-.. Our findings suggest that SIN-1 may react with heme proteins and other electron accepters in biological systems to produce (NO)-N-.. Thus, at the relatively low in vivo oxygen concentrations, SIN-1 is likely to behave more like an (NO)-N-. donor than a peroxynitrite donor. The relevance of this reaction to myocardial protection afforded by SIN-1 in ischemia/reperfusion-induced injury is discussed. (C) 1999 Academic Press.