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 (O•−2). 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 O•−2and 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 O•−2. We demonstrate that easily reducible nitroxides, such as the nitronyl and imino nitroxides, are able to oxidize SIN-1. Biological oxidizing agents such as ferricytochromecalso 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 lowin vivooxygen 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.