title: The peroxynitrite generator, SIN-1, becomes a nitric oxide donor in the presence of electron acceptors.
abstract: 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*-2 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 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 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.
authors.affiliation: Biophysics Research Institute, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Singh
authors.forename: N
authors.initials: N
authors.lastname: Hogg
authors.forename: J
authors.initials: J
authors.lastname: Joseph
authors.forename: E
authors.initials: E
authors.lastname: Konorev
authors.forename: B
authors.initials: B
authors.lastname: Kalyanaraman
mesh_terms: D000818:Animals; D003497:Cyclic N-Oxides / Q000737:chemistry; D016166:Free Radical Scavengers / Q000737:chemistry; D006420:Hemeproteins / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000737:chemistry; D009206:Myocardium / Q000378:metabolism; D009566:Nitrates / Q000097:blood / Q000737:chemistry*; D020030:Nitric Oxide Donors / Q000737:chemistry*; D016877:Oxidants / Q000737:chemistry*; D051381:Rats
chemical_list: D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D006420:Hemeproteins; D007093:Imidazoles; D009566:Nitrates; D020030:Nitric Oxide Donors; D016877:Oxidants; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; C039642:peroxynitric acid; C002385:linsidomine; D008981:Molsidomine