SIN 1 RELEASES NITRIC OXIDE IN PRESENCE OF ELECTRON ACCEPTORS

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SIN-1 has been used as an experimental tool for the generation of peroxynitrite. However, the pharmacological activity of SIN-1 resembles that of a nitric oxide donor. SIN-1 reduces oxygen by a one-electron transfer reaction to give superoxide and SIN-1 cation radical. This radical decomposes to form SIN-1C and nitric oxide. The last step is the rapid reaction between nitric oxide and superoxide. to give peroxynitrite. This mechanism suggests that, in the presence of an electron acceptor other than oxygen, SIN-1 could be converted into a nitric oxide donor. Here we demonstrate that the nitric oxide trap, nitronyl nitroxide (NNO) is able to act as an oxidizing agent for SIN-1. NNO was converted to imino nitroxide (INO) when incubated with SIN-1, as monitored by ESR. INO was further reduced to the hydroxylamine as addition of ferricyanide regenerated the ESR signal. After NNO was converted to INO, nitric oxide was detected in the headspace by chemiluminescence. Consistent with these findings, Pfeiffer et al. have shown an elevation of cGMP levels in endothelial cells when incubated with SIN-1 and NNO (FRBM 22:787-794, 1997). Biological oxidizing agents such as ferricytochrome-c also stimulated nitric oxide production from SIN-1. In addition, decomposition of SIN-1 by the homogenate of liver, kidney, and heart tissues formed nitric oxide. Our findings suggest that SIN-1 could preferentially react with heme proteins and other electron acceptors in biological systems to produce nitric oxide. As the oxygen concentration in tissues and cells is relatively low, SIN-1 reacts with other biological electron acceptors rather than with oxygen. By this mechanism, SIN-1 becomes a nitric oxide donor and could inhibit peroxynitrite-mediated oxidation. This may explain the paradoxical effects of SIN-1 in biological systems.