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Redox Biol. 2014 Jan 11;2:234-44. doi: 10.1016/j.redox.2013.12.031. eCollection 2014.

Nitrosopersulfide (SSNO(-)) accounts for sustained NO bioactivity of S-nitrosothiols following reaction with sulfide.

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Cardiovascular Research Laboratory, Department of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, UK.
Institute for Pharmacology and Toxicology, Ruhr-University Bochum, Bochum, Germany.
Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Department of Molecular Immunology and Toxicology, National Institute of Oncology, Ráth György utca 7-9, Budapest, Hungary.
Medical School, University of St-Andrews, St-Andrews, Fife, Scotland.


Sulfide salts are known to promote the release of nitric oxide (NO) from S-nitrosothiols and potentiate their vasorelaxant activity, but much of the cross-talk between hydrogen sulfide and NO is believed to occur via functional interactions of cell regulatory elements such as phosphodiesterases. Using RFL-6 cells as an NO reporter system we sought to investigate whether sulfide can also modulate nitrosothiol-mediated soluble guanylyl cyclase (sGC) activation following direct chemical interaction. We find a U-shaped dose response relationship where low sulfide concentrations attenuate sGC stimulation by S-nitrosopenicillamine (SNAP) and cyclic GMP levels are restored at equimolar ratios. Similar results are observed when intracellular sulfide levels are raised by pre-incubation with the sulfide donor, GYY4137. The outcome of direct sulfide/nitrosothiol interactions also critically depends on molar reactant ratios and is accompanied by oxygen consumption. With sulfide in excess, a 'yellow compound' accumulates that is indistinguishable from the product of solid-phase transnitrosation of either hydrosulfide or hydrodisulfide and assigned to be nitrosopersulfide (perthionitrite, SSNO(-); λ max 412 nm in aqueous buffers, pH 7.4; 448 nm in DMF). Time-resolved chemiluminescence and UV-visible spectroscopy analyses suggest that its generation is preceded by formation of the short-lived NO-donor, thionitrite (SNO(-)). In contrast to the latter, SSNO(-) is rather stable at physiological pH and generates both NO and polysulfides on decomposition, resulting in sustained potentiation of SNAP-induced sGC stimulation. Thus, sulfide reacts with nitrosothiols to form multiple bioactive products; SSNO(-) rather than SNO(-) may account for some of the longer-lived effects of nitrosothiols and contribute to sulfide and NO signaling.


CysNO, S-nitrosocysteine; DMF, dimetylformamide; DMSO, dimethylsulfoxide; GSNO, S-nitrosoglutathione; HSNO; Hydrogen sulfide; IPN, isopentyl nitrite; NO+, nitrosonium; NO, nitric oxide; Nitric oxide; Nitroxyl; Polysulfides; RFL-6, rat fibroblastoid-like cell line; SNAP, S-nitrosopenicillamine; SNO−, thionitrite; SSNO−, nitrosopersulfide, perthionitrite, PDE, phopsphodiesterase; cGMP; sGC, soluble guanylyl cyclase

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