title: Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl.
abstract: Experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide (H2S) signaling pathways are intimately intertwined, with mutual attenuation or potentiation of biological responses in the cardiovascular system and elsewhere. The chemical basis of this interaction is elusive. Moreover, polysulfides recently emerged as potential mediators of H2S/sulfide signaling, but their biosynthesis and relationship to NO remain enigmatic. We sought to characterize the nature, chemical biology, and bioactivity of key reaction products formed in the NO/sulfide system. At physiological pH, we find that NO and sulfide form a network of cascading chemical reactions that generate radical intermediates as well as anionic and uncharged solutes, with accumulation of three major products: nitrosopersulfide (SSNO(-)), polysulfides, and dinitrososulfite [N-nitrosohydroxylamine-N-sulfonate (SULFI/NO)], each with a distinct chemical biology and in vitro and in vivo bioactivity. SSNO(-) is resistant to thiols and cyanolysis, efficiently donates both sulfane sulfur and NO, and potently lowers blood pressure. Polysulfides are both intermediates and products of SSNO(-) synthesis/decomposition, and they also decrease blood pressure and enhance arterial compliance. SULFI/NO is a weak combined NO/nitroxyl donor that releases mainly N2O on decomposition; although it affects blood pressure only mildly, it markedly increases cardiac contractility, and formation of its precursor sulfite likely contributes to NO scavenging. Our results unveil an unexpectedly rich network of coupled chemical reactions between NO and H2S/sulfide, suggesting that the bioactivity of either transmitter is governed by concomitant formation of polysulfides and anionic S/N-hybrid species. This conceptual framework would seem to offer ample opportunities for the modulation of fundamental biological processes governed by redox switching and sulfur trafficking.
authors.affiliation: Cardiovascular Research Laboratory, Department of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, 40225 Dusseldorf, Germany;
authors.forename: Miriam M
authors.initials: MM
authors.lastname: Cortese-Krott
authors.affiliation: Department of Nutrition, University of Reading, Whiteknights, Reading RG6 6AP, United Kingdom;
authors.forename: Gunter G C
authors.initials: GG
authors.lastname: Kuhnle
authors.affiliation: Bloomsbury Institute of Intensive Care Medicine, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Alex
authors.initials: A
authors.lastname: Dyson
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital and Institute for Life Sciences, Southampton SO16 6YD, United Kingdom;
authors.forename: Bernadette O
authors.initials: BO
authors.lastname: Fernandez
authors.affiliation: Center for Molecular Medicine, Slovak Academy of Sciences, 83101 Bratislava, Slovak Republic;
authors.forename: Marian
authors.initials: M
authors.lastname: Grman
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109;
authors.forename: Jenna F
authors.initials: JF
authors.lastname: DuMond
authors.affiliation: Department of Chemistry, Warwick University, Coventry CV4 7AL, United Kingdom;
authors.forename: Mark P
authors.initials: MP
authors.lastname: Barrow
authors.affiliation: Bruker UK Ltd., Coventry CV4 9GH, United Kingdom;
authors.forename: George
authors.initials: G
authors.lastname: McLeod
authors.affiliation: Department of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya-shi, Aichi 467-8603, Japan;
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Center for Molecular Medicine, Slovak Academy of Sciences, 83101 Bratislava, Slovak Republic;
authors.forename: Karol
authors.initials: K
authors.lastname: Ondrias
authors.affiliation: Department of Molecular Immunology and Toxicology, National Institute of Oncology, 1122 Budapest, Hungary;
authors.forename: Péter
authors.initials: P
authors.lastname: Nagy
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109;
authors.forename: S Bruce
authors.initials: SB
authors.lastname: King
authors.affiliation: Leidos Biomedical Research, Inc., National Cancer Institute-Frederick, Frederick, MD 21702;
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.affiliation: National Cancer Institute-Frederick, Frederick, MD 21702;
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
authors.affiliation: Bloomsbury Institute of Intensive Care Medicine, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.affiliation: Cardiovascular Research Laboratory, Department of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, 40225 Dusseldorf, Germany;
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
authors.affiliation: Medical School, University of St. Andrews, St. Andrews, Fife KY16 9AJ, Scotland.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Butler
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital and Institute for Life Sciences, Southampton SO16 6YD, United Kingdom; M.Feelisch@soton.ac.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
mesh_terms: D000818:Animals; D001682:Biological Availability; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D009584:Nitrogen / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism*; D017208:Rats, Wistar; D013440:Sulfides / Q000378:metabolism*; D013455:Sulfur / Q000378:metabolism
chemical_list: D009589:Nitrogen Oxides; D013440:Sulfides; D009569:Nitric Oxide; D013455:Sulfur; C039900:nitroxyl; D009584:Nitrogen; D006862:Hydrogen Sulfide
keywords: gasotransmitter; nitric oxide; nitroxyl; redox; sulfide