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Nitrosopersulfide (SSNO-) targets soluble guanylyl cyclase and induces vasodilation in vivo

  • Miriam M Cortese-Krott1Email author,
  • Gunter GC Kuhnle2,
  • Alex Dyson3,
  • Bernadette O Fernandez4,
  • Marian Grman5,
  • Mark P Barrow6,
  • George McLeod7,
  • Karol Ondrias5,
  • Péter Nagy8,
  • Mervyn Singer3,
  • Malte Kelm1,
  • Anthony R Butler9 and
  • Martin Feelisch4
BMC Pharmacology and Toxicology201516(Suppl 1):A42

Published: 2 September 2015


Nitric OxideSulfideThiolHydrogen SulfideAortic Ring


Recent experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide signaling pathways are intimately intertwined particularly in the vasculature, with mutual attenuation or potentiation of biological responses under control of the soluble guanylyl cyclase (sGC) / phopshodiesterase (PDE) pathway. There is now compelling evidence that part of the NO/sulfide cross talk has a chemical foundation via the formation of S/N-hybrid molecules including thionitrous acid (HSNO) and nitrosopersulfde (SSNO-). The aim of this study was to characterize the bioactive products of the interaction between sulfide and NO metabolites targeting sGC that may potentially regulate vasodilation.


We found that the chemical interaction of sulfide with NO or nitrosothiols leads to formation of S/N-hybrid metabolites including SSNO- via intermediate formation of HSNO. Contrary to a recent report in the literature but consistent with the transient nature of HSNO, its formation was not detectable by high-resolution mass spectrometry under physiologically relevant conditions. SSNO- is also formed in non-aqueous media by the reaction of nitrite with oxidized sulfur species including colloidal sulfur and polysulfides. SSNO- is stable in the presence of high concentrations of thiols, release NO, and activates sGC in RFL-6 cells in an NO-dependent fashion. Moreover, SSNO- is a potent vasodilator in aortic rings in vitro and lowers blood pressure in rats in vivo. The presence of high concentrations of SOD or thiols does not affect SSNO- mediated sGC activation, while it potentiates and inhibits the effects of the nitroxyl (HNO) donor Angeli's salt, suggesting that HNO release from SSNO- is not involved in sGC activation.


The reaction between NO and sulfide leads to fomation of S/N-hybrid molecules including SSNO-, releasing NO, activating sGC and inducing vasodilation. SSNO- is considerably more stable than HSNO at pH 7.4 and thus a more likely biological mediator that can account for the chemical cross-talk between NO and sulfide.

Authors’ Affiliations

Cardiovascular Research Laboratory, Department of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, Universitätstrasse 1, Düsseldorf, Germany
Department of Nutrition, University of Reading, Whiteknights, UK
Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK
Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
Department of Chemistry, Warwick University, Coventry, UK
Bruker UK Ltd., Banner Lane, Coventry, UK
Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest, Hungary
Medical School, University of St-Andrews, St-Andrews, Fife, UK


© Cortese-Krott et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.