title: The reaction products of sulfide and S-nitrosoglutathione are potent vasorelaxants.
abstract: The chemical interaction of sodium sulfide (Na2S) with the NO-donor S-nitrosoglutathione (GSNO) has been described to generate new reaction products, including polysulfides and nitrosopersulfide (SSNO(-)) via intermediacy of thionitrous acid (HSNO). The aim of the present work was to investigate the vascular effects of the longer-lived products of the Sulfide/GSNO interaction. Here we show that the products of this reaction relax precontracted isolated rings of rat thoracic aorta and mesenteric artery (but to a lesser degree rat uterus) with a >2-fold potency compared with the starting material, GSNO (50 nM), whereas Na2S and polysulfides have little effect at 1-5 µM. The onset of vasorelaxation of the reaction products was 7-10 times faster in aorta and mesenteric arteries compared with GSNO. Relaxation to GSNO (100-500 nM) was blocked by an inhibitor of soluble guanylyl cyclase, ODQ (0.1 and 10 µM), and by the NO scavenger cPTIO (100 µM), but less affected by prior acidification (pH 2-4), and unaffected by N-acetylcysteine (1 mM) or methemoglobin (20 µM heme). By contrast, relaxation to the Sulfide/GSNO reaction products (100-500 nM based on the starting material) was inhibited to a lesser extent by ODQ, only slightly decreased by cPTIO, more markedly inhibited by methemoglobin and N-acetylcysteine, and abolished by acidification before addition to the organ bath. The reaction mixture was found to generate NO as detected by EPR spectroscopy using N-(dithiocarboxy)-N-methyl-D-glucamine (MGD2)-Fe(2+) as spin trap. In conclusion, the Sufide/GSNO reaction products are faster and more pronounced vasorelaxants than GSNO itself. We conclude that in addition to NO formation from SSNO(-), reaction products other than polysulfides may give rise to nitroxyl (HNO) and be involved in the pronounced relaxation induced by the Sulfide/GSNO cross-talk.
authors.affiliation: Institute of Normal and Pathological Physiology SAS, Sienkiewiczova 1, 81371 Bratislava, Slovakia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Berenyiova
authors.affiliation: Institute of Molecular Physiology and Genetics SAS, Vlarska 5, 83334 Bratislava, Slovakia; Center for Molecular Medicine SAS, Vlarska 7, 83101 Bratislava, Slovakia.
authors.forename: Marian
authors.initials: M
authors.lastname: Grman
authors.affiliation: Institute for Biological Research "Siniša Stanković", University of Belgrade, Blvd Despota Stefana 142, Belgrade, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Mijuskovic
authors.affiliation: Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovakia.
authors.forename: Andrej
authors.initials: A
authors.lastname: Stasko
authors.affiliation: Institute of Molecular Physiology and Genetics SAS, Vlarska 5, 83334 Bratislava, Slovakia.
authors.forename: Anton
authors.initials: A
authors.lastname: Misak
authors.affiliation: Department of Molecular Immunology and Toxicology, National Institute of Oncology, Ráth György utca 7-9, Budapest, 1122 Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Nagy
authors.affiliation: Faculty of Pharmacy, Comenius University, Odbojarov 10, 83232 Bratislava, Slovakia.
authors.forename: Elena
authors.initials: E
authors.lastname: Ondriasova
authors.affiliation: Institute of Normal and Pathological Physiology SAS, Sienkiewiczova 1, 81371 Bratislava, Slovakia.
authors.forename: Sona
authors.initials: S
authors.lastname: Cacanyiova
authors.affiliation: Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovakia.
authors.forename: Vlasta
authors.initials: V
authors.lastname: Brezova
authors.affiliation: Clinical & Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton, Tremona Road, Southampton, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.affiliation: Institute of Molecular Physiology and Genetics SAS, Vlarska 5, 83334 Bratislava, Slovakia. Electronic address: karol.ondrias@savba.sk.
authors.forename: Karol
authors.initials: K
authors.lastname: Ondrias
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D026422:S-Nitrosoglutathione / Q000737:chemistry / Q000378:metabolism*; D013440:Sulfides / Q000737:chemistry / Q000378:metabolism*; D014590:Uterine Contraction / Q000187:drug effects; D014665:Vasodilator Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D013440:Sulfides; D014665:Vasodilator Agents; D026422:S-Nitrosoglutathione
keywords: Aorta relaxation; Hydrogen sulfide; Nitric oxide; Nitrosopersulfide; Polysulfides; Uterus