title: Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice.
abstract: The recently described 'gasomediator' hydrogen sulfide (H2S) has been involved in pain mechanisms, but its effect on pruritus, a sensory modality that similarly to pain acts as a protective mechanism, is poorly known and controversial. The effects of the slow-releasing (GYY4137) and spontaneous H2S donors (Na2S and Lawesson's reagent, LR) were evaluated in histamine and compound 48/80 (C48/80)-dependent dorsal skin pruritus and inflammation in male BALB/c mice. Animals were intradermally (i.d.) injected with C48/80 (3μg/site) or histamine (1μmol/site) alone or co-injected with Na2S, LR or GYY4137 (within the 0.3-100nmol range). The involvement of endogenous H2S and KATPchannel-dependent mechanism were also evaluated. Pruritus was assessed by the number of scratching bouts, whilst skin inflammation was evaluated by the extravascular accumulation of intravenously injected125I-albumin (plasma extravasation) and myeloperoxidase (MPO) activity (neutrophil recruitment). Histamine or C48/80 significantly evoked itching behavior paralleled by plasma extravasation and increased MPO activity. Na2S and LR significantly ameliorated histamine or C48/80-induced pruritus and inflammation, although these effects were less pronounced or absent with GYY4137. Inhibition of endogenous H2S synthesis increased both Tyrode and C48/80-induced responses in the skin, whereas the blockade of KATPchannels by glibenclamide did not. H2S-releasing donors significantly attenuate C48/80-induced mast cell degranulation either in vivo or in vitro. We provide first evidences that H2S donors confer protective effect against histamine-mediated acute pruritus and cutaneous inflammation. These effects can be mediated, at least in part, by stabilizing mast cells, known to contain multiple mediators and to be primary initiators of allergic processes, thus making of H2S donors a potential alternative/complementary therapy for treating inflammatory allergic skin diseases and related pruritus.
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Rodrigues
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: E
authors.initials: E
authors.lastname: Ekundi-Valentim
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: Florenzano
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: A R A
authors.initials: AR
authors.lastname: Cerqueira
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: A G
authors.initials: AG
authors.lastname: Soares
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: T P
authors.initials: TP
authors.lastname: Schmidt
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: K T
authors.initials: KT
authors.lastname: Santos
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: S A
authors.initials: SA
authors.lastname: Teixeira
authors.affiliation: Department of Biotechnology, Institute of Nuclear and Energetic Research (IPEN), Sao Paulo, Brazil.
authors.forename: M T C P
authors.initials: MT
authors.lastname: Ribela
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: S F
authors.initials: SF
authors.lastname: Rodrigues
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: M H
authors.initials: MH
authors.lastname: de Carvalho
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: G
authors.initials: G
authors.lastname: De Nucci
authors.affiliation: University of Exeter Medical School, Exeter, UK.
authors.forename: M
authors.initials: M
authors.lastname: Wood
authors.affiliation: University of Exeter Medical School, Exeter, UK.
authors.forename: M
authors.initials: M
authors.lastname: Whiteman
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: M N
authors.initials: MN
authors.lastname: Muscará
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: skcosta@usp.br.
authors.forename: S K P
authors.initials: SK
authors.lastname: Costa
mesh_terms: D000818:Animals; D005905:Glyburide / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism* / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*; D011537:Pruritus / Q000188:drug therapy* / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism
chemical_list: C529376:GYY 4137; D054086:KATP Channels; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D020011:Protective Agents; D006632:Histamine; D005905:Glyburide; D006862:Hydrogen Sulfide
keywords: GYY4137; Hydrogen sulfide; Neutrophil influx; Plasma extravasation; Pruritus; Skin