title: Methylene blue counteracts H2S toxicity-induced cardiac depression by restoring L-type Ca channel activity.
abstract: We have previously reported that methylene blue (MB) can counteract hydrogen sulfide (H2S) intoxication-induced circulatory failure. Because of the multifarious effects of high concentrations of H2S on cardiac function, as well as the numerous properties of MB, the nature of this interaction, if any, remains uncertain. The aim of this study was to clarify 1) the effects of MB on H2S-induced cardiac toxicity and 2) whether L-type Ca(2+) channels, one of the targets of H2S, could transduce some of the counteracting effects of MB. In sedated rats, H2S infused at a rate that would be lethal within 5 min (24 μM·kg(-1)·min(-1)), produced a rapid fall in left ventricle ejection fraction, determined by echocardiography, leading to a pulseless electrical activity. Blood concentrations of gaseous H2S reached 7.09 ± 3.53 μM when cardiac contractility started to decrease. Two to three injections of MB (4 mg/kg) transiently restored cardiac contractility, blood pressure, and V̇o2, allowing the animals to stay alive until the end of H2S infusion. MB also delayed PEA by several minutes following H2S-induced coma and shock in unsedated rats. Applying a solution containing lethal levels of H2S (100 μM) on isolated mouse cardiomyocytes significantly reduced cell contractility, intracellular calcium concentration ([Ca(2+)]i) transient amplitudes, and L-type Ca(2+) currents (ICa) within 3 min of exposure. MB (20 mg/l) restored the cardiomyocyte function, ([Ca(2+)]i) transient, and ICa The present results offer a new approach for counteracting H2S toxicity and potentially other conditions associated with acute inhibition of L-type Ca(2+) channels.
authors.affiliation: Heart and Vascular Institute, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania; phaouzi@hmc.psu.edu.
authors.forename: Annick
authors.initials: A
authors.lastname: Judenherc-Haouzi
authors.affiliation: Center of Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Xue-Qian
authors.initials: XQ
authors.lastname: Zhang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania;
authors.forename: Takashi
authors.initials: T
authors.lastname: Sonobe
authors.affiliation: Center of Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Song
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania;
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Rannals
authors.affiliation: Center of Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: JuFang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania;
authors.forename: Nicole
authors.initials: N
authors.lastname: Tubbs
authors.affiliation: Center of Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania; and Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Joseph Y
authors.initials: JY
authors.lastname: Cheung
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania;
authors.forename: Philippe
authors.initials: P
authors.lastname: Haouzi
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage; D000975:Antioxidants / Q000008:administration & dosage; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006862:Hydrogen Sulfide / Q000506:poisoning*; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008751:Methylene Blue / Q000008:administration & dosage*; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D000931:Antidotes; D000975:Antioxidants; D020746:Calcium Channels, L-Type; D002118:Calcium; D008751:Methylene Blue; D006862:Hydrogen Sulfide
keywords: calcium channels; cardiac contractility; sulfide toxicity