Cardiovascular Toxicology

, Volume 18, Issue 5, pp 407–419 | Cite as

Methylene Blue Counteracts H2S-Induced Cardiac Ion Channel Dysfunction and ATP Reduction

  • Joseph Y. Cheung
  • JuFang Wang
  • Xue-Qian Zhang
  • Jianliang Song
  • John M. Davidyock
  • Fabian Jana Prado
  • Santhanam Shanmughapriya
  • Alison M. Worth
  • Muniswamy Madesh
  • Annick Judenherc-Haouzi
  • Philippe Haouzi


We have previously demonstrated that methylene blue (MB) counteracts the effects of hydrogen sulfide (H2S) cardiotoxicity by improving cardiomyocyte contractility and intracellular Ca2+ homeostasis disrupted by H2S poisoning. In vivo, MB restores cardiac contractility severely depressed by sulfide and protects against arrhythmias, ranging from bundle branch block to ventricular tachycardia or fibrillation. To dissect the cellular mechanisms by which MB reduces arrhythmogenesis and improves bioenergetics in myocytes intoxicated with H2S, we evaluated the effects of H2S on resting membrane potential (Em), action potential (AP), Na+/Ca2+ exchange current (INaCa), depolarization-activated K+ currents and ATP levels in adult mouse cardiac myocytes and determined whether MB could counteract the toxic effects of H2S on myocyte electrophysiology and ATP. Exposure to toxic concentrations of H2S (100 µM) significantly depolarized Em, reduced AP amplitude, prolonged AP duration at 90% repolarization (APD90), suppressed INaCa and depolarization-activated K+ currents, and reduced ATP levels in adult mouse cardiac myocytes. Treating cardiomyocytes with MB (20 µg/ml) 3 min after H2S exposure restored Em, APD90, INaCa, depolarization-activated K+ currents, and ATP levels toward normal. MB improved mitochondrial membrane potential (∆ψm) and oxygen consumption rate in myocytes in which Complex I was blocked by rotenone. We conclude that MB ameliorated H2S-induced cardiomyocyte toxicity at multiple levels: (1) reversing excitation–contraction coupling defects (Ca2+ homeostasis and L-type Ca2+ channels); (2) reducing risks of arrhythmias (Em, APD, INaCa and depolarization-activated K+ currents); and (3) improving cellular bioenergetics (ATP, ∆ψm).


Sulfide toxicity Arrhythmogenesis Ion currents Patch clamp 



This work has been partially supported by NIH RO1-HL123093, RO1-HL137426, UO1-NS097162, R21-NS098991, and American Heart Association Grant-in-Aid 15GRNT25680042.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Joseph Y. Cheung
    • 1
    • 2
  • JuFang Wang
    • 1
  • Xue-Qian Zhang
    • 1
  • Jianliang Song
    • 1
  • John M. Davidyock
    • 2
  • Fabian Jana Prado
    • 1
  • Santhanam Shanmughapriya
    • 1
  • Alison M. Worth
    • 1
  • Muniswamy Madesh
    • 1
  • Annick Judenherc-Haouzi
    • 3
  • Philippe Haouzi
    • 4
  1. 1.Center of Translational MedicineLewis Katz School of Medicine of Temple UniversityPhiladelphiaUSA
  2. 2.Department of MedicineLewis Katz School of Medicine of Temple UniversityPhiladelphiaUSA
  3. 3.Heart and Vascular InstitutePennsylvania State University College of MedicineHersheyUSA
  4. 4.Division of Pulmonary and Critical Care Medicine, Department of MedicinePennsylvania State University College of MedicineHersheyUSA

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