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

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Abstract

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).

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Acknowledgements

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

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Authors and Affiliations

  1. Center of Translational Medicine, Lewis Katz School of Medicine of Temple University, 3500 N. Broad Street, MERB 958, Philadelphia, PA, 19140, USA

    Joseph Y. Cheung, JuFang Wang, Xue-Qian Zhang, Jianliang Song, Fabian Jana Prado, Santhanam Shanmughapriya, Alison M. Worth & Muniswamy Madesh

  2. Department of Medicine, Lewis Katz School of Medicine of Temple University, Philadelphia, PA, 19140, USA

    Joseph Y. Cheung & John M. Davidyock

  3. Heart and Vascular Institute, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA

    Annick Judenherc-Haouzi

  4. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA

    Philippe Haouzi

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  1. Joseph Y. Cheung
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Correspondence to Joseph Y. Cheung.

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Cheung, J.Y., Wang, J., Zhang, XQ. et al. Methylene Blue Counteracts H2S-Induced Cardiac Ion Channel Dysfunction and ATP Reduction. Cardiovasc Toxicol 18, 407–419 (2018). https://doi.org/10.1007/s12012-018-9451-5

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