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

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

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 (E-m), action potential (AP), Na+/Ca2+ exchange current (I-NaCa), 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 mu M) significantly depolarized E-m, reduced AP amplitude, prolonged AP duration at 90% repolarization (APD(90)), suppressed I-NaCa and depolarization-activated K+ currents, and reduced ATP levels in adult mouse cardiac myocytes. Treating cardiomyocytes with MB (20 mu g/ml) 3min after H2S exposure restored E-m, APD(90), I-NaCa, depolarization-activated K+ currents, and ATP levels toward normal. MB improved mitochondrial membrane potential ((m)) 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 (E-m, APD, I-NaCa and depolarization-activated K+ currents); and (3) improving cellular bioenergetics (ATP, (m)).

Más información

Título según WOS: ID WOS:000443848300003 Not found in local WOS DB
Título de la Revista: CARDIOVASCULAR TOXICOLOGY
Volumen: 18
Número: 5
Editorial: Humana Press, Inc.
Fecha de publicación: 2018
Página de inicio: 407
Página final: 419
DOI:

10.1007/s12012-018-9451-5

Notas: ISI