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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 ?M·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 ?M when cardiac contractility started to decrease. Two to three injections of MB (4 mg/kg) transiently restored cardiac contractility, blood pressure, and V?o2, 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 ?M) 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.

SUBMITTER: Judenherc-Haouzi A

PROVIDER: S-EPMC4935501 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Methylene blue counteracts H2S toxicity-induced cardiac depression by restoring L-type Ca channel activity.

Judenherc-Haouzi Annick A Zhang Xue-Qian XQ Sonobe Takashi T Song Jianliang J Rannals Matthew D MD Wang JuFang J Tubbs Nicole N Cheung Joseph Y JY Haouzi Philippe P

American journal of physiology. Regulatory, integrative and comparative physiology 20160309 11

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 ...[more]

PMID: 26962024

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Project description:Background: Cerebral ischemia/reperfusion injury is a common secondary effect of cardiac arrest which is largely responsible for postresuscitative mortality. Therefore development of therapies which restore and protect the brain function after cardiac arrest is essential. Methylene blue (MB) has been experimentally proven neuroprotective in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. However, no comprehensive analyses have been conducted at gene expression level. Methods: Pigs underwent either untreated cardiac arrest (CA) or CA with subsequent cardiopulmonary resuscitation (CPR) accompanied with an infusion of saline or an infusion of saline with MB. Genome-wide transcriptional profiling using the Affymetrix porcine microarray was performed to 1) gain understanding of delayed neuronal death initiation in porcine brain during ischemia and after 30, 60 and 180 min following reperfusion, and 2) identify the mechanisms behind the neuroprotective effect of MB after ischemic injury (at 30, 60 and 180 min). Results: Our results show that restoration of spontaneous circulation (ROSC) induces major transcriptional changes related to stress response, inflammation, apoptosis and even cytoprotection. In contrast, the untreated ischemic and anoxic insult affected only few genes mainly involved in intra-/extracellular ionic balance. Furthermore, our data show that the neuroprotective role of MB is diverse and fulfilled by regulation of the expression of soluble guanylate cyclase and biological processes accountable for inhibition of apoptosis, modulation of stress response, neurogenesis and neuroprotection. Conclusions: Our results support that MB could be a valuable intervention and should be investigated as a therapeutic agent against neural damage associated with I/R injury induced by cardiac arrest. One group of pigs underwent cardiac arrest (CA) without subsequent cardiopulmonary resuscitation (CPR) and the brain of the animals was removed after 5, 20 or 30 min post CA for genome-wide expression study. Two groups of pigs underwent first CA for 12 min with a subsequent 8 min-long CPR and received either an infusion of saline or an infusion of saline with MB from one minute after the start of CPR until 50 min after return of spontaneous circulation (ROSC). In both latter groups the brains were removed for microarray analysis at the following time points: 30, 60, 180 min.

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Methylene blue counteracts H2S toxicity-induced cardiac depression by restoring L-type Ca channel activity.

Publications

Methylene blue counteracts H2S toxicity-induced cardiac depression by restoring L-type Ca channel activity.

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