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.
The present observations should make us consider the potential interest of MB in the treatment of CN intoxication. The mechanisms of the antidotal properties of MB cannot be accounted for by the creation of a cyanomethemoglobinemia, rather its protective effects appears to be related to the unique properties of this redox dye, which, depending on the dose, could directly oppose some of the consequences of the metabolic depression produced by CN at the cellular level.
Our objective was to determine how circulatory failure develops following systemic administration of potassium cyanide (KCN). We used a non-inhaled modality of intoxication, wherein the change in breathing pattern would not influence the diffusion of CN into the blood, akin to the effects of ingesting toxic levels of CN. In a group of 300–400 g rats, CN-induced coma (CN IP, 7 mg/kg) produced a central apnea within 2–3 minutes along with a potent and prolonged gasping pattern leading to auto-resuscitation in 38% of the animals. Motor deficits and neuronal necrosis were nevertheless observed in the surviving animals. To clarify the mechanisms leading to potential auto-resuscitation versus asystole, 12 urethane-anesthetized rats were then exposed to the lowest possible levels of CN exposure that would lead to breathing depression within 7–8 minutes; this dose averaged 0.375 mg/kg/min iv. At this level of intoxication, a cardiac depression developed several minutes only after the onset of the apnea, leading to cardiac asystole as PaO2 reached value around 15 Torr, unless breathing was maintained by mechanical ventilation or through spontaneous gasping. Higher levels of KCN exposure in 10 animals provoked a primary cardiac depression, which led to a rapid cardiac arrest by pulseless electrical activity despite the maintenance of PaO2 by mechanical ventilation. These effects were totally unrelated to the potassium contained in KCN. It is concluded that circulatory failure can develop as a direct consequence of CN induced apnea but in a narrow range of exposure. In this “low” range, maintaining pulmonary gas exchange after exposure, through mechanical ventilation (or spontaneous gasping) can reverse cardiac depression and restore spontaneous breathing. At higher level of intoxication, cardiac depression is to be treated as a specific and spontaneously irreversible consequence of CN exposure, leading to a pulseless electrical activity.
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