Sonobe Takashi, Haouzi Philippe
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Pennsylvania State University, College of Medicine , Hershey, PA , USA.
Clin Toxicol (Phila). 2015 Jul;53(6):525-39. doi: 10.3109/15563650.2015.1043440. Epub 2015 May 12.
Hydrogen sulfide (H2S) intoxication produces an acute depression in cardiac contractility-induced circulatory failure, which has been shown to be one of the major contributors to the lethality of H2S intoxication or to the neurological sequelae in surviving animals. Methylene blue (MB), a phenothiazinium dye, can antagonize the effects of the inhibition of mitochondrial electron transport chain, a major effect of H2S toxicity.
We investigated whether MB could affect the immediate outcome of H2S-induced coma in un-anesthetized animals. Second, we sought to characterize the acute cardiovascular effects of MB and two of its demethylated metabolites-azure B and thionine-in anesthetized rats during lethal infusion of H2S.
First, MB (4 mg/kg, intravenous [IV]) was administered in non-sedated rats during the phase of agonal breathing, following NaHS (20 mg/kg, IP)-induced coma. Second, in 4 groups of urethane-anesthetized rats, NaHS was infused at a rate lethal within 10 min (0.8 mg/min, IV). Whenever cardiac output (CO) reached 40% of its baseline volume, MB, azure B, thionine, or saline were injected, while sulfide infusion was maintained until cardiac arrest occurred.
Seventy-five percent of the comatose rats that received saline (n = 8) died within 7 min, while all the 7 rats that were given MB survived (p = 0.007). In the anesthetized rats, arterial, left ventricular pressures and CO decreased during NaHS infusion, leading to a pulseless electrical activity within 530 s. MB produced a significant increase in CO and dP/dtmax for about 2 min. A similar effect was produced when MB was also injected in the pre-mortem phase of sulfide exposure, significantly increasing survival time. Azure B produced an even larger increase in blood pressure than MB, while thionine had no effect.
MB can counteract NaHS-induced acute cardiogenic shock; this effect is also produced by azure B, but not by thionine, suggesting that the presence of methyl groups is a prerequisite for producing this protective effect.
硫化氢（H₂S）中毒会导致心脏收缩力急性下降，进而引发循环衰竭，这已被证明是H₂S中毒致死或存活动物出现神经后遗症的主要原因之一。亚甲蓝（MB）是一种吩噻嗪染料，可拮抗线粒体电子传递链抑制的作用，这是H₂S毒性的主要影响。
我们研究了MB是否会影响未麻醉动物中H₂S诱导昏迷的即时结果。其次，我们试图在致死性输注H₂S期间，对麻醉大鼠中MB及其两种去甲基化代谢产物天青B和硫堇的急性心血管作用进行表征。
首先，在硫氢化钠（NaHS，20mg/kg，腹腔注射）诱导昏迷后的濒死呼吸阶段，对未镇静的大鼠静脉注射MB（4mg/kg）。其次，在4组氨基甲酸乙酯麻醉的大鼠中，以在10分钟内致死的速率（0.8mg/min，静脉注射）输注NaHS。每当心输出量（CO）达到其基线体积的40%时，注射MB、天青B、硫堇或生理盐水，同时维持硫化物输注直至心脏骤停发生。
接受生理盐水的昏迷大鼠（n = 8）中有75%在7分钟内死亡，而给予MB的所有7只大鼠均存活（p = 0.007）。在麻醉大鼠中，输注NaHS期间动脉压、左心室压力和CO下降，导致在530秒内出现无脉电活动。MB使CO和最大dp/dt显著增加约2分钟。在硫化物暴露濒死期注射MB时也产生了类似的效果，显著延长了存活时间。天青B使血压升高的幅度甚至比MB更大，而硫堇没有效果。
MB可对抗NaHS诱导的急性心源性休克；天青B也有此作用，但硫堇没有，这表明甲基的存在是产生这种保护作用的先决条件。
