Acute, Sublethal Cyanide Poisoning in Mice Is Ameliorated by Nitrite Alone: Complications Arising from Concomitant Administration of Nitrite and Thiosulfate as an Antidotal Combination
Acute, Sublethal Cyanide Poisoning in Mice Is Ameliorated by Nitrite Alone: Complications Arising from Concomitant Administration of Nitrite and Thiosulfate as an Antidotal Combination
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DOI：
10.1021/tx2001042
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发表时间：
2011-07-01
影响因子：
4.1
通讯作者：
Peterson, Jim
中科院分区：
文献类型：
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作者：
Cambal, Leah K.;Swanson, Megan R.;Peterson, Jim
单独的亚硝酸钠显示出改善亚致死氰化物毒性小鼠时，从类似的1小时前，直到20分钟后的毒性剂量证明翻正能力的恢复。当腹腔内给药于小鼠时，确定了显著减轻氰化物毒性的最佳剂量（12 mg/kg）（5.0 mg/kg）。通过亚硝基血红蛋白和高铁血红蛋白引起的EPR信号的剂量依赖性外观来判断，这样给予亚硝酸盐显示出在血流中快速产生NO。有人认为，对抗氰化物抑制细胞色素c氧化酶的NO是至关重要的解毒活性，而不是高铁血红蛋白形成行动的亚硝酸盐。同时添加硫代硫酸钠亚硝酸盐处理的血液中的硫化物高铁血红蛋白的EPR光谱检测。硫化物是硫代硫酸盐水解的产物，与氰化物一样，已知是细胞色素c氧化酶的有效抑制剂，这两种抑制剂的作用在标准测定条件下基本上是相加的，而不是由任何一种控制。这些发现为观察到的与使用标准亚硝酸盐硫代硫酸盐联合治疗相关的小鼠有害作用提供了合理的解释：亚致死水平的氰化物中毒。
Sodium nitrite alone is shown to ameliorate sublethal cyanide toxicity in mice when given from similar to 1 h before until 20 min after the toxic dose as demonstrated by the recovery of righting ability. An optimum dose (12 mg/kg) was determined to significantly relieve cyanide toxicity (5.0 mg/kg) when administered to mice intraperitoneally. Nitrite so administered was shown to rapidly produce NO in the bloodsteam as judged by the dose-dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. It is argued that antagonism of cyanide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity rather than the methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood resulted in the detection of sulfidomethemoblobin by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase, the effects of the two inhibitors being essentially additive under standard assay conditions rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite thiosulfate combination therapy:at sublethal levels of cyanide intoxication.