Acute Cyanide Toxicity, Complex IV, NO, & Nitrite

突然使用氰化氢气体（HCN）作为武器，直接针对被欺骗的个人， 被限制在封闭的空间内，可能会迅速造成大规模伤亡。一氧化氮（NO） 目前已知的唯一能够从细胞色素c的活性位点置换氰化物（CN）的试剂 氧化酶-急性中毒期间抑制的关键部位。热衷于使用传统的 解毒剂，亚硝酸盐（戊基和/或亚硝酸钠），已经减少，部分原因是不确定的假设， 其作用机制是诱导高铁血红蛋白（MetHb）。巧合的是，最近 已经将努力转向亚硝酸盐在人体生理学中的作用（作为NO的来源）。我们现在 表明亚硝酸盐对CN毒性逆转较少依赖于MetHb的产生， 由于亚硝酸盐和一氧化氮已经被批准用于人类使用， 提供了一种廉价的解毒剂，其易于给药（通过吸入）并且可以容易地储存用于 公共卫生用途，我们建议进一步了解其分子作用机制和 其功效的临床前试验代表了化学对策的合理进展。我们建议 通过吸入施用的蒸发的亚硝酸盐溶液将导致原位产生NO， 可减轻CN的急性毒性作用。我们的具体目标是：i）建立生物化学 NO抵消HCN对分离的细胞色素c氧化酶的抑制作用的机制; 2） 阐明细胞色素c氧化酶，HCN，分子间相互作用的机制， 氧（O2）和NO，或亚硝酸钠在线粒体; 3）证明在动物中的功效，NO和 一氧化氮释放化合物，包括亚硝酸钠，在治疗急性氰化物中毒。

The surprise use of either hydrogen cyanide gas (HCN) as a weapon directed against individuals deceived into becoming confined in enclosed spaces is likely to rapidly result in mass casualties. Nitric oxide (NO) is presently the only agent known that is able to displace cyanide (CN) from the active site of cytochrome c oxidase - the critical site of inhibition during acute intoxication. Enthusiasm for the use of traditional antidotes, nitrites (amyl and/or sodium nitrite), has decreased, in part, because of the uncertain assumption that its mechanism of action is the induction of methemoglobin (MetHb). Coincidently, extraordinary recent efforts have been redirected towards the role of nitrite in human physiology (as a source of NO). We now suggest that reversal of CN toxicity by nitrite is less dependent on production of MetHb but rather is secondary to formation of NO. Since nitrites and nitric oxide are already approved for human use and may provide an inexpensive antidote that is easy to administer (via inhalation) and can be readily stockpiled for public health use, we suggest that further understanding of their molecular mechanisms of action and a preclinical trial of their efficacy represent rational advances in chemical countermeasures. We propose that vaporized nitrite solution, to be administered by inhalation, will lead to the in situ production of NO which will ameliorate the acute toxic effects of CN. Our Specific Aims are to: i) establish the biochemical mechanism through which NO counteracts the inhibition of isolated cytochrome c oxidase by HCN; 2) elucidate the mechanisms that account for the interactions between cytochrome c oxidase, HCN, molecular oxygen (O2) and NO, or sodium nitrite in mitochondria; 3) demonstrate in animals the efficacy, of NO and NO-releasing compounds, including sodium nitrite, in the treatment of acute cyanide intoxication.