The surprise use of either hydrogen cyanide gas (HCN) as a weapon directed against individuals deceivedinto becoming confined in enclosed spaces is likely to rapidly result in mass casualties. Nitric oxide (NO) ispresently the only agent known that is able to displace cyanide (CN) from the active site of cytochrome coxidase - the critical site of inhibition during acute intoxication. Enthusiasm for the use of traditionalantidotes, nitrites (amyl and/or sodium nitrite), has decreased, in part, because of the uncertain assumptionthat its mechanism of action is the induction of methemoglobin (MetHb). Coincidently, extraordinary recentefforts have been redirected towards the role of nitrite in human physiology (as a source of NO). We nowsuggest that reversal of CN toxicity by nitrite is less dependent on production of MetHb but rather issecondary to formation of NO. Since nitrites and nitric oxide are already approved for human use and mayprovide an inexpensive antidote that is easy to administer (via inhalation) and can be readily stockpiled forpublic health use, we suggest that further understanding of their molecular mechanisms of action and apreclinical trial of their efficacy represent rational advances in chemical countermeasures. We propose thatvaporized nitrite solution, to be administered by inhalation, will lead to the in situ production of NO whichwill ameliorate the acute toxic effects of CN.
Our Specific Aims are to: i) establish the biochemicalmechanism 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, molecularoxygen (O2) and NO, or sodium nitrite in mitochondria; 3) demonstrate in animals the efficacy, of NO andNO-releasing compounds, including sodium nitrite, in the treatment of acute cyanide intoxication.
