Acute Cyanide Toxicity, Complex IV, NO & Nitrite

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DESCRIPTION (provided by applicant): 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: 1) 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.