Toxicology of selected nitric oxide-donating xenobiotics, with particular reference to azide

Nitric oxide (NO) has been discovered recently to be a ubiquitous, endogenous mediator, which is responsible for a variety of normal physiological functions. However, NO also has been implicated in several pathophysiological processes. For example, the pulmonary toxicity of various nitrogen oxides, including NO, found in photochemical smog has been studied for decades; endogenous NO also is associated with bleomycin-induced lung damage, as well as other adverse effects. Recently, a variety of xenobiotics have been shown to owe their biological activity in vivo to their biotransformation to NO. Thus, the therapeutic vasodilatation produced by drugs such as nitroglycerin and sodium nitroprusside is now believed to result from their release of NO, which then mimics the effects of endogenously synthesized NO. The toxic effects of NO prodrugs are, therefore, a matter of concern, especially the extent to which, if any, NO contributes to their toxicity. As reviewed here, NO does not appear to contribute importantly to the toxicity of the NO donors nitrite, hydroxylamine, or nitroprusside. However, it is by no means clear whether or not the NO generated in vivo from sodium azide contributes in a major way to its toxicity. Azide is almost as acutely toxic as cyanide, with which it shares a number of biological effects; yet, azide also has certain cardiovascular actions in common with nitrite. Unlike either cyanide or nitrite, some evidence suggests a tendency for azide to produce low-grade cumulative toxicity. In laboratory animals, azide frequently produces nonasphyxial convulsions, whereas most human deaths appear to be the result of cardiovascular collapse. Neither of these azide-induced syndromes appears to be due to the inhibition of cytochrome c oxidase. Azide is widely used as a preservative in aqueous laboratory reagents and as the propellant in automobile air bags and aircraft escape chutes. Both of these inflable systems are generally safe, and will prevent untold numbers of injuries and deaths. However, to protect workers who handle these devices and others who may come into contact with the sodium azide propellant in these systems, our rudimentary knowledge of azide toxicity needs to be expanded.