Some therapeutically useful drugs and some xenobiotics owe their biological activity to their conversion to nitric oxide (NO) in vivo. The biological roles for endogenous NO include vasodilation, relaxation of other smooth muscles, excitatory neurotransmission, platelet aggregation, and phagocytic activity of granulocytes. Exogenous chemicals which are prodrugs for NO and may produce the same biological activities as endogenous NO include nitroprusside, nitroglycerin, azide, hydroxylamine, nitrite and many other structurally related compounds. Except for nitroprusside, the mechanisms or pathways by which these chemicals are converted to NO in vivo are largely unknown. Elucidation of these biotransformation reactions carries with it the potential for the design of drugs with more specific biological activities and a decreased tendency for the development of tolerance. The study of the reaction of nitroprusside with hemoglobin served as an extremely useful model for the reactions that nitroprusside might undergo in tissues to elicit its biological effects. Except for azide, most NO prodrugs do react with hemoglobin to generate methemoglobin and NO, but each seems to have a unique reaction mechanism. Azide, however, does generate NO in vivo. Most of the other vasodilators also react with sulfhydryl groups. We will study the mechanisms of NO prodrug reactions with hemoglobin and sulfhydryl groups as models for the reactions they must undergo in tissues to elicit biological effect. Azide is also unique in that it does not have an oxygen liganded to nitrogen. We will examine the reactions of azide with other redox heme enzymes such as peroxidases and myeloperoxidases to see if these generate NO from azide. Azide has an acute toxicity comparable to that of cyanide, and its use as the """"""""propellant"""""""" in automobile air bags will lead to enormous increases in its production and human exposure. Air bags will save thousands of lives, but we need to know more about the toxicity of azide to protect workers who are exposed in factories that pack azide into the air bag canisters and to intervene effectively in acute poisonings. In addition to profound hypotension acute exposures to azide may result in convulsions. A dozen or more human deaths have been ascribed to azide as a result of suicidal ingestion or its accidental ingestion by persons pipetting azide-preserved laboratory reagents. We propose to study the pharmacokinetics and biotransformation of azide to see if its conversion to NO in the brain is responsible for its excitatory activity.
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