© 1991 Oxford University Press
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Acute Neurotoxicity of Sodium Azide and Nitric Oxide1
Department of Pharmacology and Toxicology, Dartmouth Medical School Hanover, New Hampshire 03756
Received October 23, 1990; accepted January 31, 1991
Acute Neurotoxicity of Sodium Azide and Nitric Oxide. Smith, R, P., Louis, C. A., Kruszyna, R., and Kruszyna, H. (1991). Toxicol.AppI Pharmacol. 17, 120-127. Sodium azide is a chemical of rapidly growing commercial importance with a high acute toxicity and an unknown mechanism of action. Although it has some chemical properties and biological effects in common with cyanide, its lethality does not appear to be due to inhibition of cytochrome oxidase. Unlike cyanide it is a potent vasodilator and inhibitor of platelet aggregation presumably by virtue of its conversion to nitric oxide in vivo and in isolated preparations of blood vessels and thrombocytes. It is not clear whether the high toxicity of azide is due to nitric oxide or to the parent anion. Of a number of possible azide antagonists tested in intact mice only phenobarbital in both anesthetic and subanesthetic doses afforded statistically significant protection against death. Diazepam, phenytoin, and an anesthetic dose of a ketamine–xylazine combination had no effect. Major motor seizures are sometimes seen in human azide poisoning, and these are a regular feature of azide poisoning in laboratory rodents. Solutions of nitric oxide given systemically to mice produced no signs of toxicity, but doses 1,000-fold lower placed in the cerebroventricular system of rats produced brief but violent tonic convulsive episodes. A dose of 0.61 mmol/kg azide as given systemically regularly produced convulsions whereas a dose of 6 jimol/kg given icv produced seizures in rats. The icv convulsive dose of azide was 50-fold larger than the icv dose of nitric oxide. These results suggest that azide lethality is due to enhanced excitatory transmission in the central nervous system perhaps after its conversion to nitric oxide. Both hydroxylamine and cyanide produce seizures when given systemically which are presumably secondary to hypoxia; phenobarbital did not protect against death in either case. Thus, the azide seizures cannot be not due to hypoxia, and the seizures produced by hydroxylamine when given icv may have the same mechanism as those induced by azide.