Sodium nitroprusside (SNP) is a widely used vasodilator drug despite a few reports implicating cyanide poisoning in patients during its use. There is no question that SNP in acute overdoses produces cyanide poisoning in animals. Sodium azide is a common laboratory reagent, has been proposed for use in automobile air bags and has been responsible for human poisonings. Although azide is a known inhibitor of cytochrome c oxidase and is almost as toxic acutely as cyanide, its effects in intact animals are distinctly different from those of cyanide. Indeed, except for the fact that it does not result in cyanide poisoning, azide much more closely resembles SNP in that it is a potent, directly acting vasodilator. In fact, azide may be as effective, and perhaps safer, for the same indications as SNP. We have discovered an interesting interaction between cyanide and SNP or azide in vascular smooth muscle that does not appear to involve an effect on cytochrome c oxidase. When SNP relaxes vascular smooth muscle it also increases the tissue content of c-GMP. Both of these effects are reversed by cyanide. Although the physiologic significance of these observations remains unknown, the same mechanical responses are seen in guinea pig ileum and cyanide also reverses the inhibitory effect of SNP on platelet aggregation. Thus, SNP and cyanide may represent important tools for studying the modulation of c-GMP levels in a variety of tissues at a level that seems to be beyond autonomic or hormonal receptors. We will test the hypothesis that this cyanide sensitive mechanism is also responsible for the inactivation of SNP in some vascular beds. We will determine whether or not the inactivation mechanism is responsible for cyanide release from SNP to cause cyanide poisoning. Cyanide remains of current interest because of its alleged implication in such diseases as Leber's optic atrophy, tobacco amblyopia and in various toxic manifestations of cassava ingestion. Because sulfur deficiency may be a factor in the expression of cassava toxicity, we will test the hypothesis that liver rhodanese may not be as important as sulfane-sulfur, perhaps bound to plasma albumin, in cyanide detoxication. We will also determine whether or not liver injury increases susceptibility to cyanide poisoning.

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National Heart, Lung, and Blood Institute (NHLBI)
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Toxicology Study Section (TOX)
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Dartmouth College
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