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Cyanide toxicity in mice pretreated with diethylamine nitric oxide complex

Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA

E.W. Nealley

Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA

J.C. Lempka

Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA

1 Since the literature suggested a portion of the overall toxicity of cyanide (CN) may be affected by nitric oxide, we investigated a long acting NO releasing complex (diethy lamine/nitric oxide (DEA/NO)) which may exhibit vasodi latory as well as other nitric oxide effects to determine its ability to modify CN toxicity. Sodium nitrite, a vasodilator commonly used to treat cyanide toxicity thought to act by methemoglobin (MHb) formation, can be rapidly trans formed to nitric oxide (NO).

2 Mice (n=10 per dose) were administered one of five doses of sodium cyanide (NaCN) intraperitoneally (4.28,5.08,6.03,7.17 and 8.52 mg kg^-1). DEA/NO was given intravenously (20 mg kg^-1) 2 min prior to NaCN. As a control, N^G-monomethyl-L-arginine (L-NMMA), which inhibits NO synthesis, was administered intravenously (70 mg kg^-1) to mice, 3 min prior to DEA/NO.

3 Before CN toxicity studies, we determined whether DEA/NO was producing MHb by collecting tail vein blood from mice and measuring MHb levels. For example, 4 min after DEA/NO administration (5,10, and 20 mg kg^-1), MHb levels were 1.2 7 ± 0.28%, 2.60 ± 0.26% and 6.53 ±0.54% respectively. O₂ capacity was also decreased in a dose related manner. Carboxyhemoglobin or percent O₂ satura tion, on the other hand, was not significantly inhibited. The LD₅₀ increased from 5.75 ± 0.026 (CN alone) to 7.66 ± 0.021 mg kg^-1 (CN+DEA/NO) resulting in a protec tive ratio of 1.73.

4 Results suggest the following: (1) L-NMMA, which inhibits the synthesis of endogenous NO, appears to exacerbate the DEA/NO (or exogenous NO) response; (2) DEA/NO appears to reduce the toxicity of CN which suggests that a portion of CN toxicity may be affected by a NO component; and (3) low DEA/NO doses may act via a direct effect while higher doses (40 mg kg^-1) may allow for formation of a concentration of MHb which can bind CN to form cyanomethemoglobin and reduce the toxicity of CN.

Key Words: cyanide • diethylamine/nitric oxide • mice • methemo globin

Human & Experimental Toxicology, Vol. 15, No. 1, 13-18 (1996)
DOI: 10.1177/096032719601500103


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