title: Acute, sublethal cyanide poisoning in mice is ameliorated by nitrite alone: complications arising from concomitant administration of nitrite and thiosulfate as an antidotal combination.
abstract: Sodium nitrite alone is shown to ameliorate sublethal cyanide toxicity in mice when given from ∼1 h before until 20 min after the toxic dose as demonstrated by the recovery of righting ability. An optimum dose (12 mg/kg) was determined to significantly relieve cyanide toxicity (5.0 mg/kg) when administered to mice intraperitoneally. Nitrite so administered was shown to rapidly produce NO in the bloodsteam as judged by the dose-dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. It is argued that antagonism of cyanide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity rather than the methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood resulted in the detection of sulfidomethemoblobin by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase, the effects of the two inhibitors being essentially additive under standard assay conditions rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite-thiosulfate combination therapy at sublethal levels of cyanide intoxication.
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, The University of Pittsburgh, 100 Technology Drive, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Leah K
authors.initials: LK
authors.lastname: Cambal
authors.forename: Megan R
authors.initials: MR
authors.lastname: Swanson
authors.forename: Quan
authors.initials: Q
authors.lastname: Yuan
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Weitz
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pitt
authors.forename: Linda L
authors.initials: LL
authors.lastname: Pearce
authors.forename: Jim
authors.initials: J
authors.lastname: Peterson
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage* / Q000737:chemistry; D003486:Cyanides / Q000506:poisoning*; D004578:Electron Spin Resonance Spectroscopy; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D008706:Methemoglobin / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D012977:Sodium Nitrite / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D013885:Thiosulfates / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000931:Antidotes; D003486:Cyanides; D006454:Hemoglobins; D013885:Thiosulfates; C008657:nitrosyl hemoglobin; D009569:Nitric Oxide; D008706:Methemoglobin; D003576:Electron Transport Complex IV; C017717:sodium thiosulfate; D012977:Sodium Nitrite