title: Sodium nitrite induces acute central nervous system toxicity in guinea pigs exposed to systemic cell-free hemoglobin.
abstract: Systemic cell-free hemoglobin (Hb) released via hemolysis disrupts vascular homeostasis, in part, through the scavenging of nitric oxide (NO). Sodium nitrite (NaNO(2)) therapy can attenuate the hypertensive effects of Hb. However, the chemical reactivity of NaNO(2) with Hb may enhance heme- or iron-mediated toxicities. Here, we investigate the effect of NaNO(2) on the central nervous system (CNS) in guinea pigs exposed to systemic cell-free Hb. Intravascular infusion of NaNO(2), at doses sufficient to alleviate Hb-mediated blood pressure changes, reduced the expression of occludin, but not zona occludens-1 (ZO-1) or claudin-5, in cerebral tight junctions 4h after Hb infusion. This was accompanied by increased perivascular heme oxygenase-1 expression, neuronal iron deposition, increased astrocyte and microglial activation, and reduced expression of neuron-specific nuclear protein (NeuN). These CNS changes were not observed in animals treated with Hb or NaNO(2) alone. Taken together, these findings suggest that the use of nitrite salts to treat systemic Hb exposure may promote acute CNS toxicity.
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Buehler
authors.forename: Omer I
authors.initials: OI
authors.lastname: Butt
authors.forename: Felice
authors.initials: F
authors.lastname: D'Agnillo
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D002493:Central Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism; D057167:Claudins / Q000378:metabolism; D006168:Guinea Pigs; D006454:Hemoglobins / Q000378:metabolism*; D006461:Hemolysis; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D062793:Occludin; D010084:Oxidation-Reduction; D010750:Phosphoproteins / Q000378:metabolism; D012977:Sodium Nitrite / Q000633:toxicity*; D062826:Zonula Occludens-1 Protein
chemical_list: D057167:Claudins; D006454:Hemoglobins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D012977:Sodium Nitrite