title: The reaction of cell-free oxyhemoglobin with nitrite under physiologically relevant conditions: Implications for nitrite-based therapies.
abstract: Nitric oxide (NO*) participates in the regulation of a wide array of biological processes and its deficit contributes to the severity of many diseases. Recently, a role of NO deficiency that occurs as a result of intravascular hemolysis and increases in levels of cell-free hemoglobin in the pathway of chronic anemic pathologies has been suggested. Experimental evidence for deoxyhemoglobin-catalyzed reduction of nitrite to NO* leads to the possibility of nitrite infusion-based therapies to correct NO* deficits. However, the presence of plasma hemoglobin also raises the possibility of deleterious free radical-mediated oxidative damage from the reaction between nitrite and oxyhemoglobin in the vasculature. We show that the conditions required for the reaction between nitrite and oxyhemoglobin to exhibit free radical-mediated autocatalytic kinetics are highly unlikely to occur in the plasma compartment, even during extensive hemolysis and with pharmacological nitrite doses. Although the presence of haptoglobin enhances the rate of the reaction between nitrite and oxyhemoglobin, common plasma antioxidants-ascorbate and urate, as well as catalase-prevent autocatalysis. Our findings suggest that pharmacological doses of nitrite are unlikely to cause free radical or ferrylhemoglobin formation in plasma originating from the reaction of nitrite with cell-free oxyhemoglobin in vivo.
authors.affiliation: National Institutes of Health, NIH, NIDDK, Molecular Medicine Branch, Bethesda, MD 20892, USA.
authors.forename: Barbora
authors.initials: B
authors.lastname: Piknova
authors.forename: Agnes
authors.initials: A
authors.lastname: Keszler
authors.forename: Neil
authors.initials: N
authors.lastname: Hogg
authors.forename: Alan N
authors.initials: AN
authors.lastname: Schechter
mesh_terms: D001205:Ascorbic Acid / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000378:metabolism; D006242:Haptoglobins / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008706:Methemoglobin / Q000378:metabolism; D009573:Nitrites / Q000737:chemistry / Q000378:metabolism*; D010108:Oxyhemoglobins / Q000737:chemistry / Q000378:metabolism*; D010949:Plasma / Q000378:metabolism*; D012044:Regression Analysis; D014527:Uric Acid / Q000378:metabolism
chemical_list: D005609:Free Radicals; D006242:Haptoglobins; D006454:Hemoglobins; D009573:Nitrites; D010108:Oxyhemoglobins; C517773:ferrylhemoglobin; D014527:Uric Acid; D008706:Methemoglobin; D002374:Catalase; D001205:Ascorbic Acid