Abstract
The nitrite anion (NO(-)(2)) has recently received much attention as an endogenous nitric oxide source that has the potential to be supplemented for therapeutic benefit. One major mechanism of nitrite reduction is the direct reaction between this anion and the ferrous heme group of deoxygenated hemoglobin. However, the reaction of nitrite with oxyhemoglobin (oxyHb) is well established and generates nitrate and methemoglobin (metHb). Several mechanisms have been proposed that involve the intermediacy of protein-free radicals, ferryl heme, nitrogen dioxide (NO(2)), and hydrogen peroxide (H(2)O(2)) in an autocatalytic free radical chain reaction, which could potentially limit the usefulness of nitrite therapy. In this study we show that none of the previously published mechanisms is sufficient to fully explain the kinetics of the reaction of nitrite with oxyHb. Based on experimental data and kinetic simulation, we have modified previous models for this reaction mechanism and show that the new model proposed here is consistent with experimental data. The important feature of this model is that, whereas previously both H(2)O(2) and NO(2) were thought to be integral to both the initiation and propagation steps, H(2)O(2) now only plays a role as an initiator species, and NO(2) only plays a role as an autocatalytic propagatory species. The consequences of uncoupling the roles of H(2)O(2) and NO(2) in the reaction mechanism for the in vivo reactivity of nitrite are discussed.
Highlights
Several mechanisms have been proposed that involve the intermediacy of protein-free radicals, ferryl heme, nitrogen dioxide (NO2), and hydrogen peroxide (H2O2) in an autocatalytic free radical chain reaction, which could potentially limit the usefulness of nitrite therapy
The important feature of this model is that, whereas previously both H2O2 and NO2 were thought to be integral to both the initiation and propagation steps, H2O2 only plays a role as an initiator species, and NO2 only plays a role as an autocatalytic propagatory species
Kosaka et al [9] observed that catalase could extend the slow phase, but observed no effect of superoxide dismutase. They detected a transient protein free radical by Electron Paramagnetic Resonance Spectroscopy (EPR) spectroscopy, and proposed a model with the intermediacy of H2O2, ferryl forms of hemoglobin, and a chain propagator function of nitrogen dioxide free radical (NO2). In agreement with this model, we have recently confirmed the formation of ferrylHb as a reaction intermediate and shown that a diffusible oxidant is formed in the nitrite/oxyHb reaction consistent with the formation of nitrogen dioxide [10]
Summary
Kosaka et al [9] observed that catalase could extend the slow phase, but observed no effect of superoxide dismutase They detected a transient protein free radical by EPR spectroscopy, and proposed a model with the intermediacy of H2O2, ferryl forms of hemoglobin (ferrylHb and ferrylHb-radical, analogs of peroxidase compounds II and I, respectively), and a chain propagator function of nitrogen dioxide free radical (NO2). In agreement with this model, we have recently confirmed the formation of ferrylHb as a reaction intermediate and shown that a diffusible oxidant is formed in the nitrite/oxyHb reaction consistent with the formation of nitrogen dioxide [10]. We conclude that the oxidation of oxyHb by nitrite occurs through an autocatalytic mechanism that relies exclusively on NO2 as the autocatalyst
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