How Red Blood Cells Process Nitric Oxide
Evidence for the Nitrite Hypothesis
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Article, see p 166
Basal and shear-mediated blood flow is regulated in large part by nitric oxide (NO) produced by the endothelial NO synthase. This oxygen- and l-arginine–dependent process regulates 25% of resting blood flow and is further activated by the shear stress of exercise-induced metabolic vasodilation to enhance NO-dependent vasodilation of conduit vessels.1 NO that is produced under basal conditions and enhanced by exercise shear-activated NO synthase not only vasodilates but also is oxidized in plasma to form nitrite and S-nitrosothiol compounds.2 How these NO metabolites contribute to blood flow and endocrine NO signaling has been the subject of active research and debate over the last 15 years.3
Two dominant theories have been proposed, both of which require red blood cell and deoxyhemoglobin-dependent bioactivation. The S-nitroso-hemoglobin (SNO-Hb) hypothesis posits that NO binds covalently to the conserved cysteine 93 residue of hemoglobin and during deoxygenation releases an intermediate (still not defined) that is exported from the red blood cell as a low-molecular-weight S-nitrosothiol, leading to hypoxic vasodilation.4 The nitrite reductase hypothesis posits that the endocrine reservoir is nitrite, and during arterial-to-venous (A-V) transit, the nitrite reacts with the deoxyheme of hemoglobin to form NO (and N2O3), which produces hypoxic vasodilation.5,6 The latter hypothesis has been supported by experimental data showing that other globins, including myoglobin, cytoglobin, neuroglobin, and globin X, signal via nitrite reduction.7–9 This signaling has been shown to modulate hypoxic vasodilation, …