A model of the mechanism of vascular transport of bioactive NO by red cells and plasma during NO inhalation (based on refs. 11–15). (a) During NO inhalation, NO and oxygen in the pulmonary vasculature react to form nitrite (NO₂^–). NO also binds to deoxyheme groups of hemoglobin to form nitrosyl(heme)hemoglobin (Fe^II-NO) and possibly with oxyhemoglobin β-globin cysteine-93 to form S-nitrosohemoglobin (β-cys93-S-NO). The major reaction of NO with oxyhemoglobin to form methemoglobin and nitrate (NO₃^–) is not shown here but accounts for the rise of methemoglobin from approximately 0.2% to 1% during NO inhalation. (b) In the partially deoxygenated red cell some NO of nitrosyl(heme)hemoglobin will react with oxygen or with oxyhemoglobin to form nitrate and methemoglobin. (c) When hemoglobin saturation and tissue pO₂ are very low, these reactions are significantly reduced and NO release from the red cell becomes possible. The hemoglobin structural transition from the oxy-state (R) to the deoxy-state (T) destabilizes the remaining NO ligand. This rate is further accelerated by heterotropic effectors, such as protons and 2,3-diphosphoglycerate, and requires a high-affinity acceptor for NO. It is possible that transfer of NO (NO+) from heme to the hemoglobin β-chain cysteine-93 occurs to form a S-nitrosohemoglobin intermediate that then releases NO by transnitrosation with glutathione (GSH). In addition, plasma nitrite may be converted to NO by disproportionation or by metal- or enzyme-catalyzed (xanthine oxidoreductase) processes. Finally, plasma S-nitrosothiol proteins could bind and deliver NO. Most of these pathways will occur preferentially in regions with low O₂ tension and pH, resulting in delivery of NO to these sites.