Reaction of nitrite with human fetal oxyhemoglobin: A model simulation study with implications for blood flow regulation in sickle cell disease (SCD)

Nitrite can react in parallel with adult oxy- and deoxy-hemoglobin (HbA), resulting in oxidative denitrosylation of nitrosyl-hemoglobin and rapid dissociation of nitric oxide. Here, simulation studies are presented using a new model to analyze data in the literature comparing the reaction of nitrite with isolated human oxy-HbA, oxy-fetal hemoglobin (oxy-HbF) and oxy-Hb Bart's (a γ-chain tetramer). The results show that the kinetic constant at the rate-limiting step is 25-fold larger for the reaction of human oxy-HbF, and 63-fold larger for oxy-Hb Bart's both compared to oxy-HbA. This analysis suggests that red cells containing oxy-HbF (F-cells) should have accelerated oxidative denitrosylation. Thus, high levels of HbF present or induced in individuals homozygous for sickle cell disease may serve two functions: (a) the classical function, to directly inhibit polymerization of deoxy sickle hemoglobin, and (b) a novel function, enhanced vasodilation.