The oxyhemoglobin reaction of nitric oxide

The oxidation of nitric oxide (NO) to nitrate by oxyhemoglobin is a fundame ntal reaction that shapes our understanding of NO biology. This reaction is considered to be the major pathway for NO elimination from the body; it is the basis for a prevalent NO assay; it is a critical feature in the modeli ng of NO diffusion in the circulatory system; and it informs a variety of t herapeutic applications, including NO-inhalation therapy and blood substitu te design. Here we show that, under physiological conditions, this reaction is of little significance. Instead, NO preferentially binds to the minor p opulation of the hemoglobin's vacant hemes in a cooperative manner, nitrosy lates hemoglobin thiols, or reacts with liberated superoxide in solution. I n the red blood cell, superoxide dismutase eliminates superoxide, increasin g the yield of S-nitrosohemoglobin and nitrosylated hemes, Hemoglobin thus serves to regulate the chemistry of NO and maintain it in a bioactive state . These results represent a reversal of the conventional view of hemoglobin in NO biology and motivate a reconsideration of fundamental issues in NO b iochemistry and therapy.