Physiological reactions of nitric oxide and hemoglobin: A radical rethink

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Abstract
With the recent visit of Drs. Furchgott, Ignarro, and Murad to Nobel-land, the discovery of nitric oxide (NO) as a vascular signaling molecule achieved global appreciation. This elevates NO to the lofty status of hemoglobin (Hb), arguably the best-understood protein from a molecular structure/function viewpoint and one that has been recognized by the well-deserved award of the 1962 Nobel prize in Chemistry to Max Perutz. Nonetheless, there is trouble in paradise. At the intersection of NO and hemoglobin biochemistry lies an abyss in our understanding that is so fundamental and deep as to challenge the biological function of each molecule. This problem has been largely ignored, but it has been visited in a recent report by Gow et al. (1). Simply stated, the problem is that our dogmatic knowledge of chemical interactions of NO and hemoglobin predicts that (i) NO should not achieve a concentration in the vascular wall sufficient to elicit vasorelaxation, and (ii) nitrosylation of Hb, considered to be essentially irreversible, should result in the build-up of a complex that ultimately compromises life by interfering with tissue oxygenation. The obvious facts that endogenously produced NO is bioactive and Hb can deliver O2 indicate that the chemistry which actually occurs between NO and Hb needs major revision. Notably, this chemistry had been defined by in vitro experimentation using supraphysiological concentrations of NO under nonbiological conditions (2). Although correct, it fails to adequately describe the situation at normal physiological levels of NO (3), where interaction of NO would occur with only a single globin subunit, at most, per predominantly O2-saturated Hb tetramer. A growing body of evidence directs our attention to Hb allostery as the answer to this dilemma in adequately understanding NO/Hb chemistry. It is well accepted that reaction with Hb is the major mechanism for …
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