Hemoglobin-nitric oxide interaction and its implications.

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T HE DIATOMIC molecule, nitric oxide (NO) has stimulated a tremendous amount of interest since it was proposed to be an important intercellular and intracellular messenger? It was even the of the year in 1993. The reason for this interest is that NO fulfills a role that was predicted many years ago. The numerous biological signaling activities of NO, including an important function as the endothelium-derived relaxing factor (EDRF), occurs through its chemical reaction with guanylate cyclase (GC), a heine protein that catalyzes the conversion of guanosine monophosphate to cyclic guanosine monophosphate (cGMP). NO binding stimulates the activity of this protein by 100 to 200-fold? The discovery of Furchgott and Zawadzki 3 that vascular relaxation induced by acetylcholine was dependent on the presence of the endothelium provided the first evidence that the modulation of vascular tone was mediated by a labile humoral factor, later known as EDRE Based on the similarities in the pharmacological behavior of EDRF, nitrovasodilators, such as glyceryl nitrate, and nitrous oxide generated from acidified nitrite solutions, it was suggested that EDRF is NO or a closely related molecule, a,5 The identification of the chemical properties of EDRF and the characterization of its biochemical pathway led to a better understanding of the role of vascular endothelium as a mediator of fundamental physiological and pharmacological activities. To influence vascular tone, NO must diffuse from its site of synthesis to reach GC, either intraor intercellularly. The accessibility of GC as a target can be limited by reactions of NO with other molecules, including 02, thiols, free radicals, or other intracellular or extracellular heine proteins, in the diffusion path. Thus, the ability of NO to stimulate GC activity depends on its reactivity with these molecules. It is now well established that inactivation of NO and the consequent depletion of NO from the vascular endothelium promote coronary vasoconstriction and produce hypertension in experimental animals and humans. 6 Because of its short-lived properties, the detection of NO in biological environments has been challenging, and scavengers of this molecule have been used, Hemoglobin, which avidly binds NO with an affinity much higher than that for either O2 or carbon monoxide (CO), is probably the most important NO scavenger, and its interaction with NO has been known for a long time. 7 The clinical implications of this reaction assumed a major significance in the last decades with the advent of chemically modified acellular hemoglobins, preparations that are currently investigated as potential red cell substitutes. 8 The research for blood substitutes represents a novel alternative to red cell transfusion, but to date no solutions that can be infused safely in humans have been approved for general clinical use. The major impediments to progress in the devel-