The role of nitric oxide (NO) as the key mediator of endothelial function and vascular tone was initially recognized by Furchgott and Zawadski over two decades ago when they discovered that an intact endothelium was required for acetylcholine-stimulated vasodilation. From these studies, they determined that the endothelium released a potent vasodilator substance that they termed endothelium-derived relaxing factor; several years later, this factor was identified as NO. Since that time, NO has been shown to modulate a host of functions that maintain the integrity of the endothelium as well as regulate interactions between circulating blood components and the vessel wall. Through its chemical reactions with a variety of species, including heme iron, NO is uniquely positioned to regulate these vascular homeostatic processes.

Endothelium-derived NO serves as a paracrine regulator of vascular function. NO is released to the vascular smooth muscle cells where it activates soluble guanylyl cyclase to generate cyclic guanosine monophosphate (cGMP) and modulate cation flux which, in turn, induce vasodilation and adjust vascular tone accordingly. NO is also released to the bloodstream where it encounters erythrocytes, platelets, and plasma components. Here, the metabolic fate of NO is determined by a complex series of reactions that both consume and preserve stores of bioavailable NO. Owing to the relative abundance of erythrocytes compared with other circulating cell types, interactions between NO and redox-active hemoglobin achieve biological significance.