NO contest: nitrite versus S-nitroso-hemoglobin.

Arecent flurry of research papers and commentaries in this journal1–4 has highlighted a current major controversy in cardiovascular biochemistry and physiology: how is nitric oxide (NO) transported in the bloodstream. Two views have arisen. First, that S-nitrosated hemoglobin and albumin serve as stable storage forms of intravascular NO, and, in the case of S-nitrosated hemoglobin, as an allosterically regulated delivery vehicle for NO.5,6 The second is that the anion nitrite, which is present in relative abundance in both blood and tissue, subserves this function.7 The controversy is relevant to the study by James et al in this issue of Circulation Research that examined the ability of red blood cells treated with NO, from healthy subjects and patients with diabetes, to vasodilate rabbit aortic rings.4 The investigators report that exposure of oxygenated red blood cells to NO in vitro results in increased levels of NO-modified hemoglobin, specifically iron-nitrosyl-hemoglobin (NO bound to the heme group) and S-nitroso-hemoglobin (NO bound to the cysteine 93 residue of the -globin chain), and that these cells vasodilate rabbit aortic rings. The ability of the NO-treated red blood cells to vasodilate increases with greater NO exposure, raising intracellular S-nitrosohemoglobin levels and with progressive hypoxia. Additionally, they find that diabetic red blood cells form less S-nitroso-hemoglobin with NO exposure than normal red blood cells, dilate more at 1% oxygen concentration, and dilate less at 2% oxygen. They ascribe these observations to an impairment in NO delivery from glycohemoglobin (at 2% oxygen) and suggest that the reduced NO bioavailability in diabetes can be attributed to the red blood cells, in addition to the generally accepted mechanism of reduced endothelial NO production and NO inactivation by reactive oxygen species. Indeed, the authors suggest that elevated levels of ironnitrosyl-hemoglobin may be a marker for poor glycemic control. This commentary will not specifically focus on this newly proposed mechanism for microvascular pathology based on impaired NO delivery from blood, but on the two competing mechanisms for that delivery in the context of normal physiology—a topic far from resolved in the work of James et al.4 We begin by reviewing what we believe are the currently accepted principles, supported by both laboratory and clinical studies, for the interaction between NO and hemoglobin in blood.