Nitric Oxide And Red Blood Cells

By regulating blood vessel tone, inhibiting smooth muscle cell proliferation, blood cell adhesion and lipid oxidation, NO becomes fundamental for vascular homeostasis. Since NO is not only released abluminally to exert its effects on cells of the vascular wall, but also into the vessel lumen, a significant part of the NO produced by the endothelium is believed to come into direct contact with blood. Given the extremely short half-life of NO in blood and its rapid reaction with hemoglobin in vitro, the fate of this fraction of NO is thought to be dictated largely by its interaction with red blood cells. RBCs are believed to be a major sink for NO by virtue of the rapid co-oxidation reaction of NO with oxyhemoglobin to form methemoglobin and nitrate, the second-order rate constant of which approaches 3-4 x 107 M-1 s 1 [17]. Although this reaction has appreciated widespread recognition as the major inactivation pathway of NO in vivo, recent results obtained in humans had suggested that this may not be the predominant route under all conditions [18]. Alternatively, NO may bind to the heme group of deoxyhemoglobin to form NOHb [19]. NOHb has been detected in the blood of patients receiving nitroglycerin or inhaled NO [7,16]. A third possibility is the reaction of NO, or a higher oxidation product such as NO2 or N2O3, with cysteine-93 of the P-globin chains (P-Cys93) of hemoglobin, leading to the formation of an S-nitrosated derivative of oxyhemoglobin (SNOHb). SNOHb has been suggested to participate in the regulation of blood flow [20] and platelet aggregability [21,22]. According to this theory, hemoglobin in RBCs undergoes S-nitrosation during passage through the lungs and subsequently releases part of its bound NO during arterial-venous transit in order to enhance blood flow and aid in the delivery of oxygen in the microcirculation. In the venous circulation, deoxygenated hemoglobin preferentially binds NO at the heme group to form NOHb. This proposed dynamic cycle has had a profound impact on the way we see NO today, ascribing it a most important new regulatory role in the circulation. The central observations supporting this "SNOHb hypothesis" were two reports showing arterial-venous gradients of micromolar concentrations of SNOHb and NOHb in RBCs of rats and humans [8,23]. However, numerous reports from different groups on the basal levels of intracellular SNOHb in arterial and venous blood have cast serious doubt as to the existence of such a dynamic cycle [2,24-27]. This discrepancy may have its origin in the different methodological approaches used to determine NO adducts in RBCs and the technical difficulties inherent to trace level analysis of nitroso compounds, including artifactual SNOHb/NOHb formation during sample processing.

Of particular importance in this context is the finding that the reaction rate of NO with oxyhemoglobin within erythrocytes is limited by its diffusion into the cell and occurs ~650 times slower compared to the reaction with free oxyhemoglobin [28]. Consumption of plasma NO by RBCs is reduced by increased flow, an unstirred plasma layer surrounding the RBCs, the cell-free zone near the vascular wall, and a reduced diffusion rate over the cellular

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