The Effect of Sodium Nitrite on Acute Hemolysis in a Canine Model

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The primary goal of this study was to determine the therapeutic value of intravenous sodium nitrite in a canine model of acute intravascular hemolysis. Nitric oxide (NO) is a vasodilator which is constantly produced by the vascular endothelium. The amount of NO available in the circulation is, in part, regulated by the binding of NO to hemoglobin. Hemoglobin is normally contained within the red blood cell and reacts with nitric oxide at a relatively slow rate. However, the destruction of red blood cells within the circulation (intravascular hemolysis) causes the release of hemoglobin (cell-free hemoglobin) from the red blood cell into the circulation. The cell-free hemoglobin released into the circulation during hemolysis binds to NO at a much faster rate than hemoglobin within the red blood cell. This rapid binding of NO by cell-free hemoglobin disrupts the normal balance of NO within the circulation and leads to a decrease in the amount of NO available. This decrease in the amount of available NO leads to vasoconstriction and subsequently to decreased blood flow and organ injury. Intravenous sodium nitrite can bind to cell-free hemoglobin and may prevent the cell-free hemoglobin from binding to NO. If the nitrite can prevent the cell-free hemoglobin from binding NO, it may prevent the vasoconstriction and organ injury that occurs during hemolysis. In a canine model of low and high intensity hypotonic intravascular hemolysis, we characterized the hemodynamic responses to nitrite infusions. Hemolysis increased systemic and pulmonary arterial pressures and systemic vascular resistance. Hemolysis also inhibited NO-dependent pulmonary and systemic vasodilation by the NO-donor sodium nitroprusside. Compared with nitroprusside, nitrite demonstrated unique effects by not only inhibiting hemolysis-associated vasoconstriction, but also by potentiating vasodilation at plasma hemoglobin concentrations <25 microM. We also observed as interaction between plasma hemoglobin level and nitrite to augment nitroprusside-induced vasodilation of the pulmonary and systemic circulation. This nitrite reductase activity of hemoglobin in vivo was recapitulated in vitro using a mitochondrial NO sensor system. Nitrite infusions may promote NO generation from hemoglobin while maintaining oxygen delivery; this effect could be harnessed to treat hemolytic conditions and to detoxify the hemoglobin-based blood substitutes.