Background Nitrite (NO2−), a normal constituent of blood, reacts with deoxyhemoglobin (Hb) to produce nitric oxide (NO), a potent vasodilator. This reaction may play an important role in effecting vasodilation in hypoxic tissues, matching oxygen delivery with oxygen need. Nitrite also reacts with oxyhemoglobin (HbO2) to produce nitrate (NO3−). The reaction of nitrite with either Hb or HbO2 oxidizes the heme, producing methemoglobin (MetHb). Thus, MetHb production serves as a dosimeter of the reaction of nitrite with hemoglobin.
Objective We hypothesized that more of an IV nitrite bolus would be metabolized in the tissues compared with the blood. In addition, cycling of hemoglobin between the Hb and HbO2 states would increase nitrite reactions in blood.
Methods For in vivo measurements newborn lambs (n = 5) were anesthetized and studied during normoxia and hypoxia (FiO2 12-14%). For in vitro experiments, an extracorporeal membrane oxygenator (ECMO) circuit was built with two gas exchangers, one for oxygenating blood and one for deoxygenating it. The ECMO circuit was primed with sheep blood to Hb concentrations comparable with that of the lambs. After a baseline period, nitrite was injected both into the lambs and the ECMO circuit to a final concentration of ≈500 μM. MetHb concentrations were measured at predetermined time points over the next 80 minutes. Additional experiments were performed in sheep blood in vitro with hemoglobin saturations maintained at a constant 50%.
Results and Conclusions Significantly more MetHb was produced in the ECMO experiments compared to the in vivo experiments (see Figure; p < .001). Thus, a significant portion of the NO2− was metabolized in the tissues of the lambs as compared with the blood in the ECMO circuit. In addition, oxygenation-deoxygenation cycling in the ECMO circuit increased MetHb production compared with blood in vitro held at a constant saturation. We postulate that the increased MetHb production during oxygenation-deoxygenation cycling reflects a NO/NO2− cycle that results in vasodilating activity. These findings suggest possible mechanisms for the role of nitrite metabolism in mediating vascular tone.
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