Conference: 2008 International PHA Conference and Scientific Sessions
Release Date: 06.20.2008
Presentation Type: Abstracts
Blood A.B., Schroeder H., Terry M.H., Merrill-Henry J., Power G.G.
Loma Linda University School of Medicine, Loma Linda, CA, USA
BACKGROUND: Vasoactive nitric oxide (NO) is traditionally thought to derive from NO synthase in the vascular endothelium. This NO is rapidly converted predominantly to nitrite and nitrate with an effective half-life of fractions of a second. However, it is known that inhaled NO gas (iNO) is not only a potent pulmonary vasodilator, but also results in decreased resistance in hypoxic peripheral vascular beds. This has led to the search for a stable NO metabolite, capable of circulating in the blood, and of being converted to vasoactive NO in remote vascular beds. Much literature on this topic points to hemoglobin as an NO carrier and/or as a nitrite reductase resulting in NO production. Both proposed mechanisms suggest the erythrocytes themselves act as hypoxia-sensitive vasodilators by releasing vasoactive NO.
We hypothesized that NO released from erythrocytes is a tonic pulmonary vasodilator important to the maintenance of low basal pulmonary vascular tone and that this NO is particularly susceptible to scavenging by plasma free hemoglobin, resulting in the selective effects of hemolysis on the pulmonary vasculature. Finally, we compared the efficacy of intravenous or inhaled nitrite, or iNO at reducing pulmonary vascular resistance as well as oxidizing plasma free hemoglobin to methemoglobin (which does not scavenge NO).
METHODS: Anesthetized and mechanically ventilated newborn lambs (10 to 20 days) were acutely instrumented for measurement of pulmonary artery and wedge pressures and a flow probe on the pulmonary artery for measurement of cardiac output and calculation of vascular resistances. A continuous intravenous infusion of hemolyzed blood (1/3 of the dose to the femoral vein, 2/3 of the dose to the left ventricle) was administered to achieve steady-state plasma concentrations of 200 to 400 nM (heme basis) for 180 min. Changes in pulmonary and systemic pressures and resistances were measured. During the final 90 min of hemolysate infusion, intravenous nitrite, nebulized nitrite, or iNO (20ppm) were administered (n=5 per group).
RESULTS: Infusion of hemolyzed blood resulted in a significant increase in pulmonary (128±32%, p<0.01) but not systemic (21±17%) vascular resistance that was sustained throughout the first 90 min of hemolysate infusion (see Figure).
iNO therapy resulted in a rapid return of pulmonary vascular resistance to baseline levels. Inhaled nitrite resulted in a significant increase in exhaled NO gas, and a significant decrease in pulmonary vascular resistance, but was not as effective as iNO. Intravenous nitrite did not alter pulmonary vascular resistance significantly. iNO administration was also associated with a nearly complete oxidation of plasma-free hemoglobin to methemoglobin (p<0.01), an effect not observed with nitrite treatments.
COMMENTS AND CONCLUSIONS: These experiments demonstrate the selective vasoconstricting effects of hemolyzed blood on the pulmonary vasculature, a finding in support of the idea that NO-release from red blood cells is a constituitive pulmonary vasodilator. Furthermore, the results suggest that the benefits of iNO therapy for treatment of hemolysis-induced pulmonary hypertension may result from both direct vasodilation as well as oxidation of the plasma free hemoglobin to methemoglobin, which does not scavenge NO.