HYPOXIC PULMONARY VASOCANSTRICTION AND RED BLOOD CELLS

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DESCRIPTION (Adapted from applicants' abstract) There is evidence that nitric oxide (NO) is important in red blood cell (RBC)-mediated modulation of hypoxic pulmonary vasoconstriction (HPV). NO may be involved directly in this modulation, or may act indirectly through its combination with hemoglobin (Hb) to form S-nitrosohemoglobin (SNO-Hb). In addition, the purines adenosine and adenosine triphosphate (ATP) may play a role in modulation of pulmonary vascular tone by RBCs. The interactions between RBCs and HPV are clinically relevant because of the common coexistence of anemia and pulmonary disease in critically ill patients. The specific aims of this project are: 1. To determine the effects of manipulation of NO production and metabolism or exogenously administered NO on pulmonary vascular tone during normoxia and hypoxia. 2. To distinguish between the roles played by the intact RBC and its constituent Hb alone in NO metabolism and modulation of HPV, and to determine the potential role of SNO-Hb in modulation of pulmonary vascular tone. 3. To measure pulmonary artery endothelial cell production of NO in a closed system, and to determine the effects of hypoxia and RBCs on endothelial NO production. 4. To elucidate the role of RBCs in purinergic modulation of pulmonary vascular tone by blocking uptake of adenosine by RBCs, by blocking purine receptors, and by assaying purinergic mediator production under normoxic and hypoxic conditions. 5. To determine whether purines affect release of NO by pulmonary artery endothelial cells in a closed system. These aims will be investigated using an isolated, perfused rabbit lung model with quantitiation of HPV done during repeated hypoxic gas challenges at different hematocrits, and with a cultured pulmonary artery endothelial cell model. Mediators will be assayed using chemiluminescence for measurement of expired NO and NO metabolites in perfusate, photolysis chemiluminescence for measurement of SNO-Hb, and high pressure liquid chromatography for measurement of purines in perfusate.