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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003796-04
Application #
6343299
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
4
Fiscal Year
2001
Total Cost
$115,020
Indirect Cost

  Institution

Name
University of Washington
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Deem, Steven (2006) Red blood cells and hemoglobin in hypoxic pulmonary vasoconstriction. Adv Exp Med Biol 588:217-31
Brogan, Thomas V; Robertson, H Thomas; Lamm, Wayne J E et al. (2004) Carbon dioxide added late in inspiration reduces ventilation-perfusion heterogeneity without causing respiratory acidosis. J Appl Physiol 96:1894-8
Deem, Steven; Kim, Seong Su; Min, Jin-Hye et al. (2004) Pulmonary vascular effects of red blood cells containing S-nitrosated hemoglobin. Am J Physiol Heart Circ Physiol 287:H2561-8
Deem, Steven (2004) Nitric oxide scavenging by hemoglobin regulates hypoxic pulmonary vasoconstriction. Free Radic Biol Med 36:698-706
Vaughan, David J; Brogan, Thomas V; Kerr, Mark E et al. (2003) Contributions of nitric oxide synthase isozymes to exhaled nitric oxide and hypoxic pulmonary vasoconstriction in rabbit lungs. Am J Physiol Lung Cell Mol Physiol 284:L834-43
Deem, Steven; Kim, Joung-Uk; Manjula, Belur N et al. (2002) Effects of S-nitrosation and cross-linking of hemoglobin on hypoxic pulmonary vasoconstriction in isolated rat lungs. Circ Res 91:626-32
Swenson, Erik R; Deem, Steven; Kerr, Mark E et al. (2002) Inhibition of aquaporin-mediated CO2 diffusion and voltage-gated H+ channels by zinc does not alter rabbit lung CO2 and NO excretion. Clin Sci (Lond) 103:567-75
Deem, S; Gladwin, M T; Berg, J T et al. (2001) Effects of S-nitrosation of hemoglobin on hypoxic pulmonary vasoconstriction and nitric oxide flux. Am J Respir Crit Care Med 163:1164-70
Deem, S; Berg, J T; Kerr, M E et al. (2000) Effects of the RBC membrane and increased perfusate viscosity on hypoxic pulmonary vasoconstriction. J Appl Physiol 88:1520-8
Deem, S; Hedges, R G; Kerr, M E et al. (2000) Acetazolamide reduces hypoxic pulmonary vasoconstriction in isolated perfused rabbit lungs. Respir Physiol 123:109-19

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