Unlike other vascular beds, the lung must accept the entire cardiac output. Despite large variations in blood flow, pulmonary vascular resistance is maintained relatively constant and intrapulmonary distribution of blood flow is regulated by selectively increasing vascular resistance to alveoli with reduced oxygen tension (hypoxic pulmonary vasoconstriction, HPV). It was suggested that endogenous vasodilator substances act to moderate vasoconstrictor influences in the lung and participate in the maintenance of low pulmonary vascular resistance. Vasodilator influences may, however, oppose hypoxic vasoconstriction and permit perfusion to hypoxic alveoli resulting, thereby, in decreased oxygenation of the blood. A long-term objective of this laboratory is to define the role of products of arachidonic acid (AA) metabolism, in the regulation of the pulmonary circulation under physiological as well as pathophysiological conditions. Cytochrome P450 products of AA metabolism, epoxyeicosatrienoic acids (EET), and in particular, 5,6-EET, relax pulmonary blood vessels. 5,6-EET reduces agonist- mediated increases in pulmonary vascular resistance in the intact canine lung. Therefore, we propose that cytochrome P-450 monooxygenase metabolites of AA are local participants in the control of the pulmonary circulation. The goal of this study is to test the hypothesis that the mechanism by which pulmonary cytochrome P450 products of AA metabolism, and in particular 5,6- EET, support blood flow to hypoxic lung units is via their ability to reduce pulmonary vascular resistance. This hypothesis will be tested using chemical, biochemical, and pharmacological approaches in tissues, organs, and whole animals. We will determine the ability of these cytochrome P450 metabolites of AA to support blood flow to hypoxic lung units during unilateral alveolar hypoxia and in a model of acute lung injury (ALI). Using pharmacological tools that increase or decrease the expression or activity of phospholipase, cytochrome P450 monooxygenase, and cyclooxygenase enzymes, we will investigate the mechanism(s) by which pulmonary cytochrome P-450-mediated AA metabolites express vasodilator activity in the lung. Comprehension of the pulmonary vasodilator mechanism(s) of these endogenous compounds which maintain blood flow to hypoxic alveoli, will permit more rational therapeutic approaches to conditions such as the adult respiratory distress syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052675-06
Application #
6165045
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1995-04-01
Project End
2003-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
6
Fiscal Year
2000
Total Cost
$301,661
Indirect Cost
Name
Saint Louis University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
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Moreland, K Trent; Procknow, Jesse D; Sprague, Randy S et al. (2007) Cyclooxygenase (COX)-1 and COX-2 participate in 5,6-epoxyeicosatrienoic acid-induced contraction of rabbit intralobar pulmonary arteries. J Pharmacol Exp Ther 321:446-54
Liang, Griffith; Stephenson, Alan H; Lonigro, Andrew J et al. (2005) Erythrocytes of humans with cystic fibrosis fail to stimulate nitric oxide synthesis in isolated rabbit lungs. Am J Physiol Heart Circ Physiol 288:H1580-5
Losapio, Jennifer L; Sprague, Randy S; Lonigro, Andrew J et al. (2005) 5,6-EET-induced contraction of intralobar pulmonary arteries depends on the activation of Rho-kinase. J Appl Physiol 99:1391-6
Stephenson, Alan H; Sprague, Randy S; Losapio, Jennifer L et al. (2003) Differential effects of 5,6-EET on segmental pulmonary vasoactivity in the rabbit. Am J Physiol Heart Circ Physiol 284:H2153-61
Sprague, Randy S; Olearczyk, Jeffrey J; Spence, Dana M et al. (2003) Extracellular ATP signaling in the rabbit lung: erythrocytes as determinants of vascular resistance. Am J Physiol Heart Circ Physiol 285:H693-700
Sprague, R S; Bowles, E A; Olearczyk, J J et al. (2002) The role of G protein beta subunits in the release of ATP from human erythrocytes. J Physiol Pharmacol 53:667-74
Schuster, D P; Kozlowski, J K; McCarthy, T et al. (2001) Effect of endotoxin on oleic acid lung injury does not depend on priming. J Appl Physiol 91:2047-54
Sprague, R S; Ellsworth, M L; Stephenson, A H et al. (2001) Participation of cAMP in a signal-transduction pathway relating erythrocyte deformation to ATP release. Am J Physiol Cell Physiol 281:C1158-64
Sprague, R S; Stephenson, A H; Ellsworth, M L et al. (2001) Impaired release of ATP from red blood cells of humans with primary pulmonary hypertension. Exp Biol Med (Maywood) 226:434-9

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