EICOSANOIDS AND PULMONARY VASCULAR TONE

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DESCRIPTION (Applicant's abstract): In recent years, the importance of various factors synthesized and released from the blood vessel endothelium that contribute to the regulation of vascular tone has become apparent. In pulmonary vessels, these investigators have identified an endothelium-dependent contracting factor as the vasoconstrictor thromboxane A2. There are a number of incidences where an increased synthesis of thromboxane A2 is associated with pulmonary disease, including pulmonary hypertension and sudden death. Therefore, the long term objective of the proposed studies is to investigate the hypothesis that arachidonic acid is metabolized by pulmonary blood vessels to thromboxane A2 and that thromboxane A2 is an important mediator involved in the regulation of pulmonary vascular tone under both normal and pathophysiological states. Specifically, it is known that arachidonic acid and methacholine-induced contractions of pulmonary arteries are mediated by thromboxane A2 and removal of the endothelial layer abolishes the contractions. Yet, endothelial cells isolated from pulmonary arteries do not synthesize thromboxane A2. Experiments described by specific aim 1 will investigate the hypothesis that thromboxane A2 synthesis in pulmonary vessels requires the interaction between the endothelial cells and adherent cells. Possible candidates for the adherent cells include platelets, polymorphonuclear leukocytes or monocytes. Studies have shown that thromboxane A2-induced platelet aggregation and vascular smooth muscle vasoconstriction is mediated via activation of a membrane-bound receptor. One limitation to studying the role of thromboxane A2 in pulmonary disease is the inability to differentiate the contribution of the platelet and the vascular smooth muscle receptor to the observed hemodynamic responses because the available thromboxane receptor antagonists are unfortunately non-selective and block both the platelet and vascular receptors. The investigators have identified a subset of rabbits that are deficient in vascular, but not platelet, thromboxane A2 receptors. Experiments described by specific aim 2 will use these rabbits to investigate the hypothesis that thromboxane A2 and its vascular receptor are important to the regulation of pulmonary vascular tone. Specifically, they will investigate the influence of age and gender on the vascular responsiveness to thromboxane agonist and thromboxane A2 receptor density, characterize the differences in receptor number and functional responses in vascular cells cultured from responder and nonresponder pulmonary arteries and assess the role of the vascular thromboxane A2 receptor in a model of pulmonary embolism.