CONTROL OF MICROCIRCULATORY EXCHANGE FUNCTION

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We will investigate the hypothesis that a) microcirculatory exchange function is regulated by a system of checks and balances, and b) biochemical and molecular interactions between agonists and endothelium play a role in controlling microcirculatory exchange function. This hypothesis will be approached by pursuing the following aims: 1) to determine and characterize the differential resistance and exchange vessel responses to bradykinin (BK), adenosine (ADO) and platelet activating factor (PAF); 2) to determine the influence of leukocyte adhesion and migration on macromolecular transport; and 3) to determine the biochemical pathways by which ADO, BK and PAF influence microcirculatory exchange function. Intravital fluorescent videomicroscopy, spectrofluorometry, radioimmunoassay and computer assisted videoimage digital processing methods will be used to measure transport of macromolecules in the hamster cheek pouch microcirculation. Inhibitors of calcium entry (verapamil) and of protein kinase C (sphingosine) will be applied to gain insight into the molecular events produced by the interactions between agonists and endothelium. It is submitted that the results of this project will provide an important key to the understanding of the regulatory mechanisms of microcirculatory exchange. This knowledge of microcirculatory pathophysiology is essential for the development of therapy for inflammation and vascular diseases.