To provide a better understanding of the role of the regulation of the cytosolic form of guanylate cyclase in the control of pulmonary vascular tone is the long range objective of this proposal. The specific focus of the studies described in this application is to characterize and determine potential physiological mechanisms of pulmonary vascular regulation that involve modulation of the cytosolic form of guanylate cyclase, an enzyme which generates an intra-cellular mediator of vaso- relaxation, cyclic GMP. Our studies will attempt to elucidate the details of cyclic GMP associated mechanisms or modulation of smooth muscle tone and cytosolic guanylate cyclase regulation by hydrogen peroxide, the endothelium, changes in oxygen tension and exposure to light. A major aspect of the proposed studies will be directed toward the determination of the physiological significance of a new mechanism of activation of cytosolic guanylate cyclase by catalase mediated metabolism of peroxide that we have recently discovered. These problems will be investigated in isolated pulmonary vascular rings and with unpurified vascular and purified guanylate cyclase all obtained from bovine lungs. Measurements of changes in contractility, tissue cyclic GMP levels and guanylate cyclase activity in the presence of various agonists, antagonists and generators or scavengers of potential mediators will be employed to investigate and reconstruct the mechanisms of control of vascular tone and guanylate cyclase, and to characterize the mediators involved. Results of these studies will enable us to better understand some important physiological mechanisms of control of pulmonary vascular tone and provide the bsis for studies designed to determine their role in the pathogenesis of a variety of pulmonary vascular disorders related to pulmonary hypertension.
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