The goal of the current proposal is to elucidate the role of atrial natriuretic peptide (ANP) in hypoxia-induced pulmonary hypertension and the control of pulmonary artery pressure in normal subjects. Our experimental model is the male Sprague-Dawley rat subjected to normobaric hypoxia (10% O2, 1 atm) X 4 weeks or less. Our working hypothesis is that ANP gene expression is enhanced by exposure to hypoxia and that the ANP so generated has a protective effect against the development of hypoxic pulmonary hypertension. Studies in Specific Aims 1 and 2 will elucidate the effects of acute and chronic normobaric hypoxia on ANP gene expression, ANP release, receptor mechanisms and metabolic clearance in the rat and will relate these to the hypoxia induced increase in pulmonary artery pressure. Studies in Specific Aims 3 and 4 will test our working hypothesis by determining the effects of removing endogenous ANP by passive or active immunization against ANP and of augmenting endogenous ANP levels by administering a selective blocker of clearance (C) receptors for ANP on the natural history of hypoxia induced pulmonary hypertension in this model. A final set of experiments in Specific Aim 5 will test the hypothesis that hypoxia stimulates ANP gene expression and ANP release in rat cardiac myocytes in culture. This will permit us to dissociate hypoxia from increased pressure and stretch and from cardiac hypertrophy as possible stimuli for ANP gene expression and ANP release in the hypoxia adapted heart. These studies will increase our understanding of the role of ANP in the pathogenesis of hypoxia induced pulmonary hypertension and will lay the ground work for an interesting new approach to the treatment of hypoxic pulmonary hypertension in man.
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