The central focus of this project is to identify and elucidate the signal transduction mechanisms involved in the control of pulmonary vascular tone mediated by modulation of the production of the intracellular mediator of relaxation, cGMP, via regulation the soluble form of guanylate cyclase (sGC). We propose to (1) further define the role of peroxide metabolism via catalase in the mechanisms of pulmonary arterial relaxation and sGC activation by H2O2, (2) define the role of superoxide anion (endogenously or pharmacologically produced) as an inhibitory regulator of cGMP-mediated pulmonary arterial relaxation, (3) define roles for endothelium, the arginine-derived nitric oxide-like mediator and H2O2 in cGMP-associated responses of pulmonary arteries to changes in P02, and (4) to continue to elucidate the metabolic pathways which contribute to the action of vascular relaxants that activate sGC, including UV light, nitrovasodilator drugs (e.g. nitroglycerine and nitroprusside), endogenous nitrovasodilators and hydrazines (which generate carbon centered free radicals, e.g. hydralazine). The current proposal will employ isolated calf pulmonary arteries for tone studies with mechanistic probes, and measurements of endogenous reactive 02 species and cGMP production; arterial smooth muscle subcellular fractions to identify the metabolizing systems which generate activators and inhibitors of sGC, and sources of reactive 02 species that could function as tissue 02 sensors; and purified sGC from calf lungs in studies to establish molecular mechanisms for enzyme regulation by the processes described above. The processes examined in this proposal may contribute to further understanding aspects of hypoxic vasoconstriction, pulmonary vascular pathophysiology (e.g. ischemia reperfusion, hypertension, adult respiratory distress syndrome, etc.), the basic mechanisms of nitrovasodilator and hydrazine drug action, as well as, the photoreception of UV light.
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