Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Pulmonary hypertension (PH) affects patients of all ages, both sexes (with a predilection toward young females), is highly lethal, and frequently requires complicated, invasive, and expensive therapy. Abundant evidence supports the broad importance of nitric oxide (NO) in the maintenance of normal vascular function, and more recently of vascular structure. Evidence in a wide array of vascular disorders also suggests that availability of L-arginine, the sole substrate for NO generation, limits NO generation. Under such circumstances NO production may be enhanced by administration of exogenous arginine. These considerations could be of direct and potentially practical importance in the pathophysiology and treatment of PH, but have not been extensively evaluated. Accordingly, this proposal tests the hypothesis that patients with PH have a chronic relative deficiency of NO synthase substrate (arginine). Thus increased generation of NO in response to increased shear stress and flow would be limited by substrate availability. We further hypothesize that chronic supplementation with L-arginine or protection of NO from oxidant degradation, would augment NO activity, ameliorating pulmonary vascular injury and structural remodeling, with consequent clinical improvement in PH as measured by exercise capacity and cardiopulmonary hemodynamics. This work could define simple, inexpensive, low risk measures which might contribute to the treatment of PH. The specific aims are to determine whether: 1. NO activity (NOx, citrulline) is increased in patients with various forms of PH (PPH and SPH). 2. Levels of L-arginine (nitric oxide synthase substrate) are reduced in patients with various forms of PH. 3. Treatment of PPH with prostacyclin increases NO activity and/or decreases NOS substrate (arginine) levels. 4. L-arginine levels can be augmented in patients with PPH by chronic L-arginine supplementation, or by the administration of antioxidant vitamins. 5. Raising L-arginine levels in patients with PPH results in augmentation of NO activity (NOx, citrulline), short- term biologic effect as assessed by improvement in measures endothelial cell function, and long-term biologic effect as assessed by improvement in the 6-minute walk test and cardiopulmonary hemodynamics.
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