This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project is being undertaken to test the hypothesis that arginine supplementation is safe and well-tolerated in patients with pulmonary hypertension (PH), and serves as a pilot study toward testing the hypothesis that patients with PH have a chronic relative deficiency of nitric oxide (NO) synthase substrate (arginine - arg). We hope to ultimately test the specific hypothesis that chronic supplementation with oral L-arginine would lead to 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. PH affects patients of all ages, both sexes (with a predilection toward young females), is highly lethal, and frequently requires complicated forms of therapy. Primary pulmonary hypertension (PPH) was previously rare, but the incidence appears to have recently increased in association with the widespread use of appetite-suppressant medications. PH occurring in association with scleroderma is less rare, and the development of PH has a substantial impact on long-term prognosis. Treatment of PH has improved over the past 10 years with the advent of high-dose calcium channel blocker therapy, continuously-infused prostacyclin, and lung transplantation. However, the large majority of patients do not respond favorably to calcium channel blockers, and prostacyclin therapy and lung transplantation are highly complicated and expensive. Recognition of the importance of NO as a vasodilator was followed by observations indicating its contribution to maintenance of normal vascular function. In addition to its action as a vasodilator, several studies suggest that nitric oxide exerts important effects on vascular structure. Inhaled NO is a potent pulmonary vasodilator. It has been shown to be of benefit in persistent PH of the newborn (PPHN). Although a small number of adult patients with PH have received chronic inhaled NO, some with apparent benefit; long-term delivery of inhaled NO to adults with PH has not been formally studied. Long-term delivery is expensive and complicated, and toxicology studies remain to be performed. Supplemental arginine improves endothelial dilator responses in human coronary artery disease. Recent work points to arginine-induced restoration of deficient endothelial function in diabetes, peripheral vascular disease and aging. Whether chronic arg supplementation can reduce ongoing vascular injury and lead to structural improvement in the lung circulation in patients with PH is unknown. This project will be randomized, placebo-controlled, and double-blinded pilot study of the safety of arginine supplementation in patients with PH. Efficacy will also be assessed as part of this pilot study, looking for trends toward improvement in exercise capacity and hemodynamics.
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