RELATIVE ARGININE DEFICIENCY IN PULMONARY HYPERTENSION: PLT STDY-SUPPLEMENTATION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。该项目是为了验证补充精氨酸对肺动脉高压(PH)患者是安全和耐受性良好的假设，并作为一项初步研究，以检验PH患者患有慢性相对缺乏一氧化氮合酶底物(Arg)的假设。我们希望最终验证长期补充L精氨酸将导致运动能力和心肺血流动力学测量的PH临床改善这一特定假设。这项工作可以确定简单、廉价、低风险的措施，这些措施可能有助于PH的治疗。PH影响所有年龄段的患者，无论男女(倾向于年轻女性)，具有高度的致命性，经常需要复杂的治疗形式。原发性肺动脉高压(PPH)以前很少见，但最近随着食欲抑制药物的广泛使用，其发病率似乎有所增加。与硬皮病相关的PH并不少见，而且PH的发展对长期预后有重大影响。随着大剂量钙通道阻滞剂治疗、持续输注前列环素和肺移植的出现，PH的治疗在过去10年中得到了改善。然而，绝大多数患者对钙通道阻滞剂的反应不佳，前列环素治疗和肺移植非常复杂和昂贵。在认识到NO作为血管扩张剂的重要性之后，观察表明它对维持正常的血管功能有贡献。除了作为血管扩张剂的作用外，一些研究表明，一氧化氮对血管结构也有重要影响。吸入NO是一种有效的肺血管扩张剂。它已被证明对新生儿持续性PH(PPHN)有好处。虽然少数成年PH患者接受了慢性吸入性NO治疗，但有些人有明显的益处；吸入性NO对成年PH患者的长期给药还没有正式研究。长期给药既昂贵又复杂，毒理学研究仍有待进行。补充精氨酸可改善人类冠状动脉疾病的内皮扩张器反应。最近的研究指出，精氨酸可以恢复糖尿病、外周血管疾病和衰老患者的内皮功能。目前尚不清楚长期补充精氨酸能否减少肺高压患者持续的血管损伤并导致肺循环结构的改善。该项目将对PH患者补充精氨酸的安全性进行随机、安慰剂对照和双盲试点研究。疗效也将作为这项先导研究的一部分进行评估，以寻找运动能力和血流动力学改善的趋势。

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.