RELATIVE ARGININE DEFICIENCY IN PULMONARY HYPERTENSION

肺动脉高压中的相对精氨酸缺乏

• 批准号: 6780370
• 负责人: David B. Badesch
• 金额: $ 12.24万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780370
• 关键词: antioxidants; arginine; cardiovascular disorder chemotherapy; cardiovascular function; cardiovascular pharmacology; clinical research; diet therapy; dietary aminoacid; dietary supplements; enzyme mechanism; human subject; human therapy evaluation; nitric oxide; nitric oxide synthase; nutrition related tag; prostacyclins; pulmonary hypertension; vasomotion

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.

肺动脉高压(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、侵入性和昂贵的治疗。大量证据支持一氧化氮(NO)在维持正常血管功能中的广泛重要性，以及最近对血管结构的重要性。在一系列血管疾病中的证据也表明，L精氨酸是NO生成的唯一底物，限制了NO生成。在这种情况下，外源精氨酸不能提高产量。这些考虑在PH的病理生理学和治疗中可能具有直接的和潜在的实际重要性，但还没有得到广泛的评估。因此，这项建议验证了这样的假设，即PH患者有慢性相对缺乏NO合成酶底物(精氨酸)。因此，随着剪切力和流动的增加，NO的生成增加将受到底物可用性的限制。我们进一步假设，长期补充L精氨酸或保护NO免受氧化降解，将增强NO活性，改善肺血管损伤和结构重塑，从而改善以运动能力和心肺血流动力学为指标的PH临床表现。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。其具体目的是确定：1.在不同形式的PH(PPH和SPH)患者中，NO活性(NOx、瓜氨酸)是否升高。2.不同类型的PH患者血清中一氧化氮合酶底物L-精氨酸水平均降低。3.前列环素治疗PPH可增加NO活性和/或降低NOS底物(精氨酸)水平。4.慢性L精氨酸补充或抗氧化维生素治疗可使PPH患者血清L-精氨酸水平升高。5.提高PPH患者血清L-精氨酸水平可使NO活性(NO_x、瓜氨酸)升高，通过内皮细胞功能的改善来评价近期生物学效应，通过6分钟步行试验和心肺血流动力学的改善来评价长期生物学效应。