RELATIVE ARGININE DEFICIENCY IN PULMONARY HYPERTENSION

肺动脉高压中的相对精氨酸缺乏

• 批准号: 6051008
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6051008
• 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，包括男性和女性（尤其是年轻女性），具有高度致命性，并且经常需要复杂的、侵入性的和昂贵的治疗。 大量的证据支持一氧化氮（NO）在维持正常血管功能中的广泛重要性，最近的血管结构。大量血管疾病的证据也表明，L-精氨酸（NO生成的唯一底物）的可用性限制了NO的生成。 在这种情况下，NO的产生可以通过施用外源性精氨酸来增强。 这些考虑因素在PH的病理生理学和治疗中可能具有直接和潜在的实际重要性，但尚未进行广泛评价。因此，该建议测试PH患者具有NO合酶底物（精氨酸）的慢性相对缺乏的假设。 因此，响应于增加的剪切应力和流动而增加的NO生成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免受氧化剂降解，将增加NO活性，改善肺血管损伤和结构重塑，从而通过运动能力和心肺血流动力学测量PH的临床改善。 这项工作可以定义简单，廉价，低风险的措施，可能有助于治疗PH的具体目标是确定是否：1。NO活性（NOx，瓜氨酸）在各种形式的PH（PPH和SPH）患者中增加。 2. L-精氨酸（一氧化氮合酶底物）的水平在各种形式的PH患者中降低。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.长期补充L-精氨酸或给予抗氧化维生素可提高PPH患者的L-精氨酸水平。 5.提高PPH患者的L-精氨酸水平可增加NO活性（NOx、瓜氨酸），通过改善内皮细胞功能指标评估短期生物效应，通过改善6分钟步行试验和心肺血流动力学评估长期生物效应。