RELATIVE ARGININE DEFICIENCY IN PULMONARY HYPERTENSION

肺动脉高压（PH）可影响所有年龄、两性的患者（以年轻女性为主），具有高度致命性，通常需要复杂、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和血管结构中的广泛重要性。各种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，外源精氨酸可以促进NO的产生。这些考虑可能在PH的病理生理学和治疗中具有直接和潜在的实际重要性，但尚未得到广泛的评估。因此，本研究验证了PH患者存在一氧化氮合酶底物（精氨酸）慢性相对缺乏的假设。因此，随着剪切应力和流动的增加，NO的生成将受到基材可用性的限制。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，将增强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值的临床改善。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治疗ph。具体目的是确定是否：在各种形式的PH （PPH和SPH）患者中，NO活性（NOx，瓜氨酸）增加。2. l -精氨酸（一氧化氮合酶底物）水平在各种形式的ph 3患者中降低。用前列环素治疗PPH可增加NO活性和/或降低NOS底物（精氨酸）水平。4. 通过长期补充l -精氨酸或服用抗氧化维生素，可提高PPH患者的l -精氨酸水平。5. PPH患者l -精氨酸水平升高导致NO活性（NOx、瓜氨酸）增强，短期生物学效应可通过内皮细胞功能改善来评估，长期生物学效应可通过6分钟步行试验和心肺血流动力学改善来评估。

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.