AMMONIA, FATIGUE AND VENTILATION DURING EXERCISE

运动期间的氨、疲劳和通气

• 批准号: 6119033
• 负责人: DAVID M SYSTROM
• 金额: $ 3.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6119033
• 关键词: aerobiosis; ammonia; butyrates; chemoprevention; clinical research; drug screening /evaluation; exercise; fatigue; glutamine; human subject; lactic acidosis; orphan disease /drug; phenylacetates; prodrugs; pulmonary respiration; striated muscles

During heavy exercise under considerations which decrease (glycogen depletion, GD) or eliminate (McArdle's Syndrome, McAS) skeletal muscle lactic acid production, fatigue is noted and ventilatory control is intact. GD and McAS are characterized by an exorbitant NH3 rise in muscle and blood. NH3 inhibits oxidative metabolism3 and is a known respiratory analeptic in resting patients with liver disease. It is therefore possible that NH3 contributes to fatigue and dyspenea during exercise when lctic acidemia does not. Another possibility is that exercising skeletal muscle metabolites stimulate ventilation directly through a neural pathway. This so-called "metaboreflex" can be examined by non-invasive 31P magnetic resonance spectroscopy measurements of exercising skeletal muscle during bilateral venous occlusion (BVO) by blood pressure cuffs. An orphan drug (sodium phenylbutyrate, NaPB) was recently approved by the FDA for prevention and treatment of hyperammonemia associated with urea cycle disorders of children and adults. Peak plasma levels are acheived 1 h after 5 g po by mouth. NaPB is converted by betaoxidation in the mitochondrion to Na Phenylacetate (NaPA). NaPA congugates with glutamine in the liver and kidney to form phenylacetylglutamine which, with its 2 waste nitrogens, is excreted in the urine over the ensuing 24 h. Over 100 patient-years experience with the drug have revealed no serious toxicity. We therefore wish to use a single oral dose of NaPB to suppress muscle and blood NH3 and determine its role in fatigue and ventilation during exercise.

在剧烈运动的情况下，考虑减少（糖原 耗尽，GD）或消除（麦卡德尔综合征，McAS）骨骼肌 乳酸的产生，注意到疲劳， 完整GD和McAS的特点是NH3的过度上升， 肌肉和血液。NH3抑制氧化代谢3，是已知的 呼吸兴奋剂在休息的肝病患者。是 因此，NH3可能导致疲劳和呼吸困难， 当乳酸血症不运动时。另一种可能性是 运动骨骼肌代谢产物直接刺激通气 通过神经通路这种所谓的“代谢反射”可以通过 通过非侵入性31 P磁共振波谱测量， 在双侧静脉闭塞（BVO）期间，通过 血压袖带 一种孤儿药（苯丁酸钠，NaPB）最近被批准， FDA用于预防和治疗与 儿童和成人的尿素循环障碍。血浆峰值水平为 口服5g后1h可达高峰。NaPB通过β氧化转化 苯乙酸钠（Na Phenylacetate，NaPA）NaPA与 谷氨酰胺在肝脏和肾脏中形成苯乙酰谷氨酰胺， 与其2废物氮，是排泄在尿液中，随后 24小时超过100例患者-年的药物使用经验表明， 严重毒性。因此，我们希望使用单剂量口服NaPB 抑制肌肉和血液中的NH3，并确定其在疲劳中的作用， 运动时通风。