AMMONIA, FATIGUE AND VENTILATION DURING EXERCISE

运动期间的氨、疲劳和通气

• 批准号: 6280054
• 负责人: DAVID M SYSTROM
• 金额: $ 2.74万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6280054
• 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.

在剧烈运动时，考虑到糖原的减少