Diaphragm Fatigue:Mechanisms of Treatment by Dopamine

膈肌疲劳：多巴胺的治疗机制

• 批准号: 6623747
• 负责人: JANET Doreen PIERCE
• 金额: $ 30.65万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623747
• 关键词: DNA damage; beta adrenergic receptor; biomarker; calcium channel blockers; diaphragm; dopamine; dopamine receptor; fatigue; fluorescence microscopy; free radical oxygen; gel electrophoresis; glutathione; high performance liquid chromatography; image processing; laboratory rat; muscle contraction; muscle disorder chemotherapy; muscle pharmacology; neurotransmitter antagonist; neurotransmitters; oxidation; respirators; tissue /cell preparation; verapamil

Thousands of patients suffer from diaphragm fatigue (DF) when being weaned from mechanical ventilation. Failure to wean from ventilation is a costly and time consuming clinical problem, and an emotionally difficult experience for patients. Low dose dopamine frequently is administered to mechanically ventilated patients with the objective of increasing renal blood flow, without any regard to its effect on diaphragmatic function. Our previous study using an in-vivo rat model revealed that intravenous dopamine prevents DF and simultaneously increases diaphragm blood flow and, hence, oxygen delivery to the tissue. It is also possible that dopamine prevents DF, independent of its effect on oxygen delivery, through diaphragm muscle dopaminergic receptors, beta-2 adrenoceptors and through calcium channels. While holding oxygen delivery constant during in-vitro experiments, we observed that administering dopamine improved diaphragm muscle contraction. The goal of this project is to delineate the physiologic, cellular and biochemical changes in DF and the mechanisms accounting for the alleviation of DF by dopamine. We propose to determine whether 2 markers of oxidative damage, deoxyribonucleic acid (DNA) damage and glutathione oxidation, in the fatigued diaphragm and the effects of dopamine on these markers. We will perform a series of in-vitro experiments producing DF by electrical stimulation. After determining the optimal concentration of dopamine in the tissue bath to treat DF, class specific antagonists (butaclamol - Dopamine 1 (DA1) and a Dopamine 2 (DA2) antagonist; SCH 23390 - DA1 antagonist; domperidone - DA2 antagonist; ICI 118,551- beta-2 antagonist; and verapamil - calcium channel blocker) will be administered with dopamine to determine the mechanisms by which dopamine affects diaphragm muscle contraction. The results will indicate if dopamine directly affects oxidative damage and diaphragm performance. Data obtained from this research will advance our understanding of biological systems, and thus provide data to support clinical trials using dopamine to prevent and treat DF.

在机械通气中断奶时，成千上万的患者患有隔膜疲劳（DF）。 未能从通风中断奶是一个昂贵且耗时的临床问题，并且对患者来说是一种情绪困难的经历。 低剂量多巴胺经常用于机械通风的患者，其目的是增加肾血流，而无需考虑其对diaphragmapmatic功能的影响。 我们先前使用体内大鼠模型的研究表明，静脉多巴胺可防止DF并同时增加diaphragm的血液流动，从而增加氧气递送到组织。多巴胺也可能通过diaphragm肌肉多巴胺能受体，β-2肾上腺素受体和通过钙通道来阻止DF对氧递送的影响。在体外实验期间保持氧气递送不断的同时，我们观察到施用多巴胺改善了diaphragm肌肉收缩。 该项目的目的是描绘DF的生理，细胞和生化变化以及多巴胺减轻DF的机制。 我们建议确定在疲劳的隔膜和多巴胺对这些标记物的影响中，是否有2种氧化损伤，脱氧核糖核酸（DNA）损伤和谷胱甘肽氧化的标记。我们将执行一系列通过电刺激产生DF的体外实验。 After determining the optimal concentration of dopamine in the tissue bath to treat DF, class specific antagonists (butaclamol - Dopamine 1 (DA1) and a Dopamine 2 (DA2) antagonist; SCH 23390 - DA1 antagonist; domperidone - DA2 antagonist; ICI 118,551- beta-2 antagonist; and verapamil - calcium channel blocker) will be administered with多巴胺确定多巴胺影响diaphragm肌肉收缩的机制。 结果将表明多巴胺是否直接影响氧化损伤和隔膜性能。 从这项研究获得的数据将提高我们对生物系统的理解，从而提供数据以使用多巴胺预防和治疗DF的临床试验。