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.
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