Although the excessive work of breathing is the major cause of shortness of breath and exercise intolerance in patients with chronic obstructive pulmonary disease (COPD), fatigue of the respiratory muscles, particularly of the diaphragm, may also contribute. Since therapy directed at relieving obstruction is frequently unsuccessful, measures to prevent or reverse diaphragmatic fatigue might allow such patients to tolerate their excessive workloads. A better understanding of the pathophysiology of diaphragmatic fatigue is therefore required. This proposal would contribute to our knowledge of diaphragmatic fatigue by exploring its onset and recovery in spontaneously breathing animals exposed to excessive respiratory loads. Rabbits will be studied because their diaphragmatic fiber composition is relatively similar to human diaphragms. The respiratory loading will be supplied by an inspiratory threshold resistor, which is adjustable for precise quantitation of degree of respiratory effort required. Mean rabbit diaphragmatic endurance, the pattern of development of fatigue and of respiratory acidosis, and biochemical features of fatigued diaphragm muscle will be determined. Subsequent experiments will address the influences of anesthesia, hypoxemia, and the continuing presence of respiratory loading during recovery on the pattern of onset and/or recovery from fatigue. Finally, investigations of the influence of high or low diaphragmatic levels of pH or lactate concentration on the onset and recovery from fatigue will be carried out.
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