It has recently been postulated that diaphragm fatigue may be due, at least in part, to a form of low-grade injury to subcellular organelles. Moreover, several studies have shown that thiol-containing compounds can protect cardiac and striated skeletal muscle organelles from the deleterious effects of a number of physiological stresses. The purpose of the present study was to determine whether pretreatment with N-acetylcysteine (NAC), a thiol-containing compound, would attenuate the rate of development of diaphragmatic fatigue. Studies were performed with the use of an in situ rabbit diaphragm strip preparation that permitted direct and continuous measurement of diaphragm tension development. Diaphragm fatigue was induced by rhythmically stimulating strips to contract at 30/min (20-Hz trains) for 20 min. The diaphragm force-frequency relationship (10-, 20-, 50-, and 100-Hz stimuli) was assessed immediately before and after fatigue trials and then again 20 min into the period of recovery. Half the animals were treated with intravenous NAC before fatigue, whereas the remaining animals were given intravenous saline. The rate of development of fatigue was markedly greater in saline-treated control than in NAC-treated animals, with reductions in tension of 55 ± 3 and 34 ± 3%, respectively, in these two groups of animals over 20 min (P < 0.001). Although rhythmic stimulation resulted in a downward shift in the force-frequency relationship in both NAC- and saline-treated animals, the magnitude of this shift was substantially greater in saline-treated animals (P < 0.001). Over the first 20 min after cessation of rhythmic contractions, the high-frequency portion of the force-frequency curve increased in both groups of animals, whereas low-frequency tensions remained depressed in both groups. Force-frequency curves from NAC-treated animals, nevertheless, remained higher than curves from saline-treated animals after 20 min of recovery (P < 0.008). These data indicate that NAC attenuates the rate of development of diaphragmatic fatigue during periods of rhythmic repetitive isometric contraction.
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