DIETHYLMALEATE PRODUCES DIAPHRAGMATIC IMPAIRMENT AFTER RESISTIVE BREATHING

Formation of oxygen-derived free radicals and activation of the glutat hione (GSH) redox cycle has been associated with impaired rat diaphrag m performance. Diethylmaleate (DEM) given intraperitoneally irreversib ly conjugates with GSH, resulting in marked decreases in tissue concen trations of GSH. We have investigated the effects of acute GSH depleti on by DEM on diaphragmatic function during resistive breathing (RB) in the rat. The experimental groups were 1) control, 2) DEM alone, 3) RB , and 4) DEM with RB (DEM + RB). RB was obtained by inspiratory RB unt il the rats were unable to sustain 70% of maximum airway opening press ure. A portion of the diaphragm was frozen for biochemical assays, and the rest of the diaphragm was prepared for measurement of in vitro co ntractile properties, including maximum tetanic tension, twitch tensio n, force-frequency curves, and contraction times. DEM treatment produc ed a profound depletion of GSH in the DEM and DEM + RB groups. Neither DEM nor RB alone significantly altered diaphragm contractile properti es. In DEM + RB rats, however, there was a significant decrease in max imum tetanic tension, twitch tension, and tetanic tension. These data reveal that DEM produced an acute depletion of GSH in the diaphragm wi thout impairment of the muscle in nonstressed rats. In the presence of DEM-induced GSH depletion, RB did result in marked diaphragm impairme nt. The depletion of GSH and the subsequent impairment in diaphragm co ntractility after RB suggest that GSH may play an important role in pr otecting the diaphragm against oxidative stress associated with RB.