N-ACETYLCYSTEINE DEPRESSES CONTRACTILE FUNCTION AND INHIBITS FATIGUE OF DIAPHRAGM IN-VITRO

We have previously shown that antioxidant enzymes (superoxide dismutas e and catalase) depress contractility of unfatigued diaphragm fiber bu ndles and inhibit development of acute fatigue. In the present study, we tested for similar effects of N-acetyl-cysteine (NAC), a nonspecifi c antioxidant approved for clinical use. Diaphragms were excised from deeply anesthetized rats. Fiber bundles were removed, mounted isometri cally at 37 degrees C, and stimulated directly using supramaximal curr ent intensity. Studies of unfatigued muscle showed that 10 mM NAC redu ced peak twitch stress (P < 0.0001), shortened time to peak twitch str ess (P < 0.002), and shifted the stress-frequency curve down and to th e right (P < 0.05). Fiber bundles incubated in 0.1-10 mM NAC exhibited a dose-dependent decrease in relative stresses developed during 30-Hz contraction (P < 0.0001) with no change in maximal tetanic (200 Hz) s tress. NAC (10 mM) also inhibited acute fatigue. Throughout 10 min of intermittent contraction at 30-40 Hz, treated bundles developed higher stresses than time-matched control bundles (P < 0.0001). NAC concentr ations greater than or equal to 30 mM were toxic, causing a prompt irr eversible decrease in maximal tetanic stress (P < 0.0001). Because NAC effects mimic the effects of other antioxidant agents with different mechanisms of action, we conclude that exogenous antioxidants exert st ereotypical effects on contractile function that differ between unfati gued and fatiguing muscle. Unlike antioxidant enzymes, however, NAC ha s been approved for clinical use and may be used in future studies of human muscle fatigue.