BUTHIONINE SULFOXIMINE TREATMENT IMPAIRS RAT DIAPHRAGM FUNCTION

Activation of the glutathione (GSH) redox cycle with production of glu tathione disulfide (GSSG) has been shown to occur in the diaphragm dur ing inspiratory resistive loading (RB). Buthionine sulfoximine (BSO) l owers tissue GSH by irreversibly inhibiting the rate-limiting synthesi s enzyme gamma-glutamylcysteine synthetase. We investigated the effect s of BSO on rat diaphragm function both at rest and after a period of RB. Rats in the RB groups underwent inspiratory RB until they were una ble to sustain 70% of their maximal airway pressure. A portion of the diaphragm was analyzed for GSH and GSSG levels, and measurements of in vitro contractile properties included contraction times, maximal teta nic tension (Po), maximal twitch tension (Pt), and force frequency cur ves. BSO treatment produced a profound depletion of diaphragmatic GSH. Neither BSO nor RB alone significantly altered diaphragm contractile properties at this load of RB. But, in BSO-RB rats, there was a signif icant decrease in Pt, Po, and tetanic tension at all frequencies of st imulation compared with those in other groups. These data reveal that animals treated with BSO followed by inspiratory resistive loading exh ibit marked diaphragm impairment, suggesting that GSH may play an impo rtant role in protecting the diaphragm from the stress induced by this resistive breathing protocol.