Am. J. Respir. Crit. Care Med., Vol 149, No. 4, Apr 1994, 915-919.
Buthionine sulfoximine treatment impairs rat diaphragm function
CF Morales, A Anzueto, F Andrade, J Brassard, SM Levine, LC Maxwell, RA Lawrence and SG Jenkinson
Division of Pulmonary Diseases/Critical Care Medicine, University of Texas Health Science Center at San Antonio 78284-7885.
Activation of the glutathione (GSH) redox cycle with production of
glutathione disulfide (GSSG) has been shown to occur in the diaphragm
during inspiratory resistive loading (RB). Buthionine sulfoximine (BSO)
lowers tissue GSH by irreversibly inhibiting the rate-limiting synthesis
enzyme gamma-glutamylcysteine synthetase. We investigated the effects 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 unable 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 tetanic tension (Po),
maximal twitch tension (Pt), and force frequency curves. 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 significant decrease in Pt, Po, and
tetanic tension at all frequencies of stimulation compared with those in
other groups. These data reveal that animals treated with BSO followed by
inspiratory resistive loading exhibit marked diaphragm impairment,
suggesting that GSH may play an important role in protecting the diaphragm
from the stress induced by this resistive breathing protocol.
