EXOGENOUS GLUTATHIONE ATTENUATES STUNNING FOLLOWING INTERMITTENT HYPOXIA IN ISOLATED RAT HEARTS

An isolated rat heart model of intermittent hypoxia was used to invest igate the impact of exogenous supplementation of glutathione and two t hiol delivery vehicles on functional recovery during reoxygenation and whether efficacy was dependent on enhanced intracellular thiol concen tration. Hearts from F344 rats were perfused in the Langendorff mode a nd exposed to three, 5 minute bouts of global, substrate free, normoth ermic hypoxia separated by 5 minute reoxygenation periods. Changes in coronary flow, heart rate, systolic and diastolic pressure, and rate p ressure product were evaluated throughout in control hearts and compar ed with hearts in which one of the following was provided during the h ypoxic periods: reduced glutathione (GSH, 1 or 10 mM), 10 mM GSH mono- ethyl ester (GSHMEE), or 1 mM L-2-oxothiozolidine-4-carboxylate (OZT). After three hypoxic periods plus reoxygenation, rate pressure product in control hearts was similar to 60% of pre-hypoxic values. Exposing hearts to 1 or 10 mM GSH, 10 mM GSHMEE, or 1 mM OZT significantly (p < 0.05) enhanced post-hypoxic recovery of rate pressure product and att enuated the rise in diastolic pressure during hypoxia. This improvemen t in function was not associated with an elevated intracellular thiol concentration in treated hearts. Cumulative oxidative changes may occu r during intermittent hypoxia via a mechanism localized on or near the sarcolemmal membrane. These changes appear to precede the appearance of significant intracellular oxidative stress and may be due to altera tions in the reduced status of critical membrane bound proteins. Exoge nously administered thiols attenuate protein alterations via a localiz ed increase in thiol availability without an increase in gross measure s of intracellular thiol or glutathione content.