Electrical remodeling of the diseased ventricle is characterized by downregulation of K+ channels that control action potential repolarization. Recent studies suggest that this shift in electrophysiological phenotype involves oxidative stress and changes in intracellular glutathione (GSH), a key regulator of redox-sensitive cell functions. This study examined the role of GSH in regulating K+ currents in ventricular myocytes from rat hearts 8 wk after myocardial infarction (MI). Colorimetric analysis of tissue extracts showed that endogenous GSH levels were significantly less in post-MI hearts compared with controls, which is indicative of oxidative stress. This change in GSH status correlated with significant decreases in activities of glutathione reductase and γ-glutamylcysteine synthetase. Voltage-clamp studies of isolated myocytes from post-MI hearts demonstrated that downregulation of the transient outward K+ current (Ito) could be reversed by pretreatment with exogenous GSH or N-acetyl-cysteine, a precursor of GSH. Upregulation of Ito was also elicited by dichloroacetate, which increases glycolytic flux through the GSH-related pentose pathway. This metabolic effect was blocked by inhibitors of glutathione reductase and the pentose pathway. These data indicate that oxidative stress-induced alteration in the GSH redox state plays an important role in Ito channel remodeling and that GSH homeostasis is influenced by pathways of glucose metabolism.
|Original language||English (US)|
|Journal||American Journal of Physiology - Heart and Circulatory Physiology|
|Issue number||6 51-6|
|State||Published - Jul 2 2002|
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)