Glutathione and K(+) channel remodeling in postinfarction rat heart.
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 gamma-glutamylcysteine synthetase. Voltage-clamp studies of isolated myocytes from post-MI hearts demonstrated that downregulation of the transient outward K(+) current (I(to)) could be reversed by pretreatment with exogenous GSH or N-acetylcysteine, a precursor of GSH. Upregulation of I(to) 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 I(to) channel remodeling and that GSH homeostasis is influenced by pathways of glucose metabolism.
Rozanski
George J
GJ
Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska 68198-4575, USA. grozansk@unmc.edu
Xu
Zhi
Z
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D003124:Colorimetry; D004553:Electric Conductivity; D004594:Electrophysiology; D005947:Glucose / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D005980:Glutathione Reductase / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology*; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016276:Ventricular Function
D015221:Potassium Channels; D009249:NADP; D005980:Glutathione Reductase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D005947:Glucose; D000111:Acetylcysteine