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Articles in PresS, published online ahead of print January 31, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00894.2001
Submitted on October 16, 2001
Accepted on January 25, 2002
1 Physiology and Biophysics, University of Nebraska Medical Center, Omaha, NE, USA
* To whom correspondence should be addressed. E-mail: grozansk{at}unmc.edu.
Electrical remodeling of the diseased ventricle is characterized by a pathogenic down-regulation of cardiac K+ channels involved in repolarization of the action potential. Experimental studies suggest this shift in electrophysiological phenotype involves oxidative stress and associated changes in myocardial glutathione, an endogenous regulator of redox-sensitive cell functions. This study examined the role of glutathione in regulating K+ currents in left ventricular myocytes isolated from rat hearts 8 wk after myocardial infarction (MI). Colorimetric analysis of extracts of left ventricular tissue showed that the ratio of reduced (GSH) to oxidized (GSG) glutathione concentration was 76% less in rat hearts with MI compared with controls (p<0.05), consistent with oxidative stress conditions. This change in GSH status correlated with significant decreases in activities of two major pathways involved in GSH homeostasis: glutathione reductase (31% decrease; p<0.05) and 
-glutamylcysteine synthetase (26% decrease; p<0.05). Voltage-clamp studies of isolated myocytes confirmed that K+ channels carrying the transient outward current (Ito) are markedly down-regulated in post-MI hearts compared with controls. This property was reversed, after a time delay of several hours, by treating myocytes with GSH or N-acetylcysteine (NAC), a precursor of GSH. Neither GSH nor NAC altered Ito in myocytes from control hearts. Up-regulation of Ito density in myocytes from post-MI hearts was also elicited by dichloroacetate, a metabolic activator that increases glycolytic flux through the GSH-related pentose pathway. This metabolic effect was blocked by 1,3-bis-chloroethyl-nitrosourea, an inhibitor of glutathione reductse, and by dehydroepiandrosterone, an inhibitor of glucose-6-phosphate dehydrogenase of the pentose pathway. These data indicate that oxidative stress-induced alteration in GSH redox state plays an important role in Ito channel remodeling and that GSH homeostasis in myocytes is influenced by metabolic pathways associated with glucose utilization.
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