Glutathione and K⁺ channel remodeling in postinfarction rat heart

Abstract

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.

Role of Apoptosis Signal-Regulating Kinase-1-c-Jun NH2-Terminal Kinase-p38 Signaling in Voltage-Gated K+Channel Remodeling of the Failing Heart: Regulation by Thioredoxin

“…A chronic MI model of ventricular dysfunction was used in the present investigation as described previously (22,33,42). Briefly, male Sprague-Dawley rats (180-200 g) were intubated and artificially ventilated under Brevital (methohexital Ò sodium) anesthesia at 50 mg=kg, i.p.…”

“…In addition, there is compensatory hypertrophy of the surviving myocardium as reflected by a marked increase in heart weight-to-body weight ratio (33,42). At the cellular level, this model is characterized by marked alterations in redox balance, particularly increased superoxide production, reduced glutathione (GSH) depletion, and significant decreases in the activities of g-glutamylcysteine synthetase, glutathione reductase, and TrxR1, compared with sham-operated control rats (22,33). Thus, the chronic dysfunction of the left ventricle elicited by MI is paralleled by markers of oxidative stress and resulting shift in cell redox state.…”

“…and the hearts were excised and perfused via the coronary vasculature by the Langendorff method. In some experiments, myocytes were dissociated from perfused hearts by a collagenase digestion procedure described previously (20,22,33). Dispersed myocytes from surviving regions of the left ventricle and septum were suspended in Dulbecco's modified Eagle's medium/Ham's F12 (DMEM/F12) and stored in an incubator at 378C until used, usually within 6 h of isolation.…”

“…Although the electrophysiology of the remodeled ventricle involves changes in several types of ion channels, downregulation of voltagegated K þ (Kv) channels underlying the transient outward K þ current (I to ) is perhaps the most consistent change observed in heart failure, both in the human heart (2,14) and in animal models (2,15,20,22,33). In rodent hearts, a disease-related decrease in Kv channel expression participates in prolongation of the ventricular muscle action potential and alterations in refractory period (15).…”

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

“…Of note, the well-being of the patients affected with those diseases is improved by treatment with the glutathione precursor N-acetylcysteine (NAC) [13,14,18,19]. Previous studies pointed out the decrease in cardiac GSH/ GSSG ratio in CHF [20,21]. However, the possible deficiency in total glutathione in the failing heart, and its related possible metabolic consequences have been overlooked.…”