TNF-α downregulates transient outward potassium current in rat ventricular myocytes through iNOS overexpression and oxidant species generation

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Abstract
Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. Prolongation of the action potential duration and downregulation of several K+ currents might participate in the genesis of arrhythmias associated with chronic heart failure. Little information is available related to the mechanism by which TNF-α modulates cardiac K+ channels. The present study analyzes the effect of TNF-α on the transient outward K+ current ( I to) in rat ventricular myocytes, using the whole cell patch-clamp technique. We found that TNF-α is able to induce a significant reduction of I to density, modifies its inactivation, and downregulates the Kv4.2 protein expression, while calcium current density is not affected. We have also demonstrated that the reduction of I to density induced by TNF-α was prevented by the selective inducible nitric oxide synthase (iNOS) inhibitor 1400-W, the protein synthesis inhibitor cycloheximide, the antioxidant tocopherol, and the superoxide dismutase mimetic manganese(III) tetrakis (4-benzoic acid) porphyrin. In addition, a reduced I to density was recorded in ventricular myocytes exposed to peroxynitrite, supporting a possible participation of this oxidant in the effects of TNF-α on I to. We conclude that TNF-α exposure, through iNOS induction and generation of oxidant species, promotes electrophysiological changes (decreased I to and action potential duration prolongation) in rat ventricular myocytes, providing new insights into how cytokines modulate K+ channels in the heart.