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

Institute of Pharmacology and Toxicology (Consejo Superior de Investigaciones Científicas-Universidad Complutense Madrid), Universidad Complutense, Madrid, Spain

Submitted 13 October 2006 ; accepted in final form 25 February 2007

Tumor necrosis factor- (TNF-) 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- modulates cardiac K⁺ channels. The present study analyzes the effect of TNF- on the transient outward K⁺ current (I_to) in rat ventricular myocytes, using the whole cell patch-clamp technique. We found that TNF- 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- 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- on I_to. We conclude that TNF- 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.

cardiac electrophysiology; tumor necrosis factor; inducible nitric oxide synthase; oxidant species

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