| 17337591 |
Fernandez-Velasco M, Ruiz-Hurtado G, Hurtado O, Moro MA, Delgado C: TNF-alpha downregulates transient outward potassium current in rat ventricular myocytes through iNOS overexpression and oxidant species generation. Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H238-45. Epub 2007 Mar 2.
Tumor necrosis factor-alpha (TNF-alpha) 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-alpha modulates cardiac K (+) channels. The present study analyzes the effect of TNF-alpha on the transient outward K (+) current (I (to)) in rat ventricular myocytes, using the whole cell patch-clamp technique. We found that TNF-alpha 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-alpha 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-alpha on I (to). We conclude that TNF-alpha 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. |
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