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_todensity, 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_todensity 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_todensity 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_toand action potential duration prolongation) in rat ventricular myocytes, providing new insights into how cytokines modulate K⁺channels in the heart.

• The present review recapitulates relevant findings related to the role of the receptors of the innate immune system (TLRs and NLRs) in the progression of the most prevalent CVDs. • TLRs and NLRs play a key role in the progression of atherosclerosis, acute myocardial infarction or heart failure. • The development of new specific strategies to impair exacerbated TLR and NLR activation in CVDs are strong candidates for therapy and opens a new research field.

Hyperpolarization‐activated inward current (I_f) and changes in the messenger RNA (mRNA) expression levels of hyperpolarization‐activated cyclic nucleotide‐gated channel (HCN)2 and HCN4 encoding I_f channels of the rat heart were studied in control and hypertrophied myocytes isolated from three ventricular regions: the septum (S), the left ventricular free wall (LV) and the right ventricular free wall (RV). Electrophysiological experiments were conducted by ruptured and perforated‐patch clamp techniques and quantification of mRNA levels was carried out by quantitative reverse transcriptase polymerase chain reaction. The occurrence, density and maximal specific conductance of I_f were found to be significantly higher in hypertrophied ventricular myocytes isolated from S and LV than in those isolated from RV or sham‐operated rats. Half‐maximal activation potential, the slope of the activation curve and the threshold for activation were similar in ventricular myocytes from sham and aortic stenosed rats in the three regions studied. Isoproterenol 1 µmol l⁻¹ increased current size by shifting current activation to more positive potentials in both sham and hypertrophied myocytes. When we studied the mRNA levels of I_f channel isoforms present in the ventricle, we found a significant increase of HCN2 and HCN4 mRNA levels in hypertrophied myocytes from S and LV but not in RV. We conclude that the occurrence, density and conductance of I_f is higher in hypertrophied than in control ventricular myocytes, S being the region where all these changes were most evident. These findings are associated with a higher expression of HCN2 and HCN4 mRNA levels in the two regions that developed hypertrophy.

Computer simulations and isolated tissue experiments were used to characterize the relation between excitability and margin of safety for propagation in anisotropic ventricular myocardium. Longitudinal, uniform transverse, and nonuniform transverse tissue directions were modeled in a one-dimensional Beeler-Reuter based cable. Stimulation threshold was smallest in the nonuniform transverse direction. The safety factor for propagation was determined in the model as the total axial charge that was available for depolarizing downstream tissue divided by the threshold charge that was just sufficient for continued propagation and was largest in the longitudinal direction. The strength-interval plot for the junction between simulated longitudinal and nonuniform transverse directions identified a range of stimulus strengths and intervals that resulted in nonuniform transverse but not longitudinal propagation. When high values of transverse resistance were used, higher stimulus strengths during premature stimulation resulted in longitudinal but not nonuniform transverse propagation. The experimental strength interval plots from 17 L-shaped preparations of isolated sheep epicardial muscles had similar characteristics. In nine additional L-shaped tissue experiments, changing extracellular K+ concentrations from 4 to 20 mM resulted in progressive membrane depolarization and conduction impairment in both directions. However, in eight of nine experiments, complete block occurred first in the transverse direction. In one experiment, block was simultaneous in both directions. We conclude that, under normal conditions, threshold requirements for active propagation are lower for transverse than for longitudinal propagation. In addition, when active membrane properties are impaired, the safety factor for propagation is larger in the direction along the longitudinal axis of the cells.