Characterization of two distinct depolarization-activated K+ currents in isolated adult rat ventricular myocytes

Depolarization-activated outward K+ currents in isolated adult rat ventricular myocytes were characterized using the whole-cell variation of the patch-clamp recording technique. During brief depolarizations to potentials positive to -40 mV, Ca(2+)-independent outward K+ currents in these cells rise to a transient peak, followed by a slower decay to an apparent plateau. The analyses completed here reveal that the observed outward current waveforms result from the activation of two kinetically distinct voltage-dependent K+ currents: one that activates and inactivates rapidly, and one that activates and inactivates slowly, on membrane depolarization. These currents are referred to here as Ito (transient outward) and IK (delayed rectifier), respectively, because their properties are similar (although not identical) to these K+ current types in other cells. Although the voltage dependences of Ito and IK activation are similar, Ito activates approximately 10-fold and inactivates approximately 30-fold more rapidly than IK at all test potentials. In the composite current waveforms measured during brief depolarizations, therefore, the peak current predominantly reflects Ito, whereas IK is the primary determinant of the plateau. There are also marked differences in the voltage dependences of steady-state inactivation of these two K+ currents: IK undergoes steady-state inactivation at all potentials positive to -120 mV, and is 50% inactivated at -69 mV; Ito, in contrast, is insensitive to steady-state inactivation at membrane potentials negative to -50 mV. In addition, Ito recovers from steady-state inactivation faster than IK: at -90 mV, for example, approximately 70% recovery from the inactivation produced at -20 mV is observed within 20 ms for Ito; IK recovers approximately 25-fold more slowly. The pharmacological properties of Ito and IK are also distinct: 4-aminopyridine preferentially attenuates Ito, and tetraethylammonium suppresses predominantly IK. The voltage- and time-dependent properties of these currents are interpreted here in terms of a model in which Ito underlies the initial, rapid repolarization phase of the action potential (AP), and IK is responsible for the slower phase of AP repolarization back to the resting membrane potential, in adult rat ventricular myocytes.     

Bethanidine increased Na+ and Ca2+ currents and caused a positive inotropic effect in heart cells

The effects of bethanidine sulphate, a pharmacological analog of the cardiac antibrillatory drug, bretylium tosylate, were studied on action potentials (APs) and K+, Na+, and Ca2+ currents of single cultured embryonic chick heart cells using the whole-cell current clamp and voltage clamp technique. Extracellular application of bethanidine (3 X 10(-4) M) increased the overshoot and the duration of the APs and greatly decreased the outward K+ current (IK) and potentiated the inward fast Na+ currents (INa) and the inward slow calcium current (ICa). However, intracellular introduction of bethanidine (10(-4) M) blocked INa. In isolated atria of rat, bethanidine increased the force of contraction in a dose-dependent manner. These findings suggest that when applied extracellularly, bethanidine exerts a potentiating effect on the myocardial fast Na+ current and slow Ca2+ current and an inhibitory effect of IK. The positive inotropic effect of bethanidine could be due, at least in part, to an increase of Ca2+ influx via the slow Ca2+ channel and the Na-Ca exchange. It is suggested that the decrease of IK by bethanidine may account for its antifibrillatory action.     

Four kinetically distinct depolarization-activated K+ currents in adult mouse ventricular myocytes

In the experiments here, the time- and voltage-dependent properties of the Ca2+-independent, depolarization-activated K+ currents in adult mouse ventricular myocytes were characterized in detail. In the majority (65 of 72, approximately 90%) of cells dispersed from the ventricles, analysis of the decay phases of the outward currents revealed three distinct K+ current components: a rapidly inactivating, transient outward K+ current, Ito,f (mean +/- SEM taudecay = 85 +/- 2 ms); a slowly (mean +/- SEM taudecay = 1,162 +/- 29 ms) inactivating K+ current, IK,slow; and a non inactivating, steady state current, Iss. In a small subset (7 of 72, approximately 10%) of cells, Ito,f was absent and a slowly inactivating (mean +/- SEM taudecay = 196 +/- 7 ms) transient outward current, referred to as Ito,s, was identified; the densities and properties of IK,slow and Iss in Ito,s-expressing cells are indistinguishable from the corresponding currents in cells with Ito,f. Microdissection techniques were used to remove tissue pieces from the left ventricular apex and from the ventricular septum to allow the hypothesis that there are regional differences in Ito,f and Ito,s expression to be tested directly. Electrophysiological recordings revealed that all cells isolated from the apex express Ito,f (n = 35); Ito,s is not detected in these cells (n = 35). In the septum, by contrast, all of the cells express Ito,s (n = 28) and in the majority (22 of 28, 80%) of cells, Ito,f is also present. The density of Ito,f (mean +/- SEM at +40 mV = 6.8 +/- 0.5 pA/pF, n = 22) in septum cells, however, is significantly (P < 0.001) lower than Ito,f density in cells from the apex (mean +/- SEM at +40 mV = 34.6 +/- 2.6 pA/pF, n = 35). In addition to differences in inactivation kinetics, Ito,f, Ito,s, and IK,slow display distinct rates of recovery (from inactivation), as well as differential sensitivities to 4-aminopyridine (4-AP), tetraethylammonium (TEA), and Heteropoda toxin-3. IK,slow, for example, is blocked selectively by low (10-50 microM) concentrations of 4-AP and by (>/=25 mM) TEA. Although both Ito,f and Ito,s are blocked by high (>100 microM) 4-AP concentrations and are relatively insensitive to TEA, Ito,f is selectively blocked by nanomolar concentrations of Heteropoda toxin-3, and Ito,s (as well as IK,slow and Iss) is unaffected. Iss is partially blocked by high concentrations of 4-AP or TEA. The functional implications of the distinct properties and expression patterns of Ito,f and Ito,s, as well as the likely molecular correlates of these (and the IK,slow and Iss) currents, are discussed.     

Role of Na-Ca exchange in the action potential changes caused by drive in cardiac myocytes exposed to different Ca2+ loads.

The role of Na-Ca exchange in the membrane potential changes caused by repetitive activity ("drive") was studied in guinea pig single ventricular myocytes exposed to different [Ca2+]o. The following results were obtained. (i) In 5.4 mM [Ca2+]o, the action potentials (APs) gradually shortened during drive, and the outward current during a train of depolarizing voltage clamp steps gradually increased. (ii) The APs shortened more and were followed by a decaying voltage tail during drive in the presence of 5 mM caffeine; the outward current became larger and there was an inward tail current on repolarization during a train of depolarizing steps. (iii) These effects outlasted drive so that immediately after a train of APs, currents were already bigger and, after a train of steps, APs were already shorter. (iv) In 0.54 mM [Ca2+]o, the above effects were much smaller. (v) In high [Ca2+]o APs were shorter and outward currents larger than in low [Ca2+]o. (vi) In 10.8 mM [Ca2+]o, both outward and inward currents during long steps were exaggerated by prior drive, even with steps (+80 and +120 mV) at which there was no apparent inward current identifiable as I(Ca). (vii) In 0.54 mM [Ca2+]o, the time-dependent outward current was small and prior drive slightly increased it. (viii) During long steps, caffeine markedly increased outward and inward tail currents, and these effects were greatly decreased by low [Ca2+]o. (ix) After drive in the presence of caffeine, Ni2+ decreased the outward and inward tail currents. It is concluded that in the presence of high [Ca2+]o drive activates outward and inward Na-Ca exchange currents. During drive, the outward current participates in the plateau shortening and the inward tail current in the voltage tail after the action potential.     

Heterogeneous gap junction remodeling stabilizes reentrant circuits in the epicardial border zone of the healing canine infarct: a computational study

The ventricular tachycardias (VTs) that originate in the 5-day epicardial border zone (EBZ) of the healing canine infarcted heart are due to reentrant excitation. In cells surviving in the EBZ, both sarcolemmal ionic channels and gap junction conductance and distribution are remodeled. We previously showed that the heterogeneities in sodium current (I(Na)) and L-type calcium channel current (I(CaL)) of the center and outer pathway cells result in a homogenization of the refractory period that in turn stabilizes reentrant VTs for approximately 10 beats. To understand how heterogeneities in transverse gap junctional conductance remodeling reported experimentally contribute to the stability of these tachycardias, we studied the dynamics of reentering waves in two-dimensional computer models of the EBZ. First we used a computer model with homogeneous ionic channel properties [infarcted border zone cell model (IZ)]. These simulations show that, in the absence of heterogeneities in ionic channel properties, reentrant waves tend to drift to localized regions of uncoupling and stabilize there. Second, we used a computer model with a more realistic representation of the heterogeneous EBZ, including cellular models for both the center (IZ(c)) and outer (IZ(o)) pathway cells. These simulations show that neither a region of uniform uncoupling nor a step transition between two regions with different side-to-side (transverse) cell coupling stabilizes reentry in this substrate. However, an area of localized uncoupling did stabilize reentry in such a model. We propose that in addition to the heterogeneities in I(Na) and I(CaL) properties, heterogeneities in gap junctional conductance in the EBZ causing regions of localized uncoupling stabilize VT in the EBZ. Previous experimental in situ activation maps of the 5-day EBZ show that the lines of block form in regions of slow transverse propagation. This is consistent with our findings that areas of localized uncoupling stabilize reentry.     

Electrophysiology of cardiac myocytes of Aplysia brasiliana

The electrical properties of Aplysia brasiliana myogenic heart were evaluated. Two distinct types of action potentials (APs) were recorded from intact hearts, an AP with a slow rising phase followed by a slow repolarizing phase and an AP with a 'fast' depolarizing phase followed by a plateau. Although these two APs differ in their rates of depolarization (2.2 x 0.3 V/s), both APs were abolished by the addition of Co2+, Mn2+ and nifedipine or by omitting Ca2+ from the external solution. These data suggest that a Ca2+ inward current is responsible for the generation of both types of APs. Two outward currents activated at -40 mV membrane potential were prominent in isolated cardiac myocytes: a fast activating, fast inactivating outward current similar to the A-type K+ current and a slow activating outward current with kinetics similar to the delayed rectifier K+ current were recorded under voltage clamp conditions. Based on the effects of 4-AP and TEA on the electrical properties of ventricular myocytes, we suggest that the fast kinetic outward current substantially attenuates the peak values of the APs and that the slow activating outward current is involved on membrane repolarization.     

Tamoxifen inhibits Na+ and K+ currents in rat ventricular myocytes

Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. However, tamoxifen has been shown to induce QT prolongation of the electrocardiogram, thereby potentially causing life-threatening polymorphic ventricular arrhythmias. The purpose of the present study was to elucidate the electrophysiological mechanism(s) that underlie the arrhythmogenic effects of tamoxifen. We used standard ruptured whole cell and perforated patch-clamping techniques on rat ventricular myocytes to investigate the effects of tamoxifen on cardiac action potential (AP) waveforms and the underlying K+ currents. Tamoxifen (3 micromol/l) markedly prolonged AP duration, decreased maximal rate of depolarization, and decreased resting membrane potential. At this concentration, tamoxifen significantly depressed the Ca2+-independent transient outward K+ current (Ito), sustained outward delayed rectifier K+ current (Isus), inward rectifier K+ current (IK1), and Na+ current (INa) in the myocytes. Lower concentrations of tamoxifen (1 micromol/l) also decreased the resting membrane potential and significantly depressed IK1 to 79 +/- 5% (n = 5; at -120 mV) of pretreatment values. The results of this study indicate that inhibition of Ito, Isus, and IK1 by tamoxifen may underlie AP prolongation in cardiac myocytes and thereby contribute to prolonged QT interval observed in patients.     

Inhibition of Ca2+-activated K+ channels in pig pancreatic acinar cells by Ba2+, Ca2+, quinine and quinidine

Patch-clamp whole-cell and single-channel current recordings were made from pig pancreatic acinar cells to test the effects of quinine, quinidine, Ba2+ and Ca2+. Voltage-clamp current recordings from single isolated cells showed that high external concentrations of Ba2+ or Ca2+ (88 mM) abolished the outward K+ currents normally associated with depolarizing voltage steps. Lower concentrations of Ca2+ only had small inhibitory effects whereas 11 mM Ba2+ almost blocked the K+ current. 5.5 mM Ba2+ reduced the outward K+ current to less than 30% of the control value. Both external quinine and quinidine (200-500 microM) markedly reduced whole-cell outward K+ currents. In single-channel current studies it was shown that external Ba2+ (1-5 mM) markedly reduced the probability of opening of high-conductance Ca2+ and voltage-activated K+ channels whereas internal Ba2+ (6 X 10(-6) to 3 X 10(-5) M) caused activation at negative membrane potentials and inhibition at positive potentials. Quinidine (200-400 microM) evoked rapid chopping of single K+ channel openings acting both from the outside and inside of the membrane and in this way markedly reduced the total current passing through the channels.     

Fluctuations of the Ca2+-activated K+ current in Aplysia neurones

Fluctuations of the Ca2+-activated K+ current were measured in identified Aplysia neurones under voltage clamp conditions. The amplitude of IK,Ca was manipulated by ionophoretic injections of Ca2+. At small amplitudes of Ca2+-activated outward currents the variance of the Ca2+-activated current fluctuations increases linearly with the mean outward current. The single-channel conductance estimated from the variance of the fluctuations and the mean outward current is 11 +/- 3 pS at -30 mV. Power spectra of the Ca2+-activated K+ current can be fitted by the sum of two Lorentzian components with corner frequencies of about 10 Hz and 120 Hz.     

A Fast Transient Outward Monovalent Current in Rat Saphenous Myocytes Passing Through Ca2+ Channels

Transient outward currents in rat saphenous arterial myocytes were studied using the perforated configuration of the patch-clamp method. When myocytes were bathed in a Na-gluconate solution containing TEA to block large-conductance Ca2+-activated K+ (BK) currents, depolarizing pulses positive to +20 mV from a holding potential of -100 mV induced fast transient outward currents. The activation and inactivation time constants of the current were voltage dependent, and at +40 mV were 3.6 +/- 0.8 ms and 23.9 +/- 6.4 ms (n = 4), respectively. The steady-state inactivation of the transient outward current was steeply voltage dependent (z = 1.7), with 50% of the current inactivated at -55 mV. The current was insensitive to the A-type K+ channel blocker 4-AP (1-5 mM), and was modulated by external Ca, decreasing to approximately 0.85 of control values upon raising Ca2+ from 1 to 10 mM, and increasing approximately 3-fold upon lowering it to 0.1 mM. Transient outward currents were also recorded following replacement of internal K+ with either Na+ or Cs+, raising the possibility that the current was carried by monovalent ions passing through voltage-gated Ca2+ channels. This hypothesis was supported by the finding that the transient outward current had the same inactivation rate as the inward Ba2+ current, and that both currents were effectively blocked by the L-type Ca2+ channel blocker, nifedipine and enhanced by the agonist BAYK8644.     

Frequency-dependent and proarrhythmogenic effects of FK-506 in rat ventricular cells

FK-506, a widely used immunosuppressant, has caused a few clinical cases with QT prolongation and torsades de pointe at high blood concentration. The proarrhytmogenic potential of FK-506 was investigated in single rat ventricular cells using the whole cell clamp method to record action potentials (APs) and ionic currents. Fluorescence measurements of Ca2+ transients were performed with indo-1 AM using a multiphotonic microscope. FK-506 (25 micromol/l) hyperpolarized the resting membrane potential (RMP; -3 mV) and prolonged APs (AP duration at 90% repolarization increased by 21%) at 0.1 Hz. Prolongation was enhanced by threefold at 3.3 Hz, and early afterdepolarizations (EADs) occurred in 59% of cells. EADs were prevented by stronger intracellular Ca2+ buffering (EGTA: 10 vs. 0.5 mmol/l in the patch pipette) or replacement of extracellular Na+ by Li+, which abolishes Na+/Ca2+ exchange [Na+/Ca2+ exchanger current (INaCa)]. In indo-1-loaded cells, FK-506 generated doublets of Ca(2+) transients associated with increased diastolic Ca2+ in one-half of the cells. FK-506 reversibly decreased the L-type Ca2+ current (ICaL) by 25%, although high-frequency-dependent facilitation of ICaL persisted, and decreased three distinct K+ currents: delayed rectifier K+ current (IK; >80%), transient outward K+ current (<20%), and inward rectifier K+ current (IK1; >40%). A shift in the reversal potential of IK1 (-5 mV) accounted for RMP hyperpolarization. Numerical simulations, reproducing all experimental effects of FK-506, and the use of nifedipine showed that frequency-dependent facilitation of ICaL plays a role in the occurrence of EADs. In conclusion, the effects of FK-506 on the cardiac AP are more complex than previously reported and include inhibitions of IK1 and ICaL. Alterations in Ca2+ release and INaCa may contribute to FK-506-induced AP prolongation and EADs in addition to the permissive role of ICaL facilitation at high rates of stimulation.     

Voltage-dependent ionic currents in taste receptor cells of the larval tiger salamander

Voltage-dependent membrane currents of cells dissociated from tongues of larval tiger salamanders (Ambystoma tigrinum) were studied using whole-cell and single-channel patch-clamp techniques. Nongustatory epithelial cells displayed only passive membrane properties. Cells dissociated from taste buds, presumed to be gustatory receptor cells, generated both inward and outward currents in response to depolarizing voltage steps from a holding potential of -60 or -80 mV. Almost all taste cells displayed a transient inward current that activated at -30 mV, reached a peak between 0 and +10 mV and rapidly inactivated. This inward current was blocked by tetrodotoxin (TTX) or by substitution of choline for Na+ in the bath solution, indicating that it was a Na+ current. Approximately 60% of the taste cells also displayed a sustained inward current which activated slowly at about -30 mV and reached a peak at 0 to +10 mV. The amplitude of the slow inward current was larger when Ca2+ was replaced by Ba2+ and it was blocked by bath applied CO2+, indicating it was a Ca2+ current. Delayed outward K+ currents were observed in all taste cells although in about 10% of the cells, they were small and activated only at voltages more depolarized than +10 mV. Normally, K+ currents activated at -40 mV and usually showed some inactivation during a 25-ms voltage step. The inactivating component of outward current was not observed at holding potentials more depolarized -40 mV. The outward currents were blocked by tetraethylammonium chloride (TEA) and BaCl2 in the bath or by substitution of Cs+ for K+ in the pipette solution. Both transient and noninactivating components of outward current were partially suppressed by CO2+, suggesting the presence of a Ca2(+)-activated K+ current component. Single-channel currents were recorded in cell-attached and outside-out patches of taste cell membranes. Two types of K+ channels were partially characterized, one having a mean unitary conductance of 21 pS, and the other, a conductance of 148 pS. These experiments demonstrate that tiger salamander taste cells have a variety of voltage- and ion-dependent currents including Na+ currents, Ca2+ currents and three types of K+ currents. One or more of these conductances may be modulated either directly by taste stimuli or indirectly by stimulus-regulated second messenger systems to give rise to stimulus-activated receptor potentials. Others may play a role in modulation of neurotransmitter release at synapses with taste nerve fibers.(ABSTRACT TRUNCATED AT 400 WORDS)     

A whole-cell and single-channel study of the voltage-dependent outward potassium current in avian hepatocytes

Voltage-dependent membrane currents were studied in dissociated hepatocytes from chick, using the patch-clamp technique. All cells had voltage-dependent outward K+ currents; in 10% of the cells, a fast, transient, tetrodotoxin-sensitive Na+ current was identified. None of the cells had voltage-dependent inward Ca2+ currents. The K+ current activated at a membrane potential of about -10 mV, had a sigmoidal time course, and did not inactivate in 500 ms. The maximum outward conductance was 6.6 +/- 2.4 nS in 18 cells. The reversal potential, estimated from tail current measurements, shifted by 50 mV per 10-fold increase in the external K+ concentration. The current traces were fitted by n2 kinetics with voltage-dependent time constants. Omitting Ca2+ from the external bath or buffering the internal Ca2+ with EGTA did not alter the outward current, which shows that Ca2+-activated K+ currents were not present. 1-5 mM 4-aminopyridine, 0.5-2 mM BaCl2, and 0.1-1 mM CdCl2 reversibly inhibited the current. The block caused by Ba was voltage dependent. Single-channel currents were recorded in cell-attached and outside-out patches. The mean unitary conductance was 7 pS, and the channels displayed bursting kinetics. Thus, avian hepatocytes have a single type of K+ channel belonging to the delayed rectifier class of K+ channels.     

Ca2+-activated K+ channels in human red cells. Comparison of single-channel currents with ion fluxes

Exposure of the inner surface of intact red cells or red cell ghosts to Ca2+ evokes unitary currents that can be measured in cell-attached and cell-free membrane patches. The currents are preferentially carried by K+ (PK/PNa 17) and show rectification. Increasing the Ca2+ concentration from 0 to 5 microM increases the probability of the open state of the channels parallel to the change of K+ permeability as observed in suspensions of red cell ghosts. Prolonged incubation of red cell ghosts in the absence of external K+ prevents the Ca2+ from increasing K+ permeability. Similarly, the probability to find Ca2+-activated unitary currents in membrane patches is drastically reduced. These observations suggest that the Ca2+-induced changes of K+ permeability observed in red cell suspensions are causally related to the appearance of the unitary K+ currents. Attempts to determine the number of K+ channels per cell were made by comparing fluxes measured in suspensions of red cells with the unitary currents in membrane patches as determined under comparable ionic conditions. At 100 mM KCl in the external medium, where no net movements of K+ occur, the time course of equilibration of 86Rb+ does not follow a single exponential. This indicates a heterogeneity of the response to Ca2+ of the cells in the population. The data are compatible with the assumption that 25% of the cells respond with Pk = 33.2 X 10(-14)cm3/s and 75% with Pk = 3.1 X 10(-14)cm3/s. At 100 mM external K+ the zero current permeability of a single channel is 6.1 X 10(-14)cm3/s (corresponding to a conductance of 22 pS).(ABSTRACT TRUNCATED AT 250 WORDS)     

L-type Ca2+ channels and K+ channels specifically modulate the frequency and amplitude of spontaneous Ca2+ oscillations and have distinct roles in prolactin release in GH3 cells

GH3 cells showed spontaneous rhythmic oscillations in intracellular calcium concentration ([Ca2+]i) and spontaneous prolactin release. The L-type Ca2+ channel inhibitor nimodipine reduced the frequency of Ca2+ oscillations at lower concentrations (100nM-1 microM), whereas at higher concentrations (10 microM), it completely abolished them. Ca2+ oscillations persisted following exposure to thapsigargin, indicating that inositol 1,4,5-trisphosphate-sensitive intracellular Ca2+ stores were not required for spontaneous activity. The K+ channel inhibitors Ba2+, Cs+, and tetraethylammonium (TEA) had distinct effects on different K+ currents, as well as on Ca2+ oscillations and prolactin release. Cs+ inhibited the inward rectifier K+ current (KIR) and increased the frequency of Ca2+ oscillations. TEA inhibited outward K+ currents activated at voltages above -40 mV (grouped within the category of Ca2+ and voltage-activated currents, KCa,V) and increased the amplitude of Ca2+ oscillations. Ba2+ inhibited both KIR and KCa,V and increased both the amplitude and the frequency of Ca2+ oscillations. Prolactin release was increased by Ba2+ and Cs+ but not by TEA. These results indicate that L-type Ca2+ channels and KIR channels modulate the frequency of Ca2+ oscillations and prolactin release, whereas TEA-sensitive KCa,V channels modulate the amplitude of Ca2+ oscillations without altering prolactin release. Differential regulation of these channels can produce frequency or amplitude modulation of calcium signaling that stimulates specific pituitary cell functions.     

Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-alpha

Mice that overexpress the inflammatory cytokine tumor necrosis factor-alpha in the heart (TNF mice) develop heart failure characterized by atrial and ventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias, and increased mortality (males > females). Abnormalities in Ca2+ handling, prolonged action potential duration (APD), calcium alternans, and reentrant atrial and ventricular arrhythmias were previously observed with the use of optical mapping of perfused hearts from TNF mice. We therefore tested whether altered voltage-gated outward K+ and/or inward Ca2+ currents contribute to the altered action potential characteristics and the increased vulnerability to arrhythmias. Whole cell voltage-clamp recordings of K+ currents from left ventricular myocytes of TNF mice revealed an approximately 50% decrease in the rapidly activating, rapidly inactivating transient outward K+ current Ito and in the rapidly activating, slowly inactivating delayed rectifier current IK,slow1, an approximately 25% decrease in the rapidly activating, slowly inactivating delayed rectifier current IK,slow2, and no significant change in the steady-state current Iss compared with controls. Peak amplitudes and inactivation kinetics of the L-type Ca2+ current ICa,L were not altered. Western blot analyses revealed a reduction in the proteins underlying Kv4.2, Kv4.3, and Kv1.5. Thus decreased K+ channel expression is largely responsible for the prolonged APD in the TNF mice and may, along with abnormalities in Ca2+ handling, contribute to arrhythmias.