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CARDIOVASCULAR

Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction

Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida (Y.S.); Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, California (J.C.S., L.B.); and Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany (S.W., L.S.M.)

Received January 24, 2006; accepted March 23, 2006.

	Abstract

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Reactive oxygen species (ROS), including H₂O₂, cause intracellular calcium overload and ischemia-reperfusion damage. The objective of this study was to examine the hypothesis that H₂O₂-induced arrhythmic activity and contractile dysfunction are the results of an effect of H₂O₂ to increase the magnitude of the late sodium current (late I_Na). Guinea pig and rabbit isolated ventricular myocytes were exposed to 200 µM H₂O₂. Transmembrane voltages and currents and twitch shortening were measured using the whole-cell patch-clamp technique and video edge detection, respectively. [Na⁺]_i and [Ca²⁺]_i were determined by fluorescence measurements. H₂O₂ caused a persistent late I_Na that was almost completely inhibited by 10 µM tetrodotoxin (TTX). H₂O₂ prolonged the action potential duration (APD), slowed the relaxation rate of cell contraction, and induced early afterdepolarizations (EADs) and aftercontractions. H₂O₂ also caused increases of [Na⁺]_i and [Ca²⁺]_i. Ranolazine (10 µM), a novel inhibitor of late I_Na, attenuated H₂O₂-induced late I_Na by 51 ± 9%. TTX (2 µM) or 10 µM ranolazine attenuated H₂O₂-induced APD prolongation and suppressed EADs. Ranolazine accelerated the twitch relaxation rate in the presence of H₂O₂ and abolished H₂O₂-induced aftercontractions. Pretreatment of myocytes with ranolazine delayed and reduced the increases of APD, [Na⁺]_i, and [Ca²⁺]_i caused by H₂O₂. In conclusion, the results confirm the hypothesis that an increase in late I_Na during exposure of ventricular myocytes to H₂O₂ contributes to electrical and contractile dysfunction and suggest that inhibition of late I_Na may offer protection against ROS-induced Na⁺ and Ca²⁺ overload.

The objective of the present study was to determine the contribution of the late Na⁺ current (late I_Na) to the rises in [Na⁺]_i and [Ca²⁺]_i and to the accompanying electrical and contractile dysfunctions caused by H₂O₂. To determine the role of late I_Na, we used low concentrations (<10 µM) of the putative Na⁺ channel blocker tetrodotoxin (TTX), and of ranolazine (Ran), a cardioprotective agent that preferentially inhibits late relative to peak I_Na (Undrovinas et al., 2006). Ranolazine has previously been shown to markedly attenuate, in a concentration-dependent manner, the increase in left ventricular diastolic pressure caused by H₂O₂ in rat isolated, perfused hearts (Matsumura et al., 1998).

	Materials and Methods

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Chemicals. H₂O₂ was purchased from Fisher (Fairlawn, NJ) and Merck (Darmstadt, Germany). TTX was purchased from Sigma-Aldrich (St. Louis, MO). Ranolazine [(±)-N-(2,6-dimethylphenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine], a piperazine derivative (Matsumura et al., 1998), was synthesized by CV Therapeutics, Inc. (Palo Alto, CA).

Isolation of Ventricular Myocytes. Electrophysiological studies were performed on guinea pig ventricular myocytes at the University of Florida (Gainesville, FL); intracellular Na⁺ and Ca²⁺ measurements were conducted on rabbit ventricular myocytes at Georg-August-University Göttingen (Göttingen, Germany). Use of animals was in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication 85-23, revised 1996) and was approved by the Institutional Animal Care and Use Committee of the University of Florida. Ventricular myocytes were isolated from adult female Hartley guinea pigs and Chinchilla bastard rabbits with standard enzymatic procedures described previously (Wagner et al., 2003; Song et al., 2004).

Measurements of Transmembrane Potential and Current. Guinea pig ventricular myocytes were placed into a recording chamber that was bathed with prewarmed (35-36°C) Tyrode's solution, without or with drug(s), at a rate of 2 ml/min. The Tyrode's solution contained 135 mM NaCl, 4.6 mM KCl, 1.8 mM CaCl₂, 1.1 mM MgSO₄, 10 mM glucose, and 10 mM HEPES, pH 7.4. The temperature of the bathing media in a given experiment did not vary more than 0.3°C. Transmembrane voltages and currents were recorded from quiescent, rod-shaped myocytes with clear striations, using borosilicate glass pipettes (1- to 3-M resistance when filled) in a whole-cell configuration of the patch-clamp technique. An Axopatch-200 amplifier, a DigiData interface, and a computer with pCLAMP software (Axon Instruments, Union City, CA) were used to amplify, store, and analyze the recorded signals. The electrode capacitance and whole-cell capacitance currents were maximally compensated with the amplifier. The series resistance was compensated by 60 to 80%. The liquid junction potential between pipette and bath medium was calculated with pCLAMP software and corrected online.

When measuring action potentials, recording pipettes were filled with a solution containing 120 mM potassium aspartate, 20 mM KCl, 1 mM MgSO₄, 4 mM Na₂ATP, 0.1 mM Na₃GTP, and 10 mM HEPES, pH 7.2. For inducing action potentials, a 5-ms depolarizing pulse was applied at a frequency of 0.16 Hz. The duration of the action potential was measured from onset of upstroke to 50% of repolarization (APD₅₀).

To elicit late I_Na, myocytes were voltage-clamped at a holding potential of -90 mV, and a 300-ms depolarizing pulse to -30 mV was applied at a frequency of 0.16 Hz. In experiments to determine the effect of ranolazine on late I_Na, K⁺ and Ca²⁺ were omitted from the bath and pipette solutions to reduce contamination of I_Na by K⁺ and Ca²⁺ currents. In these experiments, recording pipettes were filled with 120 mM cesium aspartate, 20 mM CsCl, 1 mM MgSO₄, 4 mM Na₂ATP, 0.1 mM Na₃GTP, and 10 mM HEPES, pH 7.2. The magnitude of late I_Na was determined by integration of the current over the last 50 ms of the -30-mV clamp pulse, using the integration (area) feature of the pCLAMP program.

Measurement of Cell Contraction. Twitch shortenings of guinea pig ventricular myocytes were elicited by field stimulation from a Grass S88 (Quincy, MA) stimulator. The amplitude of twitch shortening was determined by a video-motion detector (Crescent Electronics, Logan, UT) and was recorded on a chart recorder (2200S; Gould, Cleveland, OH). In this study, a twitch shortening denotes a normal systolic contraction, whereas an early aftercontraction denotes an additional contraction that occurs during relaxation and is triggered by events following the preceding normal contraction. The amplitude of twitch shortening was measured from maximal cell relaxation to peak contraction, and the rate of relaxation was calculated by dividing the amplitude (micrometers) with the time (seconds) required from peak contraction to maximal relaxation.

View larger version (21K): [in this window] [in a new window]   Fig. 1. Ranolazine (10 µM; A) and 10 µM TTX (B) attenuated 200 µM H2O2-induced late sodium current of guinea pig ventricular myocytes. Sodium current was elicited by 300-ms voltage-clamp pulses from -90 to -30 mV. Myocytes were sequentially treated with no drug (control) (a), H2O2 (b), and H2O2 plus either ranolazine or TTX (c).

View larger version (21K): [in this window] [in a new window]   Fig. 2. Attenuation by 10 µM Ran and 2 µM TTX of 200 µMH2O2-induced prolongation of action potential duration of guinea pig ventricular myocytes. A and B, superimposed action potentials recorded from a single cell in the presence of no drug (control) (a), H2O2 (b), and H2O2 plus Ran (c) (A) or TTX (B). C and D, summary of data from experiments similar to those shown in A and B, respectively. * and **, p < 0.001 versus control and H2O2 alone, respectively.

Statistical Analysis. Data are expressed as mean ± S.E.M. Values of "n" indicate the number of cells studied. The Student's t test, one-way repeated measures analysis of variance followed by Student-Newman-Keuls test, and two-way analysis of variance were applied where it was appropriate. A difference with a p value <0.05 was considered statistically significant.

	Results

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Ranolazine and TTX Inhibited H₂O₂-Induced Late Sodium Current of Guinea Pig Ventricular Myocytes. Late I_Na in the absence of drug was a small inward current (Fig. 1, A and B). Incubation of cells in 200 µM H₂O₂ caused an increase of late I_Na from -3.419 ± 0.392 to -6.215 ± 0.471 nC (Fig. 1A). Ranolazine (10 µM), an inhibitor of late I_Na, reduced the current to -5.072 ± 0.440 nC in the continued presence of H₂O₂ (n = 10; p < 0.01; Fig. 1A), a 51 ± 9% decrease of H₂O₂-induced late I_Na. To confirm that the H₂O₂-induced late current was indeed a Na⁺ current, the specific Na⁺ channel blocker 10 µM TTX was applied in the presence of H₂O₂. Late I_Na was increased by 200 µM H₂O₂ from -0.114 ± 0.538 to -4.423 ± 1.384 nC and was decreased by TTX to -0.476 ± 0.850 nC (n = 5; p < 0.01; Fig. 1B), a decrease of 91 ± 5%.

View larger version (21K): [in this window] [in a new window]   Fig. 3. Inhibition by 10 µM ranolazine of 200 µMH2O2-induced early EADs of a guinea pig ventricular myocyte. The myocyte was sequentially treated with no drug (control) (a), H2O2 (b), H2O2 plus ranolazine (c), and H2O2 alone (d) (to wash out ranolazine). Each panel shows five superimposed, consecutive action potentials. Arrows indicate EADs.

View larger version (19K): [in this window] [in a new window]   Fig. 4. Inhibition by 2 µM TTX of 200 µM H2O2-induced EADs of a guinea pig ventricular myocyte. The myocyte was treated with no drug (control) (a), H2O2 (b), H2O2 plus TTX (c), and H2O2 alone (d) (to wash out TTX). Each panel shows three superimposed, consecutive action potentials. Arrows indicate EADs.

View larger version (13K): [in this window] [in a new window]   Fig. 5. Pretreatment of guinea pig ventricular myocytes with 10 µM ranolazine prevented 200 µM H2O2-induced prolongation of action potential duration. H2O2 was applied in the absence (closed circle) or presence (open circle) of ranolazine. The action potential duration at APD50 was normalized as percentage of control (before application of H2O2) and was plotted against H2O2 exposure time. Each point represents data collected from 3 to 10 cells. *, p < 0.01 versus ranolazine-treated group.

Ranolazine Reversed H₂O₂-Induced Contractile Dysfunction of Guinea Pig Ventricular Myocytes. H₂O₂ (200 µM) initially increased the amplitude of myocyte contractile shortening and induced aftercontractions that delayed contractile relaxation (Fig. 6A, b). Prolonged treatment of myocytes with H₂O₂ eventually caused spontaneous contractions and decreases of contractile amplitude and rate and extent of relaxation (Fig. 6A, d). Ranolazine (10 µM) did not significantly change contractile amplitude in the presence of H₂O₂ (Fig. 6B), but it suppressed aftercontractions (Fig. 6A, c). H₂O₂ increased myocyte contractile amplitude from 4.7 ± 0.8 to 6.3 ± 1.1 µm and decreased the rate of contractile relaxation from 12.2 ± 1.0 to 7.3 ± 1.3 µm/s (Fig. 6B). Ranolazine accelerated the relaxation rate from 7.3 ± 1.3 to 15.0 ± 1.9 µm/s (n = 5; p < 0.05) in the presence of H₂O₂ (Fig. 6B).

View larger version (34K): [in this window] [in a new window]   Fig. 6. Ran (10 µM) attenuates 200 µM H2O2-induced contractile dysfunction of guinea pig ventricular myocytes. A, amplitudes of twitch shortening of a single myocyte. Records were obtained in the absence (a) and presence (b-d) of drugs as indicated. H2O2 (b) increased the amplitude of twitch shortening and induced aftercontractions (additional contractions during relaxation). Ran (c) suppressed the aftercontractions, but had little effect on the twitch amplitude. During washout of Ran in the continued presence of H2O2 (d), the aftercontractions resumed, and eventually, spontaneous contractions with a decreased twitch amplitude occurred. B, summary of experiments similar to those shown in A. Each bar represents data collected from five cells. * and **, p < 0.05 versus control and H2O2 alone, respectively; NS, no significant difference versus H2O2 alone.

View larger version (26K): [in this window] [in a new window]   Fig. 7. Ranolazine (10 µM) slows 200 µM H2O2-induced increases of [Na+]i and diastolic [Ca2+]i in rabbit ventricular myocytes. A to C, effect of H2O2 on [Na+]i. A, original traces of SBFI fluorescence in the absence and presence of ranolazine before (0 min) and after a 12-min exposure to H2O2 (in gray). B, time course of changes in [Na+]i. Mean values for calibrated signals are normalized to baseline. C, concentrations of Na+ measured at the end of a 12-min exposure to H2O2. D to F, effect of H2O2 on [Ca2+]i. D, original traces of Ca2+ transient in the absence and presence of ranolazine before (0 min) and after a 12-min exposure to H2O2 (in gray). Please note that in the absence of ranolazine, at the end of 12-min H2O2 treatment the Ca+ transients had disappeared, consistent with an early hypercontracture. E, time course of changes in diastolic [Ca2+]i. Mean values for diastolic [Ca2+]i are normalized to baseline. F, diastolic [Ca2+]i determined after a 12-min exposure to H2O2.

	Discussion

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The major finding of this study is that blocking late I_Na with either ranolazine or TTX attenuates H₂O₂-induced arrhythmic activity and contractile dysfunction in cardiac myocytes. In addition, ranolazine was found to significantly reduce the rise in [Na⁺]_i and [Ca²⁺]_i caused by H₂O₂. The results of the study suggest that inhibition of late I_Na may attenuate reactive oxygen species-induced cardiac dysfunction.

The hypothesis tested in the present study can be summarized as follows (Fig. 8): ROS, such as H₂O₂, increase late I_Na and thereby cause 1) prolongation of APD and induction of EADs; and 2) a rise in [Na⁺]_i, which, because intracellular Na⁺ is exchanged for extracellular Ca²⁺ via NCX, causes cellular Ca²⁺ overload. Ca²⁺ overload of cardiomyocytes is associated with electrical instability (i.e., arrhythmias) and contractile dysfunction (i.e., impaired relaxation). Hence, by reducing the increase in late I_Na, the deleterious effects of H₂O₂ on cardiomyocyte function (electrical and contractile) can be attenuated. In support of the hypothesis (Fig. 8), results of other studies have shown that H₂O₂ can cause increases of late I_Na (Ward and Giles, 1997; Ma et al., 2005), intracellular Na⁺ and Ca²⁺ (Wagner et al., 2003), and ventricular diastolic tension and pressure (Hara et al., 1993; Zeitz et al., 2002).

View larger version (14K): [in this window] [in a new window]   Fig. 8. An action of H2O2 to increase late INa is a potential mechanism by which H2O2 prolongs APD and causes EADs and increases of intracellular [Na+] and [Ca2+]. TTX and ranolazine inhibit H2O2-induced late INa (dashed arrow).

Although the amplitude of late I_Na recorded in the absence of drugs is small, late I_Na is found to contribute to the regulation of APD (Kiyosue and Arita, 1989; Maltsev et al., 1998; Sakmann et al., 2000). Blocking late I_Na with TTX caused a 10 to 20% decrease of APD (Kiyosue and Arita, 1989; Maltsev et al., 1998; Sakmann et al., 2000) and suppressed EADs of myocytes isolated from failing hearts (Maltsev et al., 1998). We found that in the absence of TTX or ranolazine, the amplitude of late I_Na can be markedly enhanced by H₂O₂ by severalfold (data not shown). Therefore, an increase by H₂O₂ of late I_Na is expected to cause a significant prolongation of APD. Consistent with previous reports (Beresewicz and Horackova, 1991), we found that the early effect of H₂O₂ on myocyte membrane potential was an increase in the duration of action potentials. This effect of H₂O₂ can be largely explained by an increase of late I_Na, because it was significantly attenuated by either ranolazine or TTX. Thus, blocking late I_Na may be the key to reduce H₂O₂-induced arrhythmic activity and contractile dysfunction.

In myocytes pretreated with ranolazine, both [Na⁺]_i and [Ca²⁺]_i were found to be lower, before the addition of H₂O₂, than in untreated myocytes. Whether this observation is due to an inherent variation in the intracellular ion concentrations or to a true effect of ranolazine remains to be investigated. However, in another study of rat isolated perfused hearts in which this issue was investigated, ranolazine at a concentration of 10 µM did not lower baseline systolic or diastolic [Ca²⁺]_i (Fraser et al., 2005). Regardless, a possible explanation for the lower [Na⁺]_i and [Ca²⁺]_i in myocytes pretreated with ranolazine is that this piperazine derivative by reducing basal I_Na, albeit small in normal myocytes, could indeed reduce basal [Na⁺]_i and [Ca²⁺]_i. Evidence in support of this explanation is that ranolazine, like TTX, can cause small shortening of the APD. The net effect of ranolazine on ventricular APD depends on the relative contribution of delayed rectifier K⁺ current and late I_Na to the repolarization (Song et al., 2004).

There are potential limitations to this study. First, H₂O₂ might elevate [Na⁺]_i via enhancing Na⁺-H⁺ exchange (Sabri et al., 1998) or reducing Na⁺-K⁺-ATPase (Kim and Akera, 1987) activity. Inhibition of Na⁺-K⁺-ATPase may cause a transient prolongation of action potential (Levi, 1991). However, it is unlikely that modulation of Na⁺-K⁺-ATPase plays a significant role in H₂O₂-induced action potential prolongation and EADs, because the effect of H₂O₂ was blocked by TTX. Furthermore, ranolazine at 20 µM had no effect on the Na⁺-H⁺ exchanger in Madin-Darby canine kidney cells (CV Therapeutics, Inc., 2003).

Second, our data interpretation is dependent on the selectivity of TTX and ranolazine for Na⁺ channels. The late (persistent) I_Na is more susceptible than the peak inward I_Na to the inhibitory effect of TTX (Kiyosue and Arita, 1989; Maltsev et al., 1998). In the present study, TTX at a low concentration of 2 µM significantly attenuated H₂O₂-induced action potential prolongation and EADs, whereas it had little effect on the basal action potentials (in the absence of H₂O₂; data not shown). This result indicates that the prolongation of APD caused by H₂O₂ can be mainly attributed to an increase of late I_Na. Consistent with the findings of the present study, TTX has been shown to markedly attenuate the deleterious effects (Ca²⁺ overload, diastolic dysfunction, and so on) caused by ROS and palmitoyl-L-carnitine, known to increase late I_Na (Ver Donck and Borgers, 1991; Hara et al., 1997). Ranolazine has also been reported to be a rather selective (38-fold) inhibitor of late relative to peak I_Na (Undrovinas et al., 2006). In ventricular myocytes of dogs with chronic heart failure, ranolazine inhibited peak and late I_Na with potencies of 244 and 6.5 µM, respectively (Undrovinas et al., 2006). Ranolazine at a concentration of 10 µM has been shown to effectively attenuate anemone toxin II-induced late I_Na, prolongation of APD and formation of EADs (Song et al., 2004). Alternative explanations for the effect of ranolazine to attenuate H₂O₂-induced action potential prolongation and EADs are an inhibition of the L-type Ca²⁺ current [I_Ca(L)] and/or Na⁺-Ca²⁺ exchange current (I_Na-Ca). However, the IC₅₀ values for ranolazine to inhibit I_Ca(L) and I_Na-Ca were reported to be around 300 and 91 µM, respectively (Antzelevitch et al., 2004; Schram et al., 2004). Moreover, we found that H₂O₂ caused a decrease of I_Ca(L) in guinea pig ventricular myocytes (data not shown). Therefore, it is unlikely that putative inhibition by ranolazine of I_Ca(L), I_Na-Ca, and/or peak I_Na can explain its attenuation of the effect of H₂O₂. It is also unlikely that ranolazine reduces the effects of H₂O₂ via radical scavenging or antioxidant actions, because ranolazine does not decrease H₂O₂-induced lipid peroxidation (Matsumura et al., 1998).

In summary, block of late I_Na by TTX or ranolazine attenuates the deleterious effects of H₂O₂ on electrical and contractile functions and cellular Na⁺ and Ca²⁺ homeostasis of cardiac myocytes. The results of the present study suggest that an increase of late I_Na is a major ionic mechanism underlying the cardiac actions of H₂O₂. Reducing late I_Na may be a critical step to attenuate ROS-induced myocardial dysfunction.

	Footnotes

 
Y.S. received a research grant from CV Therapeutics, Inc. L.S.M. is funded by the Deutsche Forschungsgemeinschaft through Emmy Noether Grant MA 1982/1-4, by a Young Investigator Award of the GlaxoSmithKline Research Foundation, and by a grant from the Medical Faculty of the University of Göttingen (Anschubfinanzierung).

L.S.M. and L.B. contributed equally.

Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.106.101832.

ABBREVIATIONS: ROS, reactive oxygen species; NCX, sodium-calcium exchange(r); I_Na, sodium current; TTX, tetrodotoxin; Ran, ranolazine; APD, action potential duration; APD₅₀, duration of the action potential measured from onset of upstroke to 50% of repolarization; SBFI, sodium-binding benzofuran isophthalate; EAD, early afterdepolarization; I_Ca(L), L-type Ca²⁺ current; I_Na-Ca, Na⁺-Ca²⁺ exchange current.

Address correspondence to: Dr. Yejia Song, Division of Cardiovascular Medicine, University of Florida, 1600 SW Archer Rd., M-411, Gainesville, FL 32610-0277. E-mail: songy{at}medicine.ufl.edu

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