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CARDIOVASCULAR
Department of Physiology, Seoul National University College of Dentistry, Yeongun-Dong, Seoul, Korea (S.-Y.C.); and Departments of Microbiology (Y.-S.K.) and Physiology (S.-H.J.), Cheju National University College of Medicine, Jeju, Korea
Received November 23, 2004; accepted February 17, 2005.
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= 0.65. The block of HERG by trifluoperazine was use-dependent, exhibiting more rapid onset and greater steady-state block at higher frequencies of activation; there was partial relief of the block with decreasing frequency. In guinea pig ventricular myocytes, bath applications of 0.5 and 2 µM trifluoperazine at 36°C blocked the rapidly activating delayed rectifier K+ current by 32.4 and 72.9%, respectively; however, the same concentrations of trifluoperazine failed to significantly block the slowly activating delayed rectifier K+ current. Our findings suggest the arrhythmogenic side effect of trifluoperazine is caused by a blockade of HERG and the rapid component of the delayed rectifier K+ current rather than by the blockade of the slow component.
; Buckley and Sanders, 2000), which raises the concern that some of these deaths may be due to drug-induced arrhythmias (Reilly et al., 2000). Polymorphic ventricular arrhythmias, known as torsades de pointes, have been recorded during antipsychotic drug overdose (Raehl et al., 1985; Witchel et al., 2003). Several antipsychotic drugs are associated with the lengthening of the rate-corrected QT interval (QTc) on the electrocardiogram (ECG) (Reilly et al., 2000), which often precedes torsades de pointes (Faber et al., 1994). Trifluoperazine, a phenothiazine, is used for the treatment of schizophrenia since it can block dopamine receptors in the central nervous system, particularly the D2 subpopulation (Seeman, 1980). However, trifluoperazine induces adverse effects on the cardiovascular system, such as QTc prolongation (Reilly et al., 2000), ventricular tachycardia, torsades de pointes (Raehl et al., 1985), and sudden death (Jusic and Lader, 1994). Intentional use of this drug for suicidal purposes is also common; therefore, it is important to examine the electrophysiological mechanisms of trifluoperazine-induced arrhythmias.
Repolarization of cardiac ventricular myocytes is mainly due to outward K+ currents. One of the most important currents is the delayed rectifier cardiac K+ current, IK, which has rapidly and slowly activating components (IKr and IKs, respectively) (Sanguinetti and Jurkiewicz, 1990). Activation of IKr leads to initiation of repolarization of the cardiac action potential (Sanguinetti et al., 1995), and the human ether-a-go-go-related gene (HERG) encodes the major protein underlying IKr (Sanguinetti et al., 1995). Mutations of HERG have been shown to cause chromosome 7-linked inherited long QT syndrome (LQT2) (Curran et al., 1995), and several drugs that block IKr and HERG cause acquired LQT and torsades de pointes (Suessbrich et al., 1996, 1997). In many cases, the cardiotoxicity of numerous drugs can be solely attributed to their interaction with the HERG K+ channel (Taglialatela et al., 1998). Another component of the delayed rectifier K+ channel, IKs, is also responsible for terminating the plateau phase of the action potential-like IKr (Sanguinetti and Jurkiewicz, 1990). The gene coding IKs was identified from positional cloning studies that identified mutations in the most common congenital form of LQT (LQT1) (Wang et al., 1996).
Phenothiazines were reported to delay repolarization by prolonging phase 3 of the action potential (Arita and Surawicz, 1973) and to produce ECG abnormalities, such as QTc prolongation (Lathers and Lipka, 1987). This raises the possibility that trifluoperazine, a phenothiazine, may prolong APD in vivo and cause LQT by inhibiting IKr, the HERG channel, or IKs, eventually resulting in torsades de pointes and sudden death. In this study, we used the HERG channel expressed in Xenopus oocytes to test whether trifluoperazine would block the HERG channel. To confirm the hypothesis, we also measured native IKr in guinea pig ventricular myocytes. Finally, we tested whether the drug could change the slow component of the delayed rectifier K+ current, IKs.
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Materials and Methods |
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Solutions and Voltage-Clamp Recording from Oocytes. Normal Ringer solution contained 96 mM NaCl, 2 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, and 10 mM Hepes (pH adjusted to 7.4 with NaOH). The antipsychotic drug trifluoperazine and all salts were purchased from Sigma-Aldrich. Stock solution of trifluoperazine was made up in distilled water and then added to the external solutions at suitable concentrations shortly before the experiment. Solutions were applied to the oocyte by continuous perfusion of the chamber during recording. Solution exchanges were completed within 3 min, and the HERG current was recorded after 5 min, when the solution exchange was completed. We examined the effects of several concentrations of trifluoperazine on the HERG current after observing the reversibility of current by washing with normal Ringer solution. It took about 10 min for the washout of 
10 µM drug and about 20 min for the washout of 
20 µM drug. We rejected the oocyte if it did not recover after 30 min of washing with normal Ringer. Usually, four to six concentrations of trifluoperazine were examined in one oocyte. Currents were measured at room temperature (21–23°C) with a two-microelectrode voltage-clamp amplifier (Warner Instruments, Hamden, CT). Electrodes were filled with 3 M KCl and had a resistance of 2 to 4 M
for voltage-recording electrodes and 0.6 to 1 M for current-passing electrodes. Stimulation and data acquisition were controlled with Digidata and pCLAMP software (Axon Instruments Inc., Union City, CA). Data were expressed as mean values ± S.E.M.
The fractional electrical distance (), i.e., the fraction of the transmembraneous electrical field sensed by a single positive charge at the binding site, was determined with half-blocking concentrations (KD) obtained from the fractional current (fo) as the current with 20 µM trifluoperazine and under control conditions at the end of the voltage step with the equation KD = (fo/(1 – fo)) x 20 (in µM). The value of was obtained by fitting the KD values with the equation KD = KD 0mV x exp(–zFV/RT), where KD 0mV represents the half-blocking concentration at the reference potential of 0 mV. V represents the membrane potential, and z, R, F, and T have their usual meanings (Snyders et al., 1992).
Solutions and Voltage-Clamp Recording from Guinea Pig Ventricular Myocytes. Single ventricular myocytes were isolated from each guinea pig heart by a standard enzymatic technique (Jo et al., 2000). Isolated cells were superfused at 36°C with a normal Tyrode's solution, which contained 140 mM NaCl, 4.4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 5 mM Hepes, and 10 mM glucose (pH 7.4 with 4 M NaOH). Inward rectifier K+ currents were inhibited by adding 5 mM CsCl to the normal Tyrode's solution. The patch pipette (outer diameter 1.5 mm; World Precision Instruments, Inc., Sarasota, FL) had resistances around 1 to 2 M. The pipette solution for the potassium current measurement contained 140 mM KCl, 1 mM MgCl2, 5 mM EGTA, 5 mM MgATP, 2.5 mM diTris-phosphocreatine, and 2.5 mM disodium phosphocreatine (pH 7.4 with KOH). The "pipette-to-bath" liquid junction potential was small (–3.5 mV) and was uncorrected. Membrane capacitance (the time integral of the capacitive response to a 10-mV hyperpolarizing pulse from a holding potential of 0 mV, divided by the voltage drop) averaged 121.5 ± 24.5 pF (n = 10). Measurements were made using an Axopatch 200A amplifier (Axon Instruments Inc.) and a CV-201 headstage. Voltage-clamp commands were generated using "WinWCP" (John Dempster, Strathclyde University, Glasgow, Scotland) or pClamp (version 5.1; Axon Instruments). The current signals were filtered via a 1- to 10-kHz, eight-pole Bessel-type low-pass filter and digitized by an AD/DA converter (Digidata 1200; Axon Instruments Inc.) for subsequent analysis (pCLAMP software 6.0.3). All chemicals were from Sigma-Aldrich except E-4031, which was kindly provided by Eisai Co., Ltd (Tokyo, Japan).
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After the depolarizing steps, repolarization to –60 mV induced outward Itail; its amplitude was even larger than the amplitude of IHERG observed during depolarization. This is a characteristic property of HERG current, and it is known to be due to the rapid recovery from inactivation and slow deactivation mechanism (Sanguinetti et al., 1995). The amplitude of Itail increased with depolarizing steps from –60 to +10 mV and was then superimposed on further depolarizing steps to +40 mV. When 10 µM trifluoperazine was added to the perfusate, not only IHERG but also Itail was suppressed, as shown in the bottom panel of Fig. 1A. The amplitude of Itail was normalized to the peak amplitude obtained in the control condition at a maximum depolarization and was plotted against the potential of the step depolarization (Fig. 1C). The normalized Itail reflects a voltage-dependent activation of the HERG channels. Data obtained in control conditions were well fitted by the Boltzmann equation with half-maximal activation (V1/2) at –20.8 mV. When the concentration of trifluoperazine increased, the peak Itail amplitude decreased, indicating the maximum conductance of HERG channels is decreased by trifluoperazine. Also, note that in the presence of trifluoperazine, Itail does not reach the steady-state level but declines with more positive potentials, indicating the blocking effect is more pronounced at more positive potentials.
This result may suggest that the effect of trifluoperazine is voltage-dependent. We tested this possibility by comparing the decrease of Itail by trifluoperazine at different potentials (Fig. 2). Indeed, a higher degree of blockade was present at more positive voltages (Fig. 2A). At –40 mV, 20 µM trifluoperazine reduced the amplitude of normalized Itail by 46.6% (from 0.07 ± 0.02 to 0.04 ± 0.01; n = 7, P < 0.05), whereas at +40 mV it reduced the amplitude of normalized Itail by 68.4% (from 1.00 ± 0.01 to 0.32 ± 0.05; n = 7, P < 0.05). Dose-response relationships were obtained at +40 mV and –40 mV and are plotted in Fig. 2B. Data were fitted by Hill equations, and IC50 values for trifluoperazine blockade of HERG current were obtained at different membrane potentials. IC50 values at –40, 0, and +40 mV were 21.6, 16.6, and 9.29 µM, respectively (n = 7). These results indicate that the trifluoperazine block of HERG current exhibits voltage dependence.
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For further analysis, the relative current under 20 µM trifluoperazine was calculated for each potential (Fig. 3, filled squares; n = 7). The relative currents with the drug, as fractions of the control current, were found to decrease steadily with positive trending potentials and from 0.534 ± 0.089 at –40 mV reached 0.316 ± 0.054 at +40 mV (n = 7, P < 0.05). The voltage dependence of the block was fitted with a monoexponential function (Fig. 3, solid line). Since the relative conductance of the HERG control current reached more than 90% of its maximal value at potentials positive to 0 mV (Fig. 3, dashed line; mean open probability at 0 mV obtained by Boltzmann fit, 0.91), the range between 0 and +40 mV was taken to estimate the fractional electrical distance (), i.e., the fraction of the transmembranous electrical field sensed at the receptor site of trifluoperazine. From the fraction of control current achieved with trifluoperazine, half-blocking concentrations (KD) were calculated. Fitting the mean KD values in the potential range from 0 to +40 mV with the mean KD at the reference potential of 0 mV (KD 0mV = 20.6 µM) yielded a fractional electrical distance of = 0.65.
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In addition to the voltage dependence of the trifluoperazine effect, a time-dependent block was found. We activated currents using a protocol with a single depolarizing step to 0 mV for 8 s (Fig. 4A). After having obtained the control measurement, we applied 10 µM trifluoperazine and then recordings with the drug were performed. Analysis of the test pulse after trifluoperazine application revealed a time-dependent increase of block to 44% at 1700 ms in a representative cell (Fig. 4A). The fractional sustained current (obtained by normalizing the currents with trifluoperazine to the control currents) decreased with ongoing depolarization (Fig. 4B). The fractional current at the beginning of the pulse was 0.928 ± 0.053 of the control and declined to 0.531 ± 0.074 after 2 s at a test potential of 0 mV (Fig. 4B; n = 6), thus indicating that HERG channels are only slightly blocked by trifluoperazine while remaining at the holding potential.
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Next, we examined the use dependence of the trifluoperazine effect (Fig. 5). To analyze this, HERG channels were activated by 0.5-s depolarizing steps to +30 mV at intervals of 3, 12, or 36 s in the presence of 5 µM trifluoperazine (n = 8). Figure 5A shows that the time course of the channel blockade is dramatically dependent on the activation frequency; HERG-blockade by trifluoperazine occurred much faster at higher activation frequency. In Fig. 5B, the data shown in Fig. 5A were plotted as a function of the number of test pulses. After the same number of test pulses, the block by 5 µM trifluoperazine was stronger at high activation frequency than at lower activation frequency, indicating favored binding of the drug at higher frequency. In additional experiments, the steady-state HERG channel block by trifluoperazine was initially obtained with depolarization at 3-s intervals (Fig. 5C). Subsequent increase of the depolarization intervals to 36 s resulted in a partial relief of the HERG channel blockade (n = 5). These results indicate that the blockade of HERG channels by trifluoperazine is strongly use-dependent.
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In further experiments, we tested the effect of trifluoperazine on the rapid and slow components of delayed rectifier in guinea pig ventricular myocytes at 36°C using electrophysiological separation of the currents with a voltage-clamp protocol (Carmeliet, 1992; Heath and Terrar, 1996) shown in the inset of Fig. 6A (stimulation frequency of 0.03 Hz). Depolarization to +40 mV activates both IKr and IKs, and repolarization to –10 mV revealed IKs as deactivating Itail, whereas subsequent repolarization to –50 mV showed the deactivation of IKr. We confirmed that 2 µM E-4031, a selective blocker of IKr (Sanguinetti and Jurkiewicz, 1990), blocked the rapid component of delayed rectifier K+ current; however, it did not change IKs (n = 9, Fig. 6B). As shown in Fig. 6, A and B, 0.5 and 2 µM trifluoperazine dose-dependently inhibited IKr by 32.4 ± 6.10 and 72.9 ± 3.23%, respectively (n = 12–21; P < 0.05), suggesting native IKr is more sensitive to the drug than the HERG channel expressed in Xenopus oocytes, considering that the IC50 value for the HERG channel blockade was about 10 µM. However, 0.5 and 2 µM trifluoperazine did not block IKs significantly (n = 12–21) in our experimental condition (e.g., 36°C). This result shows that trifluoperazine preferentially blocked the rapid component of delayed rectifier K+ current rather than the slow component, suggesting that trifluoperazine may prolong APD primarily by blocking IKr and not IKs.
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In addition, we tested the effects of trifluoperazine on the activation curve of IKr using a voltage protocol that requires only short depolarization steps and allows the recording of the current-voltage relationship for IKr deactivating at –40 mV (Fig. 7A, inset) (Sanguinetti and Jurkiewicz, 1990; Heath and Terrar, 1996). To prevent possible contamination by IKs, we treated each myocyte with 2 µM E-4031 after trifluoperazine experiments and then used the E-4031-sensitive component for data analysis by subtracting the amplitude of E-4031-insensitive tail current from that obtained in the absence or presence of trifluoperazine (Fig. 7A). Trifluoperazine at 0.5 µM significantly reduced IKr only at prepulses positive to 0 mV; however, 2 µM trifluoperazine significantly inhibited the current at all prepulses (n = 5–7; Fig. 7B). Also, the degree of blockade increased with more positive voltages; 2 µM trifluoperazine blocked IKr at –30 and +30 mV by 53.6 ± 2.51 and 80.4 ± 1.94%, respectively (n = 5–7, P < 0.05; Fig. 7B). The results show that a higher degree of blockade was present at more positive voltages, which is consistent with the data from the HERG channel.
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) and by the antiarrhythmic drug BRL-32872 (Thomas et al., 2001) gave IC50 values that were 10- to 20-fold higher when the drug was applied to the bath compared with the application of the drug to the internal membrane surface in inside-out patches. One possible explanation for this observation is that the vitelline membrane and yolk reduce the concentration of drugs at the cell membrane.
In patients using trifluoperazine, the plasma concentration of the drug was estimated to be in the range of 10–7 and 10–6 M in therapeutic use (Buckley and Sanders, 2000). Trifluoperazine was shown to be toxic at 0.5 to 10 µM in the myocardium (Hull and Lockwood, 1986) and 25 µM in T-lymphocytes (Stavitsky et al., 1984). In cases of sudden unexpected death, the postmortem blood concentration of trifluoperazine was 0.1 and 2 µM (Jusic and Lader, 1994), and the use of antipsychotic drugs in therapeutic doses has been associated with sudden death (Kelly et al., 1963). The drug is metabolized through an oxidative process mediated by hepatic cytochrome P450 microsomal oxidase and by conjugation processes with an elimination half-life of 
18 h (Ereshefsky, 1996). However, the half-life may be prolonged in patients with hepatic disease and renal insufficiency (Buckley and Sanders, 2000). Our results demonstrated that trifluoperazine blocked the HERG channel with an IC50 value of 9.29 µM (at +40 mV) and IKr of mammalian cardiomyocytes at a value of 1 µM, which is a similar level to the serum concentration under normal conditions (Buckley and Sanders, 2000) and to the postmortem drug concentration of sudden death (Jusic and Lader, 1994). Furthermore, we observed that trifluoperazine inhibited the Itail of the HERG channel stably expressed in HEK cell (Zhou et al., 1998) dose-dependently, and the result gives us IC50 value of 0.23 µM(n = 4, data not shown), suggesting that serological levels of the drug can inhibit HERG currents. Therefore, the present study strongly indicates that the blockade of HERG current may underlie the proarrhythmic effect of trifluoperazine in psychiatric patients, like LQT and torsades de pointes, which could induce sudden death.
Several drugs that cause acquired LQT and torsades de pointes also have been shown to block the HERG channel in a voltage-dependent manner, suggesting that the drugs bind to the open or inactivated state of HERG channels. Haloperidol, an antipsychotic drug (Suessbrich et al., 1997), and two histamine receptor antagonists, terfenadine and astemizole (Suessbrich et al., 1996), have been known to bind the inactivated-state of HERG preferentially. In contrast, a gastrointestinal prokinetic agent, cisapride has been shown to block the channel in its open state (Rampe et al., 1997). In the present study, the amount of block increased with more positive voltages, which increase the open probability and enhance the inactivation (Figs. 1, 2, and 3). Also, the fraction of block was very low at the beginning and increased with the duration of the voltage step (Fig. 4), suggesting the channel was not blocked in the resting state at hyperpolarized potentials but during opening at depolarization. Therefore, these voltage and time dependences of the trifluoperazine block support that the drug preferentially blocks HERG channels either in the open state or in the inactivated state.
It is possible that trifluoperazine could prolong APD by blocking not only the rapid component of delayed rectifier K+ current but also the slow component, because Herzer et al. (1994) reported that trifluoperazine blocked human depolarization-activated very slowly activating voltage-gated K+ current (IsK) expressed in Xenopus oocytes with an EC50 value of 76.9 µM. The guinea pig IsK protein has been suggested to underlie the K+ conductance of IKs in guinea pig cardiomyocytes due to its electrophysiological and pharmacological properties, characteristic of IKs (Varnum et al., 1993). The present study shows that trifluoperazine inhibited E-4031-sensitive IKr current and the expressed major component of IKr, HERG. However, the drug did not reduce IKs significantly even at 2 µM (Fig. 6), suggesting that trifluoperazine preferentially blocked the rapid component of delayed rectifier K+ current rather than the slow component in our condition. It is still possible that cardiac arrhythmia by trifluoperazine is due to other K+ channels, such as the inward rectifier K+ channel or the transient outward K+ channel, which are important channels determining cardiac APD. The possible effect of the drug on each molecular equivalent of various K+ channels other than HERG awaits future investigation.
The present study showed that trifluoperazine blocks HERG and possibly IKr more at positive voltage and at high frequency, which may not be consistent with reverse use-dependent repolarization lengthening by other IKr blockers in cardiac cells. Reverse use dependence has been implicated in the bradycardia-dependent proarrhythmic effects of various class III antiarrhythmic agents, and this effect has been demonstrated with various IKr blocking agents, including E-4031, dofetilide, sotasol, and [(4-methylsulfonyl)amido]-benzenesulfonamide (Hondeghem and Snyders, 1990). The possibility trifluoperazine prolongs action potential duration of cardiomyocytes in a frequency-dependent manner should be examined in future investigation.
Our present study suggested that trifluoperazine directly inhibited the HERG channel and IKr, possibly resulting in prolongation of APD and cardiac arrhythmia. This hypothesis of the drug's direct action on myocardiac channels in sarcolemma can be supported by the study showing that phenothiazine-induced arrhythmia and death were not produced via the central nervous system (Lipka et al., 1988). Also, it can be speculated that many effects of trifluoperazine on channels are due to nonspecific membrane effects such as general perturbation of membrane proteins because trifluoperazine changes the membrane fluidity (Minetti and Di Stasi, 1987). However, those studies have shown the drug increased the freedom of membrane lipid motion, which would be related to phenothiazine-induced toxic cardiomyopathy (Hull and Lockwood, 1986) rather than inhibition of IKr or HERG by trifluoperazine. Also, the concentration used in this study was lower than those associated with nonspecific membrane effects (Weiss et al., 1982). Therefore, it is likely that trifluoperazine interacts directly with the HERG channel proteins or HERG channel-relating structure.
In summary, the present study shows that an antipsychotic drug, trifluoperazine, at near-physiological levels, blocks the HERG channel and IKr but not IKs of guinea pig cardiomyocytes, suggesting that the drug-induced arrhythmia observed in psychiatric patients would be due to, at least in part, inhibition of IKr.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: QTc, rate-corrected QT interval; IKr, rapidly activating delayed rectifier K+ current; IKs, slowly activating delayed rectifier K+ current; HERG, human ether-a-go-go-related gene; LQT, long QT syndrome; APD, action potential duration; Itail, tail current(s); IHERG, current at the end of voltage step; E-4031, (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)-piperidine); BRL-32872, N-(3,4-dimethoxyphenyl)-N-[3[2-(3,4-dimethoxyphenyl)ethyl]propyl]-4-nitrobenzamide hydrochloride; TFZ, trifluoperazine.
Address correspondence to: Su-Hyun Jo, Department of Physiology, Cheju National University College of Medicine, Ara 1-Dong, Jeju 690-756, Korea. E-mail: shjo{at}cheju.ac.kr
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), 12 (
), and 36 s (
), respectively. B, the HERG channel blockade data from A were plotted against the number of test pulses. C, steady-state HERG channel blockade by 5 µM trifluoperazine after 16 pulses at 3-s intervals (
) resulted in a partial relief, and changing back to 3-s intervals increased the HERG channel blockade again. Symbols with error bars in A and B represent mean ± S.E.M.; each data point was obtained from eight cells. Symbols in C are representative of five experiments.
