There is growing concern that antipsychotic drugs that prolong the QT interval almost always increase the risk for patients to develop life-threatening ventricular tachyarrhythmias (VTs) of the torsade de pointes type. We therefore sought to compare the electrophysiologic effects of the psychotropic agent sertindole, which prolongs cardiac repolarization by inhibiting the rapid component of the delayed rectifier potassium current (I Kr) but has a low torsadogenic potential to the antiarrhythmic agent dl-sotalol. In 18 Langendorff-perfused rabbit hearts, sotalol (10 μM,n = 8) and sertindole (0.5, 1.0, and 1.5 μM;n = 10) led to significant and comparable QT prolongation. In the presence of sotalol, torsade de pointes reproducibly occurred in atrioventricular node-blocked hearts after lowering the potassium concentration to 1.5 mM. High doses of sertindole (1.5 μM) only caused monomorphic VT (n= 4) and nonsustained polymorphic VT (n = 2) in the presence of QRS prolongation. Multiple simultaneous epi- and endocardial monophasic action potentials and a volume-conducted ECG demonstrated widening of the T/U wave, early afterdepolarizations, and increased dispersion of repolarization in the presence ofdl-sotalol. In contrast to sotalol, QT and monophasic action potential prolongation were cycle length-independent in the presence of sertindole. Sertindole had no significant effect on transmural or interventricular dispersion of repolarization. Early afterdepolarizations did not occur. Despite comparable QT prolongation, sertindole did not display the proarrhythmic profile typical of other blockers of I Kr such asdl-sotalol. It is likely that a different mode of interaction between sertindole and the channel and/or additional pharmacological effects of sertindole, e.g., its ability to inhibitI Na and/or its ability to block α1-receptors, play a role.
QT interval prolongation is a risk factor in a number of cardiovascular as well as noncardiovascular diseases. In the congenital long QT syndrome (LQTS), prolongation of the QT interval is associated with recurrent syncope and sudden cardiac death. Both result from potentially fatal arrhythmias, known as torsade de pointes (TdP). The occurrence of this particular form of ventricular tachyarrhythmia (VT) is not restricted to patients with LQTS. The most common cause of such proarrhythmia seems to be administration of antiarrhythmic drugs that prolong the action potential, i.e., the so-called class IA and class III antiarrhythmic agents (Haverkamp et al., 2000). The incidence of TdP in patients treated with quinidine (class IA) has been estimated to range between 1 and 4% (Selzer and Wray, 1964; Roden et al., 1986). For dl-sotalol, an incidence ranging between 1.8 and 4.8% has been reported (Lehmann et al., 1996; Haverkamp et al., 1997). A similar incidence has been seen for newer class III agents, e.g., dofetilide and ibutilide (Hohnloser and Singh, 1995; Chen et al., 1999). All these drugs have in common the fact that they block the rapidly activating component of the delayed rectifier potassium currentI Kr (Haverkamp et al., 2000). QT prolongation and TdP have been reported to occur secondary to treatment not only with antiarrhythmic drugs, but also with several drugs not generally thought to have significant effects on myocardial repolarization (e.g., antidepressants and other psychotropic drugs; antihistamines such as terfenadine and astemizole; some antibiotics, particularly macrolide antibiotics and some quinolones; and the promotility agent cisapride) (Haverkamp et al., 2000). Estimation of the true incidence of TdP during treatment with noncardiovascular drugs is difficult. For several noncardiovascular drugs that have been involved in the generation of TdP, only a few case reports are available. This is also true for sertindole, as well as for other new antipsychotics. For sertindole, most of the reported cases have occurred either in overdose or in combination with other drugs known to be associated with TdP. The occurrence of TdP secondary to a repolarization-prolonging drug is not a drug-specific but rather a patient-specific response. Patients with TdP typically show excessive, abnormal drug-induced prolongation of repolarization. Thus, the arrhythmia does not occur when drug-induced prolongation of repolarization is within the “normal” range. However, this does not necessarily mean that the individual patient will always show abnormal QT prolongation and TdP during exposure to repolarization-prolonging stimuli. This becomes obvious when considering the highly variable intervals between the initiation of drug therapy and the occurrence of TdP reported in the literature. The mechanisms responsible for these phenomena are not well understood. It has been suggested that a reduced “repolarization reserve”, i.e., a lowered threshold for the development of abnormal QT prolongation and TdP upon challenge with a drug that lengthens myocardial repolarization may play a role (Roden, 1998). In addition, in some patients with TdP, the presence of a “forme fruste” of the LQTS has been reported (Abbott et al., 1999).
Sertindole (5-chloro-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)-ethyl]-4-piperidyl]-1H-indole) is a new indolylpiperidine antipsychotic agent, which has nanomolar affinities for dopamine D2, serotonin 5-HT2, and α1-adrenergic receptors (Zimbroff et al., 1997; Arnt and Skarsfeldt, 1998). Together with risperidone, ziprazidone, quetiapine, pimozide, and olanzapine, sertindole belongs to the group of newer antipsychotic drugs that have been considered to exhibit both a greater antipsychotic efficacy than previously available agents and fewer extrapyramidal effects (Ereshefsky, 1996; Leucht et al., 1999). However, clinical (van Kammen et al., 1996) as well as experimental data (Drici et al., 1998) show that sertindole, as do other newer antipsychotics, may prolong myocardial repolarization and, in individual patients, cause ventricular proarrhythmia of the TdP type. This has raised concerns regarding the benefit/risk profile of sertindole and led to a temporary market suspension in 1998. H. Lundbeck A/S (Copenhagen, Denmark), the company producing sertindole, has consistently argued that there is no increased cardiac or all-cause mortality for patients treated with sertindole. These arguments are based on epidemiological studies, including comparative cohort studies, in more than 8500 patients after the initial approval. A recent comparative postmarketing surveillance study on sertindole and two other atypical antipsychotics, risperidone and olanzapine, showed no statistically significant differences in mortality rates between sertindole and comparator cohorts (Pezawas et al., 2000; Wilton et al., 2001). Due to the temporary suspension, the sertindole cohort was, however, too small to make firm conclusions on its proposed low proarrhythmic potential. The regulatory authorities in Europe are now reviewing available data to reach a final decision regarding its availability on the market.
To better understand the electrophysiologic effects of sertindole and its suggested low torsadogenic potential, we compared the electrophysiologic effects of sertindole to those of the antiarrhythmic agent dl-sotalol. As an experimental model we chose the isolated Langendorff-perfused rabbit heart. In this model, our group has previously demonstrated a high degree of proarrhythmia with drugs that are also clinically known to be torsadogenic, such as sotalol or erythromycin (Eckardt et al., 1998b).
Materials and Methods
Preparation of Hearts for Perfusion.
The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (National Institutes of Health Publication 85-23, revised 1996). The rabbit heart model of TdP used in the present study has previously been described in detail (Eckardt et al., 1998b). In brief, male New Zealand White rabbits (n = 18) weighing 2.5 to 3.0 kg were anesthetized with sodium thiopental (100 mg, i.v.) and sacrificed by cervical dislocation. After midsternal incision, the hearts were removed and immediately placed in an ice-cold Krebs-Henseleit solution (1.80 mM CaCl2, 4.70 mM KCl, 1.18 mM KH2PO4, 0.83 mM MgSO4, 118 mM NaCl, 24.88 mM NaHCO3, 2.0 mM sodium pyruvate, and 5.55 mMd-glucose). The aorta was cannulated, and the hearts were retrogradely perfused at constant flow (52 ml/min) with warm (36.8–37.2°C) Krebs-Henseleit solution. The perfusate was equilibrated with 95% O2 and 5% CO2 (pH 7.35; 37°C). The cannulated and perfused hearts were attached to a vertical Langendorff apparatus (Hugo Sachs Elektronik, Medical Research Instrumentation, March-Hugstetten, Germany). The atrioventricular (AV) node was ablated to slow the intrinsic heart rate. This resulted in complete AV dissociation with a ventricular escape below 60 beats per min.
Electrocardiographic and Electrophysiologic Measurements.
ECG recording and QT measurements were performed as described previously (Eckardt et al., 1998b, 2000). A volume-conducted ECG was recorded by complete immersion of the heart into a bath of Krebs-Henseleit solution that had been thermally equilibrated with the myocardial perfusate. Signals from a simulated “Einthoven” configuration were amplified by a standard ECG amplifier (filter settings: 0.1–300 Hz).
Monophasic action potential (MAP) recording and stimulation were accomplished simultaneously using contact MAP-pacing catheters (EP Technologies, Mountain View, CA). The MAP electrograms were amplified and filtered (low pass 0.1 Hz, high pass 300 Hz). MAPs were analyzed using software specifically designed by Franz et al. (1995), permitting precise definition of the amplitude and duration of the digitized signals. The recordings were considered reproducible and, therefore, acceptable for analysis only if they had a stable baseline, stable amplitude with a variation of less than 20%, and a stable duration [MAP duration at 90% repolarization (APD90) was reproducible within 4 ms]. MAPs were recorded simultaneously from up to eight sites. Up to seven MAPs were evenly spread in a circular pattern around both ventricles. In addition, one left endocardial MAP was recorded. The endocardial catheter was used to pace the preparation. Early afterdepolarizations (EADs) were defined as an interruption of the smooth contour of phase 2 or 3 of the action potential.
Pacing at twice diastolic threshold was performed for 2 min at each cycle length (CL) from 900 to 300 ms using a Universal programmable stimulator (UHS 20; Biotronik, Berlin, Germany), which delivered square-wave pulses of 2-ms pulse width. All data were digitized at a rate of 1 kHz with 12-bit resolution and subsequently stored on a removable hard disk (BARD LabSystem Duo; Bard Electrophysiology, Murray Hill, MA).
After placing the MAP catheters and achieving complete AV block, CL dependence was first investigated under baseline conditions. Thereafter, sertindole (H. Lundbeck A/S, Copenhagen, Denmark; 0.5, 1.0, and 1.5 μM), or dl-sotalol (Knoll, Ludwigshaven, Germany; 10 μM) was infused through a side port positioned just above the aorta by a peristaltic pump. The clinical therapeutic concentration of sertindole is 100 to 200 nM. The plasma protein binding of sertindole is 99%, and the concentrations studied were thus several multiples higher than the expected free plasma concentration in patients. The lower dose of 0.5 μM sertindole reflects the fact that sertindole, like other basic amines such as quinidine, accumulates in heart tissue with a factor of 5 to 10 to the total plasma concentration at steady-state conditions (Yata et al., 1990). For sertindole, an accumulation in myocardial tissue with a tissue to plasma ratio of 5 to 10 has been confirmed in Lundbeck toxicological studies with sertindole in rats and dogs (H. Lundbeck, A/S, Copenhagen, Denmark, personal communication). Sotalol, a class III antiarrhythmic drug, was used to create a model of drug-induced LQTS. It has been reported to induce TdP in several experimental studies (Eckardt et al., 1998a). The concentration of 10 μM was chosen as a high therapeutic concentration (considering the plasma protein binding) (Eckardt et al., 1998b).
The experimental setup was designed to reproduce conditions and circumstances that are clinically known to be associated with an increased propensity to the development of TdP (i.e., severe bradycardia resulting from complete AV block and hypokalemia). Pacing, MAP recording, and measurement of ECG parameters were repeated after drug infusion. Thereafter, the potassium concentration was lowered to 1.5 mM to increase the proarrhythmic milieu. Five minutes later, the potassium concentration was again increased to 5.8 mM, the drug concentration of sertindole was thereafter increased to the next dosage, and pacing was repeated. Again, this was followed by lowering the potassium concentration for 5 min. The latter two steps were repeated for each drug concentration.
Data Acquisition and Statistical Analysis.
ECG, pressure, volume, and MAPs were recorded on a multichannel recorder. Data were digitized online at a rate of 1 kHz with 12-bit resolution and stored on a disk. All data are presented as mean ± S.D. The influence of each drug on ECG parameters and MAP duration, as well as dispersion of repolarization (estimated as the maximal difference of the simultaneously recorded MAP durations), were assessed using a paired and unpaired t test. Analysis of variance was used to investigate cycle length dependence. A value of p < 0.05 was the criterion for statistical significance.
Dose-Dependent Effects of Sertindole and Sotalol on QT Interval and Action Potential Duration.
All electrocardiographic parameters reached equilibrium within 10 min after AV block. MAP recordings and pacing thresholds (mean threshold 1.6 ± 1.4 mA) remained highly reproducible throughout the experimental protocol. In the presence of sertindole, there was a slight increase in pacing thresholds (mean threshold 1.9 ± 1.4 mA, p = N.S.). After an initial stabilization period of approximately 5 to 10 min, the MAP amplitude did not change by more than 20% for the subsequent investigation period.
Figure 1 illustrates the dose-dependent effect of sertindole on QT interval. Sertindole in concentrations ≥ 1.0 μM significantly prolonged the QT interval (p= 0.003). In the presence of 1.5 μM sertindole, the increase ranged between 17% at a CL of 900 ms and 15% at a CL of 300 ms. These rate-independent changes in the QT interval were closely approximated by changes in endocardial as well as epicardial APD90 (Fig. 2). No significant effects of 0.5 and 1.0 μM sertindole on QRS duration were observed. In the presence of high doses of sertindole (1.5 μM), there was a trend to QRS prolongation (from 70 ± 12 ms at baseline to 92 ± 18 ms, p = N.S.). Of note, QRS prolongation reached statistical significance in the four hearts (mean QRS 102 ± 12 ms as compared with 75 ± 8 ms at baseline;p < 0.05), which developed sustained monomorphic VT (see Induction of Arrhythmias).
The increase in QT interval with 1.0 and 1.5 μM sertindole was comparable to that observed with 10 μM sotalol (Fig.3). However, sotalol demonstrated marked CL dependence. The increase in QT interval with sotalol ranged between only 6% at a CL of 300 ms and 14% at 900 ms (p < 0.05). For both drugs the increase in QT interval was paralleled by a dose-dependent increase in APD90. For sertindole, the mean increase at a CL of 900 ms ranged between 7 and 18% for 0.5 μM and 1.5 μM, respectively (Fig. 2). In accordance with the QT interval, the increase in MAP duration was also CL-independent. Epicardial and endocardial MAP recordings demonstrated a comparable increase in APD90 (Fig. 2). In contrast, 10 μM sotalol showed a CL-dependent increase in APD90(Fig. 3). In the presence of sotalol, the endocardial MAP recordings showed the largest increase in MAP duration. It ranged between 8% at a CL of 300 ms to 21% at a CL of 900 ms (p = 0.01).
Induction of Arrhythmias.
No sustained arrhythmias were observed in the presence of 0.5 and 1.0 μM sertindole in the AV-blocked normokalemic (5.8 mM KCl) rabbit hearts. In 5 of the 10 hearts, spontaneous ventricular premature beats were observed that often occurred in a bigeminal pattern (Fig.4A). One of these hearts also demonstrated an episode of nonsustained monomorphic ventricular tachycardia. This episode did not show the typical characteristics of TdP (including the polymorphic nature of the arrhythmia with undulating QRS complexes). After increasing the sertindole concentration to 1.5 μM, 4 of 10 hearts (those demonstrating significant QRS prolongation; see above) developed nonsustained monomorphic ventricular tachycardia (mean cycle length 280 ms). Lowering potassium concentration to 1.5 mM resulted in the occurrence of nonsustained monomorphic VT in all hearts studied (Fig. 4B). However, only 2 of 10 animals showed arrhythmias of polymorphic character (Fig. 4C).
In the same model, sotalol displayed high torsadogenic potency. No arrhythmias occurred during infusion of sotalol. When the potassium concentration was lowered, six of eight hearts reproducibly developed premature ventricular extrasystoles and nonsustained episodes of TdP (Fig. 5). The average CL of TdP was 240 ms. The occurrence of TdP was accompanied by a marked increase in T-wave amplitude with broad T/U-wave complexes (Fig. 5A).
Early Afterdepolarizations and Dispersion of Repolarization.
In the presence of sotalol, EADs and triggered activity were a frequent finding (Fig. 5). Seven hearts (88%) showed MAP recordings with EADs in the presence of low potassium. EADs mainly occurred on endocardial recordings. The occurrence of EADs and triggered activity was associated with a significant CL-independent increase in dispersion of repolarization (Fig. 3C). The mean increase in transmural APD90 dispersion measured 62 ms. For sotalol, the increase of APD90 dispersion was more a transmural than an interventricular phenomenon. It was to a large extent based on the effect of sotalol on the endocardial APD90. In contrast, with sertindole there was no significant effect on APD dispersion (Fig.6). In the presence of sertindole, the increase in APD was homogeneous. Compared with sotalol, sertindole did not significantly increase transmural APD dispersion at any rate. Even a high concentration of 1.5 μM sertindole demonstrated no significant increase in APD90 dispersion (Fig. 6D). This was paralleled by a more moderate effect on the endocardial MAP duration as compared with sotalol. In addition, few endocardial MAP recordings (2 in 10 hearts, 1.5 mM KCl) demonstrated humps in the late phase of repolarization that only resembled EADs but never did give rise to triggered activity or nonsustained polymorphic VT.
Sertindole belongs to the new generation of antipsychotics that have led to significant improvements in the treatment of schizophrenia. However, clinical studies have shown that sertindole, as well as the other members of this group of drugs (e.g., risperidone, ziprazodine, haloperidol, olanzapine, and clozapine) may affect cardiac repolarization, i.e., induce prolongation of the QT interval (van Kammen et al., 1996). Although extremely rare, in individual patients proarrhythmia of the TdP type resulting from abnormal drug-induced prolongation of myocardial repolarization has been reported for antipsychotics (Kiriike et al., 1987; Hunt and Stern, 1995;Krahenbuhl et al., 1995; Jackson et al., 1997).
The principal finding of our study is that the pattern by which sertindole affects repolarization differs from that of the typical class III antiarrhythmic agent sotalol. This observation may lead to a better understanding of the low proarrhythmic potential of several drugs, such as sertindole, that prolong the QT interval but only rarely result in TdP. Although we found comparable QT prolongation between sertindole and dl-sotalol, sertindole displayed no significant inverse use dependence. EADs did not occur in the presence of sertindole, and compared with sotalol there was no increase in transmural or interventricular dispersion of repolarization. Thus, in contrast to the I Kr blocker sotalol, channel block produced by sertindole seems to be less torsadogenic.
Effects of Sertindole on Myocardial Repolarization.
The major mechanism by which sertindole induces prolongation of myocardial repolarization has been considered to be inhibition ofI Kr. In studies that assessed the effects of sertindole on human I Kr the IC50 varied between 12.6 and 64 nM, depending on the experimental conditions (Rampe et al., 1998; Maginn et al., 2000). In a comparative study, I Kr(HERG) was also blocked by haloperidol, risperidone, olanzapine, ziprazidone, and pimozide with IC50values of 28, 163, 181, 152, and 49 nM, respectively (Crumb and Cavero, 1999). However, the IC50 measured in vitro should not be considered as an absolute criterion for estimation of drug potency. Extrapolation of in vitro drug concentrations to in vivo conditions is extremely difficult. Many factors control drug concentration in vivo and produce both therapeutic and adverse effects. Verapamil is an example of a potentI Kr blocker in vitro (IC50, 143 nM) (Zhang et al., 1999). It may also prolong the QT interval at very high plasma concentrations, but so far no documented clinical report of verapamil-related TdP is available. The effects of sertindole on repolarization have previously been studied in isolated feline hearts (Drici et al., 1998). In this model, the potency of sertindole in lengthening QT interval was compared with that of haloperidol, risperidone, clozapine, and olanzapine (Drici et al., 1998). The hearts were infused with increasing concentrations for 40-min intervals at each concentration. All tested drugs caused a concentration-dependent increase in QT interval. Haloperidol and risperidone were significantly more potent than sertindole; olanzapine and clozapine were less potent. Noteworthy, the all-cause mortality rate for sertindole-treated patients was less than half that for risperidone-treated patients, and also considerably lower than that for olanzapine-treated patients (Mackay et al., 1998). The QT-prolonging potency of sertindole was equivalent to that of its metabolites Lu 28–092 and Lu 25–073 (Drici et al., 1998).
Low Torsadogenic Potential of Sertindole: Possible Causes.
Lack of early afterdepolarizations and lack of an increase in dispersion of repolarization are two possible causes of the low torsadogenic potenial of sertindole. Slowing of myocardial repolarization and critical lengthening of APD appear to be necessary, but not sufficient to evoke EADs and triggered activity. For the occurrence of EADs, a net depolarizing current flowing during the repolarization phase of the action potential is necessary. Currents implicated in the generation of EADs include the sodium window current, the L-type calcium current, the Na/Ca exchange current, and repolarizing potassium currents (Eckardt et al., 1998a). For almost all agents that are clinically associated with abnormal QT prolongation and TdP, the generation of EADs and triggered activity under appropriate experimental conditions has been demonstrated. The premature beat that initiates TdP is generally thought to be due to an EAD-induced triggered response, arising from either Purkinje or subendocardial cells (M cell region); both are capable of developing EAD-induced triggered activity (Eckardt et al., 1998a).
Antiarrhythmic drugs such as sotalol were reported to evoke EADs in numerous experimental in vitro (Eckardt et al., 1998a,b) as well as in vivo models (Vos et al., 1995). In the present study, sotalol nicely mimicked the long QT intervals, the rate dependence of the QT interval, and the bifid or notched T/U waves, as well as the characteristic polymorphic tachyarrhythmias observed in LQTS patients. Vos et al. (1995) reported spontaneous (10% of the experiments) and pacing-dependent TdP (52% of the experiments) in their canine in vivo model. TdP induction was related to the presence of EADs on endocardial MAP recordings. Due to this relation, the provocation of EADs in vitro serves as a surrogate for the ability of a drug to generate TdP in vivo. It is remarkable that, although sertindole prolongs myocardial repolarization, the generation of EADs could not be demonstrated in the present study. It is unlikely that methodological factors may have prevented the occurrence of EADs, since in the same experimental setup, dl-sotalol reproducibly led to the generation of EADs (88% of hearts) and triggered activity. It may well be that the ability of sertindole to block the sodium inward current (I Na) counterbalanced the tendency to induce EADs (Maginn et al., 2000). The few arrhythmias that developed after exposure with high concentrations of sertindole did so in the presence of QRS prolongation, i.e., slowing of conduction preferentially showed a monomorphic QRS pattern. This may have been the consequence of conduction slowing resulting from inhibition of I Na, which is not expected at therapeutic dosage. In the clinic, sertindole is not associated with QRS prolongation (Fritze and Bandelow, 1998), which is an indication that the concentration of sertindole used in this study is well beyond therapeutic exposure. The lack of EADs very well fits to our observations that typical TdP did not occur, even with a high concentration of sertindole and associated predisposing factors (hypokalemia and bradycardia).
Other electrophysiologic effects of sertindole [i.e., calcium-antagonistic effects and/or the blockade of α1-receptors (Ipsen et al., 1997; Arnt, 1998), each possibly influencing the others] may also be of importance. It is of note that Carlsson et al. (1990) reported that an infusion of the α1-agonist methoxamine facilitated the occurrence of TdP in α-chloralose-anesthetized rabbits treated with the I Kr blockers clofilium, almokalant, dofetilide, or sematilide.
Amiodarone seems to be another agent in which additional pharmacological properties seem to oppose marked drug-induced TdP in the presence of QT prolongation. The fact that TdP is rare with amiodarone has been attributed to its ability to block sodium and calcium channels (Hohnloser et al., 1994). Thus, although a close relationship between drug concentration and the extent of QT prolongation can often be observed, this does not mean that such a relationship is also present with respect to the risk for TdP. With this study, amiodarone and sertindole are the only two drugs in which experimental evidence exists for their low torsadogenic potential in the presence of marked QT prolongation. Interestingly Mitcheson et al. (Mitcheson et al., 2000) very recently reported a structural basis for drug-induced LQTS, suggesting that the site and mode of interaction with HERG may be of particular importance.
Increased dispersion of repolarization has been suggested to play an important role for the maintenance of TdP-like tachyarrhythmias. In the present study, sertindole did not affect dispersion of APD90. In contrast, dispersion of repolarization markedly increased in response to sotalol. The lack of increase in dispersion was mainly due to a weak effect of sertindole on the endocardial APD90. Because the endocardial cell layer is thin in rabbit hearts, it is possible that, instead, endocardial MAP represent recordings from subendocardial tissue. The marked increase in dispersion of repolarization with sotalol was mainly a transmural phenomenon due to the marked effect of sotalol on the endocardial MAP recordings.
Sertindole is a psychotropic agent that prolongs myocardial repolarization. This effect is due to a concentration-dependent inhibition of I Kr. Compared with other agents that also inhibit this current, the torsadogenic potential of sertindole seems to be remarkably low. In the Langendorff-perfused rabbit heart model of TdP, sertindole did not display the proarrhythmic profile typical of other blockers ofI Kr such as sotalol. The mechanisms responsible for this behavior of sertindole are probably multifactorial. Next to a lack of reverse use dependence, we could demonstrate that even high doses of sertindole had no significant effect on dispersion of repolarization. It is possible that a different mode of interaction between sertindole and the channel and/or additional pharmacological effects of sertindole, e.g., its ability to inhibit I Na and/or its ability to block α1-receptors, may play a role. Further studies will be necessary to investigate whether similar effects are observed with other drugs that prolong repolarization but exhibit a low torsadogenic potential.
We thank Irina Schulz for expert technical assistance.
- long QT syndrome
- action potential duration at 90% repolarization
- cycle length
- early afterdepolarization
- human ether-a-go-go-related gene
- rapid component of delayed rectifier current
- sodium current
- monophasic action potential
- torsade de pointes
- ventricular tachyarrhythmia
- Received August 17, 2001.
- Accepted October 5, 2001.
- The American Society for Pharmacology and Experimental Therapeutics