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CARDIOVASCULAR
Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan
Received for publication
February 18, 2004
Accepted
March 15, 2004.
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Abstract |
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; Honerjager and Meissner, 1983; Ameri, 1998). The arrhythmogenic effects of aconitine include the induction of premature ventricular contractions (PVC), ventricular tachycardia (VT), torsades de pointes, ventricular fibrillation (VF), and mortality in a dose-dependent manner (Lu and Clerck, 1993). Experimentally, aconitine-induced arrhythmias are thought to be induced by triggered activity due to delayed afterdepolarization and early afterdepolarization. At the molecular level, aconitine binds to Na+ channels and prolongs their open state favoring entry of a large quantity of Na+ into cytosol, which may be accompanied by Ca2+ overload via an electrogenic Na+-Ca2+ exchange (NCX) system and eventually induces triggered activity (Sawanobori et al., 1987; Watano et al., 1999). Thus, the role of NCX is suspected to be important to generate triggered activity in the heart (Adaniya et al., 1994; Sawanobori et al., 1996).
NCX inhibitors, KBR [KB-R7943, 2-[2-[4-(4-nitrobenzyloxyl)phenyl]ethyl] isothiourea methansulfonate] and SEA [SEA0400, 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline], have been developed recently (Iwamoto et al., 1996, 1999; Watano et al., 1996; Kimura et al., 1999; Matsuda et al., 2001; Shigekawa and Iwamoto, 2001; Tanaka et al., 2002). SEA has been found to be about 10 times more potent than KBR in inhibiting the NCX current in guinea pig ventricular cells.
To elucidate the involvement of NCX in aconitine-induced arrhythmias and triggered activity, we tried to explore the effects of NCX inhibitors, KBR and SEA, on the aconitine-induced arrhythmias in the whole-animal, single cardiac myocyte, and computer simulation models.
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Materials and Methods |
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Aconitine-Induced Arrhythmias in Whole Guinea Pigs. Guinea pigs weighing 300 to 400 g were anesthetized with sodium pentobarbital (50 mg/kg i.p.). Respiration was maintained with artificial ventilation (under room air, volume 1.5 ml/100 g, rate 55 strokes/min) through the cannula in the trachea to maintain pCO2, pO2, and pH within the normal range. Polyethylene tubing was inserted into the right jugular vein to administer aconitine and the test drugs. The left carotid artery was cannulated to monitor systemic blood pressure. The standard limb leads of the ECG were recorded. Blood pressure, heart rate, and ECG (lead I and II) were continuously monitored using a polygraph recorder (NEC San-ei Instruments Ltd., Tokyo, Japan). After 15 min of stabilization, vehicle or NCX inhibitors were administered to different groups for each dose of the drug or vehicle (i.e., 0–30 mg/kg) as i.v. bolus injection through the jugular vein. Five minutes later, 25 µg/kg of aconitine was injected to induce ventricular arrhythmias in the whole-animal model (Lu and Clerck, 1993) (Fig. 1, protocol I). Each animal received only one dose (treatment) of either vehicle or any of the NCX inhibitors. The doses of SEA were 1 to 10 mg/kg and those of KBR were 1 to 30 mg/kg.
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; Homma et al., 2000). Briefly, guinea pigs weighing 300 to 400 g were anesthetized with pentobarbital (50 mg/kg, i.p.) and sacrificed. The hearts were quickly removed and rinsed in calcium-free cold Tyrode's solution. Using a Langendorff retrograde apparatus, 0.2 mg/ml collagenase (type-I; Worthington Biochemicals, Freehold, NJ) or 0.03 mg/ml collagenase (Blendzyme-3; Roche Diagnostics, Mannheim, Germany) was perfused for 15 to 20 min at 36 ± 1°C. The left ventricular muscles were minced by scissors, dispersed with gentle agitation in Kraft-Brühe (KB) medium, and filtered by a 200-µm pore nylon mesh. Cells were stored in KB medium at room temperature until use. More than 80% of the myocytes were rod-shaped and viable, and 65% of the total isolated myocytes were tolerant to 1.8 mM extracellular calcium. Only cells exhibiting a rod-shaped morphology and no signs of membrane damage were used for the experiments. Once isolated, the cells were used up to 12 h. Tyrode's solution for isolation contained (in mM): NaCl, 135; KCl, 5.4; NaH2PO4, 11; MgCl2, 2; glucose, 20. Tyrode's solution for perfusion (bath solution) contained (in mM): NaCl, 135; KCl, 5.4; NaH2PO4, 1; HEPES (sodium salt), 10; MgCl2, 1; glucose, 20; and CaCl2, 1.8. The pH was adjusted to 7.4 with NaOH in both solutions. The KB medium contained (in mM): glutamate K, 90; taurine, 10; KCl, 25; KH2PO4, 20; MgCl2, 3; and glucose, 10. The pH was adjusted to 7.25 with KOH. Electrophysiological Recordings. Cell suspension was placed on the microscopic groove, and Tyrode's solution containing 1.8 mM of Ca2+ was perfused for 10 min for stabilization of the cells. Cells exhibiting a rod-shaped morphology and no signs of membrane damage were selected on the microscopic groove. The microelectrode was carefully touched on the membrane of the selected cell and a gigaseal was made by gentle suction through the polyethylene tubing connected to a 1-ml syringe. To induce electrical abnormality, aconitine (1 µM) dissolved in Tyrode's solution containing 1.8 mM Ca2+, was perfused. Electrical abnormality appeared within 1 min after perfusion of aconitine solution. At this stage, the vehicle (DMSO) (control or 0 µM NCX inhibitors) or any dose of the NCX inhibitors (1, 3, 10, 100 µM NCX inhibitors) and aconitine (1 µM), dissolved in Tyrode's solution containing 1.8 mM Ca2+, was simultaneously perfused to observe the effects of the vehicle or NCX inhibitors on aconitine-induced triggered activity (Fig. 1, protocol II). Each cell from each vehicle/drug dose group received only one dose (treatment) of aconitine, vehicle, or NCX inhibitors. The temperature was maintained at 37°C.
A patch-clamp L/M-EPC7 amplifier (D-6100; List Electronics, Darmstadt, Germany) was used in the current-clamp experiments for recording action potential configurations with an extracellular Ca2+ concentration of 1.8 mM (Hamill et al., 1981). Pipettes with 2 to 4 M
resistance were made from aluminosilicate capillary glass using a programmable multistep puller (Sutter Instrument Company, Novato, CA). Pulse generation and data acquisition were controlled by pCLAMP software and by a running Compaq PC computer that was interfaced with Digidata 1200 interface (Axon Instruments Inc., Union City, CA). Gigaseals were made by suction. Action potentials were displayed on the computer monitor and simultaneously recorded in a recorder (Nihon Kohden Corporation, Tokyo, Japan). The temperature was controlled by a bath temperature controller (DTC 300T; Dia Medical System LLC, Tokyo, Japan) and monitored on the microscopic groove by Thermistor (Class 1.0; Shibaru Electronics, Tokyo, Japan). The recording microelectrodes were filled with a solution containing (in mM): KCl, 20; K-aspartate, 120; Mg-ATP, 5; and HEPES (salt), 10. The pH was adjusted to 7.25 with KOH.
Reconstructed Action Potential by Computer Simulation. We used the Luo and Rudy model of action potential of mammalian ventricular myocyte as the basis of this simulation study (Luo and Rudy, 1991). The source code of the Luo and Rudy model described by common computer language was obtained from the Web site http://www.cwru.edu/med/CBRTC/LRdOnline/. Many of the membrane ionic currents, pumps, and exchangers were incorporated in this model. At the baseline condition, the model was paced at a basic cycle length of 500 ms.
The effects of aconitine on the kinetics of the sodium channels were produced by the shift of m (activation) and h (inactivation) parameters to negative membrane potential. Nilius et al. (1986) reported that aconitine shifted m to -31 mV and h to -13 mV in isolated mouse ventricular myocytes. In the Luo and Rudy model, the kinetics of sodium channels are defined using one activation parameter (m) and two inactivation parameters (h and j). We followed the results of Nilius et al. (1986) and shifted m to -31 mV and only h to -13 mV and mimicked the condition in which aconitine was applied.
To mimic the condition in which a NCX inhibitor was applied, the contributions of the NCX in the model were simply reduced as follows:
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Exclusion Criteria. A total of 130 guinea pigs were used in these series of studies on the whole-animal and single-cell experiments. Experiments were terminated or excluded from the final data analysis, if either of the following occurred (Aye et al., 1999): arrhythmias or low mean arterial pressure (less than 15 mm Hg) before drug or vehicle administration due to surgery. Six guinea pigs were excluded for the absence of arrhythmias after and sudden death during drug or vehicle administration.
Chemicals and Drugs. KB-R7943 and SEA0400 were kind gifts from Kanebo Pharmaceutical Co. (Osaka, Japan), Organon Japan Co. (Osaka, Japan), and Taisho Pharmaceutical Co. Ltd. (Tokyo, Japan), respectively. KBR was dissolved in a vehicle (10% polyethylene glycol, 10% ethanol, 10% DMSO, and 70% saline) in the whole-animal experiments, and in DMSO in single-cell experiments. SEA was dissolved in a vehicle supplied by Taisho. Aconitine and other agents were directly dissolved in Tyrode's solution. The final concentration of DMSO was less than 0.05%. DMSO and vehicles had no significant effects on the whole-animal and single-cell experiments (Data not shown). All other chemicals were purchased from Sigma-Aldrich (St. Louis, MO) and Wako Pure Chemicals (Tokyo, Japan).
Data Analysis and Statistics. Statistical analysis was based on the guidelines for statistics (Wallenstein et al., 1980) and modified for the study of arrhythmias using guinea pig hearts (Dennis et al., 1980; Pfeiffer and Kenner, 1983). In the whole-animal study, each drug dose group consisted of 10 to 13 animals, and in the single-cell study, each drug dose group consisted of five to eight individual cells. Data were expressed as mean ± S.E.M. Differences in mean values between experimental groups were analyzed by one-way analysis of variance, followed by Dunnett's multiple comparison test where applicable. A p value less than 0.01 was defined to be significant.
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Results |
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Figure 3 shows the effects of KBR and SEA on each arrhythmia as shown in Fig. 2. In the control condition (without NCX inhibitors), the duration of normal sinus rhythm, PVC, narrow QRS VT, and wide QRS VT were 18.7 ± 9.8, 2.6 ± 3.7, 15.7 ± 15.3, and 19.1 ± 15.3 min. In the presence of KBR (10 mg/kg), those durations changed to 25.8 ± 11.7, 8.1 ± 11.7, 23.5 ± 16.6, and 2.7 ± 6.1 min, respectively. In the dose range of KBR from 1 to 30 mg/kg, the duration of the normal sinus rhythm was dose-dependently prolonged and that of the wide QRS VT was shortened. In the presence of SEA (10 mg/kg), those arrhythmia durations were 21.5 ± 13.2, 4.3 ± 4.3, 17.3 ± 5.7, and 16.8 ± 11.9 min, showing no significant changes in comparison with those of the control condition. KBR suppressed the wide QRS VT, but SEA did not show such an effect.
Aconitine-Induced Abnormal Electrical Activity in Single Ventricular Myocytes
Figure 4 shows abnormal electrical activity in isolated ventricular myocytes of guinea pigs induced by aconitine (1 µM). The abnormal electrical activity occurred as a form of triggered automaticity within 1 min after perfusion of aconitine, with spontaneous diastolic depolarization, gradually increasing its firing rate (warming-up phenomenon) and finally developing to the continuous chaotic oscillatory activity, appearing similar to VT and VF (Fig. 4, b and c), as in the case of the whole-animal experiments. Because of the lack of automaticity in normal ventricular myocytes and the lack of syncytium in isolated cells, this abnormal activity must have been induced by triggered activity. The abnormal activity started after the membrane potential was once repolarized, indicating the characteristics of delayed afterdepolarization.
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Effects of KBR and SEA on the Aconitine-Induced Abnormal Electrical Activity. We examined the effects of KBR and SEA on the abnormal electrical activity induced by aconitine, as shown in Fig. 5, a and c. KBR (10 µM) completely suppressed the abnormal activity (Fig. 5b), but SEA (100 µM) did not show such an effect (Fig. 5d).
Effects of KBR and SEA on Action Potential Configurations of Ventricular Myocytes. We investigated the effects of KBR (1–10 µM) and SEA (1–100 µM) on the action potential configurations in isolated ventricular myocytes. KBR (10 µM) made the shape of the action potential (Fig. 6a) almost triangular, but SEA caused no significant change of the action potential (Fig. 6b). Figure 6, c and d, show dose-dependent effects of KBR and SEA on the action potential duration at 50% and 90% depolarization (APD50 and APD90), respectively. KBR (10 µM) preferentially decreased APD50 to APD90. APD50 at the control condition significantly decreased from 126 ± 51 ms to 64 ± 27 ms by 10 µM KBR. APD90 changed from 169 ± 50 ms (control) to 152 ± 43 ms (KBR 10 µM). SEA altered neither APD50 nor APD90; APD50 and APD90 were 134 ± 46 and 161 ± 47 ms at the control conditions, and were 121 ± 34 and 149 ± 28 ms in the presence of SEA (100 µM). Washout of KBR restored the normal shape of action potentials (data not shown).
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Reconstructed Action Potential Modified by the Kinetics of Sodium Channels and the NCX Activity
The contribution of changes in sodium channel kinetics and the reduction in NCX activity on membrane potential were evaluated using a mathematical model of a mammalian ventricular myocyte (Luo and Rudy model). In Fig. 7a, the kinetic parameters (m and h) of sodium channels are plotted against membrane voltage (mV). After shifting the parameters to a negative value to mimic the effect of aconitine, as described under Materials and Methods, the simulated membrane potential at rest became unstable and started to oscillate (Fig. 7d). The oscillation occurred after deep repolarization like delayed afterdepolarization and declined spontaneously, and the mean potential at rest was higher than that of the control (Fig. 7b). These changes (i.e., in Fig. 7d) were similar to those shown in Fig. 4c. As shown in Fig. 7e, both the change of sodium channel kinetics and the inhibition of NCX by 90% were incorporated in the program to mimic the effect of aconitine and NCX inhibitor. This enhanced the instability of the membrane potential at rest. The simulation study indicates that the inhibition of NCX may be ineffective to suppress the aconitine-induced activity in isolated cardiac ventricular myocytes.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionThe Limitations of our...References |
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; Honerjager and Meissner, 1983; Sawanobori et al., 1987; Lu and Clerck, 1993; Arita et al., 1996). In the whole-animal models, various types of ventricular tachyarrhythmias were induced as PVC, VT, torsades de pointes, and VF. In recording action potentials, both early and delayed afterdepolarization were induced (Sawanobori et al., 1987). Figure 4, which shows abnormal activity in a single ventricular myocyte, indicates that triggered activity, not re-entry or enhanced automaticity mechanism, is responsible for aconitine-induced arrhythmias.
The binding site of aconitine is voltage-dependent cardiac Na+ channels (Catterall, 1988, 2000). Aconitine shifted the activation and inactivation kinetics of the channels toward more hyperpolarized potentials. It caused repetitive or persistent activation of the Na+ current even at the resting membrane potentials (Schmidt and Schmitt, 1974; Grischenko et al., 1983; Honerjager and Meissner, 1983). The sustained influx of Na+ ions is speculated to cause intracellular Na+ overload leading to intracellular Ca2+ overload through NCX. It is controversial whether or not this Na+ overload only, Ca2+ overload, or both (Na+ and Ca2+ overload) is responsible for the aconitine-induced cellular activity and the whole-animal-triggered activity. However, in previous studies selective NCX inhibitors have not been available, so the involvement of the NCX in aconitine-induced arrhythmia remains uncertain.
In our whole-animal experiments, two types of ventricular tachycardias were observed after i.v. injection of aconitine. Aconitine enhances automaticity in the atrioventricular node, inducing accelerated atrioventricular junctional rhythm (narrow QRS tachycardia in Fig. 2c) and may induce triggered activity in ventricular myocytes (wide QRS VT in Fig. 2d). KBR dose-dependently decreased the duration of wide QRS tachycardia and increased that of normal and atrial rhythm as a trade-off. However, SEA did not suppress either narrow or wide QRS tachycardia, even at concentrations that should maximally suppress NCX (i.e., 10 mg/kg; see Fig. 2). These results indicate that KBR is potent enough to inhibit the triggered activity in ventricular myocytes.
In action potential recordings from isolated ventricular myocytes (Fig. 4), aconitine induced abnormal electrical activity, known as triggered responses, that are important causes of lethal arrhythmias. KBR was effective in suppressing the triggered activity, whereas SEA proved to be ineffective. KBR not only suppresses NCX but also suppresses Na+ and Ca2+ channels simultaneously and thus prevents both Na+ and Ca2+ overload. SEA, on the other hand, being a relatively more potent and more selective NCX inhibitor and less effective on Na+ and Ca2+ channels, did not prevent these triggered responses induced by aconitine due to abnormal kinetics of Na+ channels.
SEA has been reported to be more potent and more selective than KBR as a NCX inhibitor (Matsuda et al., 2001; Tanaka et al., 2002). SEA was 6.5 to 14.3 times more potent than KBR, because it inhibited the outward NCX current (reverse or influx mode of Ca2+ by NCX) in guinea pig ventricular cells, with IC50 value 32 to 40 nM SEA and 263 to 457 nM KBR. SEA is a pure NCX inhibitor, because SEA (1 µM) inhibited the NCX current by 80%, reduced the Na+ current, the L-type Ca2+ current, the delayed rectifier K+ current, and the inwardly rectifying K+ current by only 4, 9, 4, and 2%, respectively. However, KBR (10 µM) inhibited the NCX current by 80%, simultaneously reducing those ionic currents by 54, 55, 94, and 73%, respectively (Tanaka et al., 2002). A radioligand binding study that examined the effects of SEA on neurons (Matsuda et al., 2001) showed that the IC50 values for SEA to inhibit NCX, Na+ current, and L-type Ca2+ current were 33 nM, 20 µM, and 14 µM, and those for KBR were 3.8 µM, 3 µM, and 1 µM, respectively. In both of our experiments in which ECG was monitored and action potential was recorded, the more potent and selective NCX inhibitor, SEA, showed no suppression of aconitine-induced arrhythmia or abnormal electrical activity. Those results indicate that the role of NCX is insignificant in the triggered activity induced by aconitine and that the effect of KBR on other channels (Na+ and Ca2+) may contribute to its inhibition of the triggered activity. These conclusions are also consistent with our results shown in Figs. 3 and 6 that KBR shortened APD and changed the configuration of action potentials.
The long QT syndrome is a rare congenital disorder. Mutations in the cardiac sodium channel gene SCN5A are responsible for type-3 long QT disease that leads to sudden cardiac death. It produces a persistent sodium current in the plateau phase of cardiac action potential and results in lethal arrhythmias (Clancy and Rudy, 1999; Chiang and Roden, 2000; Moric et al., 2003; Xiao-Li et al., 2004). It was mentioned earlier that, at the molecular level, aconitine binds to Na+ channels and prolongs their open-state favoring entry of a large quantity of Na+ into cytosol and eventually induces triggered activity (Sawanobori et al., 1987; Watano et al., 1999). KBR seems to be effective in suppressing aconitine-induced cardiac arrhythmias but KBR is a "not so selective NCX inhibitor" and at the same time "also blocks Na+,Ca+2, and K+ channels" significantly (Tanaka et al., 2002; Amran et al., 2003). Type-3 long QT disease might, therefore, be treated with multichannel blockers, including KBR that also blocks the NCX system.
The simulation study on an integrated mathematical model for ventricular action potential has been performed to determine whether or not NCX is involved in aconitine-induced arrhythmias. The abnormal activity with membrane oscillation after aconitine in real cardiomyocytes (Fig. 4c) was well mimicked by the reconstructed action potential by a computer simulation (Fig. 7d), with the shift of the kinetics of Na+ channels to negative potentials following the experimental data of Nilius et al. (1986). As to the effects of the inhibition of NCX on the membrane oscillation after aconitine, there was some difference between wet tissue and simulated experiments. The oscillation was not affected by SEA in the myocytes (Fig. 4c) but was aggravated in the simulation study (Fig. 7e). It is difficult to explain this difference, but it might suggest that the oscillation was never suppressed by the inhibition of NCX.
Our results indicate that NCX is not strongly involved in the aconitine-induced triggered activity, i.e., kinetic shift of Na+ channels, themselves induced by aconitine, might be enough to cause the triggered activities.
Antiarrhythmic effects of NCX inhibitors are still controversial. Miyamoto et al. (2002) showed that KBR did not suppress either the ischemia/reperfusion arrhythmias or the ouabain-induced arrhythmias in dog models. They showed that NCX inhibition might not be a useful strategy in suppressing those arrhythmias. On the other hand, Watano et al. (1999) found that the intravenous injection of KBR significantly increased the doses of ouabain required to induce ventricular arrhythmias (PVC, VT, and VF) in anesthetized guinea pigs and concluded that KBR suppressed ouabain-induced arrhythmias through inhibition of NCX. Yeih et al. (2000) reported recently a successful treatment of aconitine-induced life-threatening ventricular tachyarrhythmia by amiodarone in a clinical case. As amiodarone in therapeutic concentrations binds to many membrane/channel proteins (multichannel blocker) like KBR, their clinical results support our experimental results observed in this study.
In conclusion, our results indicate that aconitine-induced ventricular arrhythmia is induced by triggered activity due to the abnormal kinetics of the Na+ channels, and protective effects of KBR resulted from a mechanism other than the inhibition of NCX (non-NCX action); thus, NCX probably has little or no role in the arrhythmias induced by aconitine. The simulation study also provided the same results, i.e., NCX is not significantly involved in aconitine-induced arrhythmias. Comprehensive analysis with the whole-animal model, recordings from single ventricular myocytes, and the computer simulation study may be helpful for better understanding of the mechanism of lethal arrhythmias and for evaluation of effects of new drugs.
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The Limitations of our Study |
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(1) In the aconitine-induced arrhythmias, intracellular Ca2+ overload was proposed to be the mechanism in many previous studies. Aconitine-modified sodium channels remain open even at the resting potential, and repetitive depolarization and continuous influx of Na+ ion result in sodium overload. Consequently, the Na+ gradient may decrease and Ca2+ overload is followed by this Na+ overload, which might induce triggered activity. Our results indicate that triggered activity is induced by abnormal kinetics of Na+ channels. Direct measurement of the intracellular Ca2+ concentration, [Ca2+]i, during aconitine-induced activity might be necessary to elucidate this point. To the best of our knowledge, there are no studies on the change of [Ca2+]i under aconitine-induced activity.
(2) With the development in computer simulation of cardiac action potentials, the Markovian model instead of a traditional Hodgkin-Huxley model (Clancy and Rudy, 1999) has been used to describe the kinetics of Na+ channels. Because the effect of aconitine on the cardiac Na+ channels was experimentally analyzed following the Hodgkin-Huxley model (Nilius et al., 1986), and because it was difficult to apply the experimental data of Hodgkin-Huxley style to the Markovian model, we simply used the Luo and Rudy model in which the Na+ channel was described as a Hodgkin-Huxley equation. Although the membrane oscillation by aconitine (Fig. 4c) was well reconstructed in the simulation (Fig. 7d), further analysis might be necessary to explain why the oscillation is not affected by SEA and is aggravated only in the simulation study.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: PVC, premature ventricular contraction; VT, ventricular tachycardia; VF, ventricular fibrillation; NCX, sodium-calcium exchange; KB-R7943, 2-[2-[4-(4-nitrobenzyloxyl)phenyl]ethyl]isothiourea methansulfonate; SEA0400, 2-[4-[(2,5-difluorophenyl)methoxy] phenoxy]-5-ethoxyaniline; KB, Kraft-Brühe (medium); DMSO, dimethyl sulfoxide; APD50 and APD90, action potential duration at 50% and 90% repolarization, respectively.
Address correspondence to: Dr. Nobuo Homma, Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato 1110, Tamaho, Nakakoma, Yamanashi 409-3898, Japan. E-mail: nhomma{at}res.yamanashi-med.ac.jp
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