There was no direct correlation between the occurrence of TdP and the infusion rate or the dose of d -sotalol and almokalant, because the percentage incidences of this arrhythmia were greatest after the administration of the second doses of the drugs (Table 1).
There was a significant difference between d -sotalol and almokalant in terms of ventricular tachyarrhythmia, e.g., ventricular tachycardia and TdP onset. Almokalant induced ventricular tachyarrhythmias shortly after the start of the administration of its second dose (log 10 onset time, 2.206 ± 0.089 s, n = 6). In contrast, a delay of several minutes occurred before the onset of ventricular tachyarrhythmias after the start of the administration of the second dose of d -sotalol (log 10 onset time, 2.816 ± 0.084 s, n = 6; p < 0.05 versus almokalant).
Blood pressure and heart rate
When saline infusion was begun (control group) during continuous phenylephrine infusion, the blood pressure and the heart rate (sinus and ventricular) did not change further (Table 2).
Addition of d -sotalol reduced blood pressure and ventricular rate dose relatedly (Table 2). There was dissociation between sinus and ventricular rate after administration of 30 mg/kg of d -sotalol caused by frequent occurrence of 2:1 atrioventricular block (Table 2).
Similarly to d -sotalol, almokalant reduced blood pressure and there was dissociation between sinus and ventricular rate after administration of each dose of the drug caused by frequent 2:1 atrioventricular blocks (Table 2). Five minutes after administration of 88 and 260 μg/kg of almokalant, sinus rate increased significantly compared with saline control (232 ± 9 beats/min versus 196 ± 9 beats/min, p < 0.05 and 240 ± 12 beats/min versus 188 ± 14 beats/min, p < 0.05, respectively). These differences remained significant till the end of the 20-min drug-free intervals (Table 2). After the administration of the second dose of almokalant, sinus rate was also significantly different from those after the administration of the second dose of d -sotalol (Table 2). This difference remained significant between d -sotalol and almokalant nearly until the end of the experiment. Conversely, there was no significant difference between the effect of almokalant and d -sotalol on the blood pressure and ventricular rate during the whole experiment.
Quinidine treatment decreased the blood pressure markedly. The pressure drop after each dose of quinidine was significantly greater than those at the same time points in all other groups (Table 2). The first dose of quinidine (3 mg/kg) elevated heart rate, whereas the third dose (30 mg/kg) caused 2:1 (and total) atrioventricular blocks, allowing dissociation of sinus and ventricular rates (Table 2). After administration of 30 mg/kg of quinidine, ventricular rate decreased and sinus rate increased significantly compared with control (Table 2).
Amiodarone lowered blood pressure in a dose-related manner. Ten minutes after administration of 10 mg/kg of amiodarone, heart rate (sinus and ventricular rate) decreased significantly compared with saline control (170 ± 9/min versus 197 ± 9/min, p < 0.05). From this time point, heart rate decreased constantly in amiodarone-treated animals and remained significantly different from control till the end of the experiment (Table 2).
Saline infusion had no significant effect on the QT and QT c widening effect of the maintained infusion of phenylephrine (Table 3). Amiodarone did not add to the QT and QT c widening caused by phenylephrine (Table 3). However, d -sotalol and almokalant increased the QT and QT c in a dose-related manner (Table 3) and there was no difference between the time course of QT and QT c prolonging effects of the two drugs. Interestingly, only the third dose of quinidine (30 mg/kg) prolonged QT, whereas the rate-corrected QT intervals were already widened by the first dose of the drug (3 mg/kg) (Table 3). The second dose of d -sotalol and almokalant (10 mg/kg and 88 μg/kg, respectively) widened QT and QT c to such an extent that these were significantly different from those after administration of the second dose of quinidine and amiodarone (10 mg/kg)(Table 3).
Variables measured before torsades de pointes occurrence
Because there was no statistical difference between the d -sotalol- and almokalant-treated animals in terms of blood pressure, ventricular rate, QT, and QT c, these data from the animals with TdP induced by either d -sotalol or almokalant were summarized. The values measured before the first TdP at the last sinus-origin beats were compared with those measured before phenylephrine was begun. In animals with TdP (n = 10), mean arterial blood pressure was elevated (120 ± 3 mm Hg versus 85 ± 2 mm Hg at baseline, p < 0.05) and ventricular rate was reduced significantly (183 ± 13 beats/min versus 286 ± 9 beats/min, p < 0.05) at the first incidence of TdP. Furthermore, QT and the rate-corrected QT intervals were prolonged markedly at this time (QT, 262 ± 8 ms versus 162 ± 5 ms at baseline, p < 0.05; QT c -Carlsson, 255 ± 8 ms versus 178 ± 4 ms, p < 0.05; QT c -Bazett, 453 ± 15 versus 353 ± 8 ms, p < 0.05).
The present study has demonstrated that in anesthetized rabbits, of four antiarrhythmic agents administered i.v., only d -sotalol and almokalant induced TdP, whereas quinidine and amiodarone did not. Moreover, the present results showed no direct correlation between the occurrence of TdP and the infusion rate or the dose of antiarrhythmics.
In our investigation we modified the protocol of Carlsson et al. (12,13). Instead of giving repolarization-prolonging drugs in continuous infusions, we applied stepwise elevation of doses with an interval between each dose. This was for the following reasons: According to Carlsson et al. (13), the infusion rate of drugs is an important predisposing factor for TdP. With our protocol, three different infusion rates were tested in one animal, which decreased the total number of animals required. Not only the dose dependence, but also the time dependence of the occurrence of arrhythmias, can be compared between different treatment groups with this protocol as there is an interval between administrations of increasing doses of drugs.
No torsade de pointes with quinidine
In our experiments quinidine did not evoke TdP, though this drug is by far the most frequently reported drug associated with this arrhythmia (1). In patients with TdP caused by quinidine, the plasma level of the drug is usually within or below the therapeutic range (22). Quinidine's clinical proarrhythmic profile (especially the dose dependence) is not mimicked in any of the presently available animal proarrhythmia models. In anesthetized dogs, Inoue and Sugimoto (23) used toxic dose of quinidine (30 mg/kg over 5 min, i.v.) to evoke TdP. Despite the observation that this dose prolonged QT in their study, TdP never occurred spontaneously and required additional programmed electrical stimulation to evoke it. Likewise, in conscious hypokalemic dogs with chronic complete atrioventricular block, TdP did not occur spontaneously during or after a continuous infusion of quinidine (∼20 mg/kg over 3 h), though QT interval was widened significantly by this dose (24); and an additional propranolol infusion was necessary to allow the generation of TdP in that study. In methoxamine-primed anesthetized rabbits, continuous quinidine infusion (1.25 mg/kg/min for 60 min) did not evoke TdP despite increasing QT, QT c, and QT dispersion significantly, but conversely, the drug evoked conduction blocks frequently (25). Thus, the lack of quinidine-induced TdP in the current study is in good accordance with the results of the previous in vivo animal studies.
In our investigations, in contrast to d -sotalol and almokalant, only the highest dose of quinidine prolonged QT intervals whereas QT c was already prolonged by the lower doses. Moreover, the second dose of quinidine was less potent in prolonging either QT or QT c intervals than the middle dose of almokalant and d -sotalol. This smaller QT- and QT c -prolonging potency might be a reason for the low proarrhythmic activity of the lower doses of quinidine in the current study. However, TdP was also absent even when marked QT and QT c prolongations were achieved by the highest dose of quinidine. This observation accords well with that of Carlsson et al. (13) and suggests that QT and QT c prolongation are not the only contributing factors to TdP generation in the anesthetized rabbit model.
The high heart rate of the rabbit compared with that of humans could also contribute to the blunted proarrhythmic activity of quinidine compared with its effects in humans. At high frequencies, quinidine's sodium channel inhibiting property is increased (use-dependent block) (26), which may prevent TdP at these high heart rates of the rabbit (27). In addition, after the administration of the first dose of quinidine, its antimuscarinic action on atrial muscarinic receptors (28) or its blood pressure–lowering effect might prevent phenylephrine-induced reflex bradycardia, which could predispose to TdP. However, this lack of reflex bradycardia became irrelevant especially after the administration of the third dose of quinidine, as this dose decreased the ventricular rate markedly caused by frequent occurrence of 2:1 and total atrioventricular blocks. However, this relatively low ventricular rate, which coincided with marked QT and QT c prolongation, was still insufficient to allow generation of TdP. Likewise, quinidine and terfenadine reduced heart rate and prolonged QT and QT c markedly without evoking TdP in α 1 -adrenoceptor-stimulated rabbits (25). These findings suggest that low ventricular (or heart) rate and prolonged QT and QT c intervals are not the only contributing factors to TdP generation in the rabbit model of the acquired long QT syndrome.
In the present investigation, quinidine dose-dependently lowered blood pressure and the pressure drops were significantly greater than those with any other drug. In methoxamine-sensitized anesthetized rabbits, terfenadine and quinidine reduced blood pressure to a very low level and did not evoke TdP despite increasing QT, QT c, and QT dispersion and reducing heart rate (25). These results suggest that marked blood pressure reduction may prevent TdP generation in the anesthetized rabbit model.
Quinidine inhibits α 1 -adrenoceptors competitively at therapeutic blood levels (29), thereby preventing the complex sensitizing effect of α 1 -adrenoceptor stimulation in this animal model. A similar effect was seen in a recent study in which cisapride, a potent inhibitor of the rapid component of delayed rectifier potassium current (I Kr ), was found to have very low proarrhythmic potential in the rabbit model of acquired long QT syndrome (30). This was attributed to the drug's high α 1 -adrenoceptor blocking potency.
No torsade de pointes with amiodarone
Intravenous amiodarone did not induce ventricular tachyarrhythmias and did not significantly prolong QT and QT c in our experiments. Lack of i.v. amiodarone-induced QT and QT c prolongation in the current study is consistent with the findings of previous in vivo and in vitro rabbit studies. In anesthetized rabbits, 10 mg/kg i.v. bolus amiodarone failed to exert any effect electrocardiographically (31,32). Likewise, perfusion of isolated rabbit hearts with a buffer solution containing 1 μg/ml amiodarone had no effect on electrocardiographic intervals (33).
In anesthetized rabbits, the time of maximal uptake of i.v. bolus amiodarone by the myocardium has been estimated as between 5–15 min (31). Therefore, low accumulation of amiodarone in our experiments cannot be responsible for the low proarrhythmic activity. Amiodarone dose-relatedly lowered blood pressure, and the highest dose of the drug (30 mg/kg) induced marked blood pressure drop and bradycardia. This indicates that higher doses of the drug could not have been administered to the animals without inducing catastrophic hemodynamic effects. This suggests that despite the lack of effect on QT/QT c interval, amiodarone was not underdosed in the current study.
Acute and chronic electrophysiologic effects of amiodarone differ substantially (34,35). Although long-term administration of the drug prolongs repolarization markedly, it induces TdP only very rarely in humans (36). Though it is debatable whether acute amiodarone prolongs QT interval (5), TdP may be evoked by this administration of the drug in humans (4–6). However, proarrhythmic events are rare in patients treated with i.v. amiodarone (5), similarly to that seen in patients treated with long-term amiodarone therapy (36).
Intravenously administered amiodarone inhibits the delayed rectifier outward potassium current (I K ), the inward sodium current (I Na ), and the inward l -type calcium current (I Ca-L ) (34,37). The simultaneous inhibition of I K and I Na or I K and I Ca-L, achieved by combination of selective inhibitors, has been shown to have low proarrhythmic activity in the rabbit model of Carlsson et al. (16,17,27,38), probably as a result of the early after depolarization–suppressing or repolarization prolongation–limiting effect of I Ca-L and I Na inhibition, respectively. Intravenous amiodarone inhibits α-adrenoceptor in a noncompetitive manner (39), which could also contribute to the low proarrhythmic activity of the drug in this model.
Torsade de pointes with d -sotalol and almokalant
In the current study, only d -sotalol and almokalant induced TdP. Moreover, these drugs induced large number of ventricular tachycardias and noncomplex arrhythmias, e.g., ventricular premature beat, bigeminy, and salvo. In fact, TdP was always preceded by frequent occurrence of noncomplex arrhythmias and sometimes, ventricular tachycardia. Conversely, similarly to quinidine, d -sotalol and almokalant also induced conduction blocks in a dose-related manner. This agrees with the results of Lu et al. (25), who showed that the selective I Kr blocker dofetilide and the nonselective I Kr blockers clofilium, quinidine, and terfenadine evoke conduction blocks frequently in α 1 -adrenergically stimulated rabbits. The primary targets of I Kr blockers are the cells of the conductive system and the M cells (3). Extreme repolarization and refractory period prolongation of these cells may lead to blocks, especially at the relatively short cycle length of the rabbit. The initiating mechanism of TdP is probably related to ventricular premature beats, whereas the maintenance mechanism is related to reentry (3). Thus, frequent noncomplex arrhythmias and conduction blocks may play a role in the generation of TdP and other reentrant arrhythmias, e.g., ventricular tachycardia and ventricular fibrillation in the rabbit model of acquired long QT syndrome.
In the current study, TdPs induced by either d -sotalol or almokalant were always preceded by markedly prolonged QT and QT c intervals, elevated blood pressure, and relatively slow ventricular rate. In contrast, neither of these factors coincided, nor did TdP develop in amiodarone- and quinidine-treated animals. These findings suggest that the coincidence of markedly prolonged QT and QT c intervals, elevated blood pressure, and slow ventricular rate may be a prerequisite for TdP generation in the presently used animal model.
In the present investigation, almokalant and d -sotalol showed different proarrhythmic profiles in terms of ventricular tachyarrhythmia onset. These arrhythmias occurred before, during, or after the administration of the middle dose of almokalant compared with those after the administration of the middle dose of d -sotalol. This earlier onset of ventricular tachyarrhythmias coincided with elevated sinus rate in the almokalant group, whereas the effects of d -sotalol and almokalant were not different on the QT and QT c intervals, ventricular rate, and blood pressure. This suggests that not only QT and QT c prolongation, relatively low ventricular rate, and elevated blood pressure play a role in arrhythmia genesis in the rabbit model of TdP. Similarly to our findings, the proarrhythmic effects of these two relatively selective potassium channel blockers were different in a dog torsade model (40). Although both drugs widened QT in that study (40) also, only almokalant evoked TdP spontaneously, whereas programmed electrical stimulation was necessary to initiate this arrhythmia in d -sotalol-treated animals. In that study, almokalant increased the interventricular dispersion of repolarization and the number of early after depolarizations to a greater degree than d -sotalol.
Almokalant is a selective I Kr inhibitor (41), whereas d -sotalol inhibits I Kr and other potassium currents, i.e., transient outward current (I to ) and inward rectifier current (I K1 ) (8). This difference in potassium channel selectivity, or d -sotalol's residual β-adrenoceptor-blocking property (42) or possible differences between the time course of the development of repolarization dispersion between the drugs, might play a role in this different proarrhythmic profile of the two drugs.
Infusion rate of antiarrhythmics and occurrence of torsade de pointes
In the current study there was no direct correlation between the occurrence of TdP and the infusion rate or the dose of d -sotalol and almokalant, because the percentage incidences of this arrhythmia were greatest after the administration of the middle doses of the drugs. Carlsson et al. (13) reported that the occurrence of TdP is dependent on infusion rate. They suggested that this was fundamental to the occurrence of TdP. The present data demonstrate that dependence on infusion rate may be particular to the continuous infusion (13,15) and not to short-term infusions.
Selective and nonselective I Kr blockers evoke torsade de pointes in the rabbit
Recently Lu et al. (25) concluded that nonselective I Kr blockers do not induce TdP in the rabbit model of long QT syndrome, as quinidine and terfenadine did not evoke this arrhythmia in their studies, whereas dofetilide and clofilium did so. However, clofilium is not a selective I Kr blocker, as it affects I Na, I Ca-L, I to, I Kr, the slow component of the delayed rectifier potassium currents (I Ks ), and the ATP-dependent potassium current (I KATP ) in a similar concentration range (43–46). Similarly to clofilium, other nonselective I Kr blockers, e.g., the combined I Kr and I Ca-L blocker BRL-32872 (16), the combined I Kr and I Ks blocker azimilide (47), the combined I Kr and I K1 blocker sematilide (12,47), the combined I Na enhancer and I Kr blocker ibutilide (14,17), and the combined β-adrenoceptor and multiple potassium channel inhibitor d, l -sotalol (47), have hitherto been shown to induce TdP in the rabbit model of Carlsson et al. In our study, almokalant and d -sotalol evoked TdP. Almokalant is a selective I Kr inhibitor (41), whereas d -sotalol inhibits I Kr, I to, and I K1(8). These results and the previously published studies with several nonselective I Kr blockers show that I Kr selectivity is not an exclusive factor in TdP generation in the rabbit model of acquired long QT syndrome.
Our results suggest that the incidence of TdP may not depend on the infusion rate or the dose of antiarrhythmics when graded doses are applied with an interval. Furthermore, TdP generation may be a multifactorial process in the rabbit model of TdP, and the contributing factors may be slightly different from those in humans. Thus, drugs that have different pharmacodynamic actions at high heart rates (seen in the rabbit) compared with effects at lower heart rates (seen in humans), drugs that decrease blood pressure markedly, or drugs that possess α 1 -adrenoceptor inhibitory effects could elicit a false-negative outcome (i.e., low proarrhythmic activity) in the rabbit model of TdP.
The authors thank Dr. Leif Carlsson (Astra-Zeneca, Sweden) for the generous gift of almokalant; Mrs. Mária Györfi-Kosztka and Mrs. Zsuzsa Ábrahám for their skillful technical assistance; and Dr. Susan J. Coker (Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, U.K.) and Dr. Michael J. Curtis (The Rayne Institute, St. Thomas' Hospital, London, U.K.) for their helpful comments in the preparation of the manuscript.
This work was supported by the Hungarian National Research Fund (OTKA T 022300), Ministry of Health (ETT 06127, 06521, 10/2000), and the Ministry of Education (FKFP 0263/1999).
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Keywords:© 2002 Lippincott Williams & Wilkins, Inc.
α1 -Adrenoceptor stimulation; Almokalant; Amiodarone; Quinidine; d -sotalol; Torsade de pointes