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Cardiovascular Research 2001 50(2):328-334; doi:10.1016/S0008-6363(01)00232-2
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Copyright © 2001, European Society of Cardiology

Transgenic mice overexpressing human KvLQT1 dominant-negative isoform Part II: Pharmacological profile

Gilles Landea, Sophie Demolombea, Antoine Bammerta, Antoon Moormanb, Flavien Charpentiera and Denis Escandea,*

aINSERM U533, Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires G&R Laennec, Faculté de Médecine, 1 rue Gaston Veil, 44035 Nantes Cedex 01, France
bExperimental and Molecular Cardiology Group, and Facility for Genetically Modified Mice, Academic Medical Center, Amsterdam, The Netherlands

* Corresponding author. Tel.: +33-2-4041-2949; fax: +33-2-4041-2950 denis.escande{at}nantes.inserm.fr

Received 17 October 2000; accepted 19 January 2001


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: The acquired long QT syndrome results most often from the action of IKr blocking-drugs on cardiac repolarization. We have evaluated a transgenic (TG) mouse (FVB) overexpressing a dominant-negative KvLQT1 isoform, as an in vivo screening model for IKr blocking drugs. Results: In TG mice, six-lead ECGs demonstrated sinus bradycardia, atrioventricular block, and QTc prolongation. Various drugs were injected intraperitoneally after blockade of the autonomic nervous system and serial ECGs were recorded. The end of the initial rapid phase of the T wave corrected for heart rate using a formula for mouse heart (QTrc), was used as a surrogate for the QT interval. Dofetilide, a specific IKr blocker, did not prolong the QTrc interval either in TG or in wild-type (WT) mice but dose-dependently lengthened the sinus period in TG mice but not in WT mice. Other IKr blockers including E 4031, haloperidol, sultopride, astemizole, cisapride and terikalant behaved similarly to dofetilide. Tedisamil, a blocker of the transient outward current, dose-dependently prolonged the QTrc in WT mice but not in TG mice and also reduced the sinus rhythm in both WT and TG mice. Lidocaine dose-dependently shortened the QTrc interval in TG mice and also lengthened the P wave duration. Nicardipine dose-dependently shortened QTrc and also produced sinus arrest in both WT and TG mice. Conclusions: We conclude that KvLQT1-invalidated TG mice discriminates in vivo drugs that blocks IKr from drugs that block the transient outward current, the sodium current or the calcium current.

KEYWORDS Antiarrhythmic agents; Congenital defects; ECG; K-channel; Long QT syndrome; Repolarization


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
The congenital long QT (LQT) syndrome is characterised by a prolonged QT interval on the surface ECG, and is most often related to mutations in KCNQ1, a gene encoding for KvLQT1 K+ channel proteins [1]. In concert with its regulator minK, KvLQT1 channel underlies the slow component of the cardiac delayed rectifier current IKs [2,3]. It has been suggested that the acquired (drug-induced) long QT syndrome matches with silent forms of LQT gene mutations revealed by drugs. Indeed, the LQT syndrome has a low penetrance with up to 70% of LQT silent gene carriers having normal QTc interval in some families [4,5]. Silent gene carriers remain at high risk for sudden death, particularly after intake of one of the numerous drugs that delayed cardiac repolarization [6]. Most of these drugs alter cardiac repolarization by blocking the fast component of the cardiac delayed rectifier current IKr. Their identification at a preclinical stage remains a complex and challenging issue. In vitro testing can be conducted using action potential recordings and patch-clamp experiments [6]. In vivo testing exploring the effects of the parent compound but also of its metabolites can be established using multilead ECG recordings. However, currently available in vivo models are unsatisfactory (for a recent review see [6]).

We have established a transgenic (TG) mouse model in which KvLQT1 has been functionally invalidated by overexpression of its dominant negative isoform [7]. This KvLQT1 mouse model shares some common features with the long QT syndrome in patients including long QT and sinus node dysfunction [8,9]. We hypothesised that transgenic mice would be sensitised to the action of IKr pharmacological blockers and therefore that the TG model may demonstrate some value as an in vivo model to identify drugs that delay repolarization in human. Using standard ECG recordings, we found that drugs known to alter cardiac repolarization in human do not prolong the QTc interval in TG mice but instead profoundly affect sinus node automaticity in TG mice. Using various ECG parameters, we show that our transgenic LQT model discriminates drugs that block IKr from drugs that block the transient outward current, the sodium current or the calcium current.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Study design
Pharmacological characterisation of KvLQT1 deficient TG mice was conducted in 124 WT and 132 TG mice by means of surface ECG recordings. We have established different KvLQT1-deficient lineages [7]. Among these, a lineage with a phenotype of intermediary severity (H08 lineage) but with well-defined P and T waves, was selected for the present study. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). All animals were 4–6 weeks-old (18–22 g) male and female TG mice, and age- and weight-matched littermate WT controls. Mice were anaesthetised with etomidate (15 mg/kg) given intraperitoneally (i.p.). They were placed under a heating lamp to prevent loss of body heat, which was continuously monitored with an electronic thermometer. The autonomic nervous system was blocked 5 min after anaesthesia using atropine sulphate (0.5 mg/kg i.p.) and propanolol (1 mg/kg i.p) [10]. A single dose of the drug under investigation was i.p. injected 10 min after anaesthesia. All drugs were given individually. The maximum effects of drugs as assessed by continuous ECG monitoring were observed at around 10 min post i.p. injection, and remained stable for several minutes. Serial surface electrocardiograms were collected 15 min after i.p. injection. The effects of a drug dosage were compared with those of its vehicle alone. Six mice were used per pharmacological intervention for each set of data analysed.

2.2 Surface electrocardiogram recording
To record surface ECGs, the mouse's four paws and four Ag electrodes were plunged into eight Eppendorf tubes, filled with KCl (2 mol/l) solution, and connected with KCl (2 mol/l) Agar bridges. The signal was amplified and filtered (bandwidth, 0.5–125 Hz), and the cardiac ECG was continuously monitored (Monitor 123, Roche, Bio-Electronics, Digital Electronics). Surface six-lead ECGs (I, II, III, aVR, aVL, aVF) were displayed with a chart recorder (Easy Graph, TA 240, Gould Electronics) at a paper speed of 100 mm/s. All reported measurements were averaged from five consecutive PQRST complexes in lead I. [7]. In both WT and TG animals, the T wave had a biphasic appearance with an initial rapid component (Tr positive in lead DI) and a late slower component (Ts negative in lead DI). The rapid component Tr was markedly prolonged in the H08 lineage used for the present study. The P wave often superposed with the terminal phase of the previous slower component of the T wave because of dramatic QT and PR lengthening (Fig. 1). For more accuracy, we considered the end of the Tr wave as a surrogate for the end of the T wave. The QTr interval was measured from the beginning of the QRS complex wave to the end of the Tr wave (Fig. 1). The QTr interval was corrected for heart rate using the formula, QTrc=QTr /(RR/100)1/2 with QTr and RR expressed in ms, which yields a theoretical QTrc interval for a 100-ms cycle length [11].


Figure 1
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  		Fig. 1 Measurement of ventricular repolarization on surface ECG in transgenic mice (lead I). For clarity, QRS peaks have been erased. The QTr interval was measured from the beginning of the QRS complex to the end of the Tr wave (arrow). The end of Tr coincides with the point at which the T wave deviates from the tangent to the steepest slope of the Tr wave (plain line).

 
2.3 Drugs
We used commercially available solutions for etomidate (Janssen-Cilag), atropine sulphate (Renaudin), propanolol chlorhydrate (Zeneca Pharma), sultopride chlorhydrate (Delagrange), lidocaine chlorhydrate (Aguettant), nicardipine chlorhydrate (Novartis), and haloperidol (Janssen-Cilag). Dofetilide, E4031, terikalant, tedisamil, astemizole and cisapride were obtained as free bases. Atropine sulphate and propanolol were 1/3 diluted in 0.9% NaCl. Other solutions and hydrophilic free bases were diluted in HEPES Tyrode's solution at pH 5 and then buffered at pH 7.4 using NaOH. Prior dilution in acid water was performed for dofetilide. The final dilution was adjusted so that the injected volume per dose and per animal was always 300 µl. Hydrophobic drugs (astemizole and cisapride) were diluted in dimethylsulfoxide (Sigma), so that the injected volume per dose and per animal was always 25 µl.

2.4 Statistical analysis
All ECG data are presented as a mean±standard deviation. Mean data were compared using analysis of variance. If a statistically significant level was reached (P<0.05), a multiple comparison procedure (Fisher's PLSD test) was performed to determine which pair(s) of means were statistically different.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Effects of IKr blockers
We first evaluated the effects of dofetilide, a well-established specific blocker of the IKr potassium current [12,13]. The dose-dependent effects of dofetilide were investigated in WT and TG mice. As shown in Fig. 2, dofetilide produced no significant effects on the QTrc duration either in WT or TG mice. The P wave duration was not significantly altered by dofetilide either in WT or TG mice. In contrast, dofetilide dose-dependently lengthened the PP interval in both WT (P = 0.0001 with analysis of variance) and TG mice (P = 0.0001). The dofetilide-induced PP interval lengthening was more pronounced in TG than in WT mice: in TG mice the PP interval increased from 136±21 ms (vehicle) to 266±23 ms (+96%; dofetilide 2 mg/kg), whereas in WT mice, it increased from 112±15 ms (vehicle) to 154±16 ms (+ 37%) only. In addition, dofetilide consistently shortened the PR interval in TG mice (P = 0.03) but not in WT mice. In TG mice, the PR interval shortening was dose-dependent, and paralleled the lengthening of the PP interval.


Figure 2
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  		Fig. 2 Effects of dofetilide on surface ECG in wild-type (WT) and transgenic (TG) mice. (A) Representative ECG recordings (lead I) obtained in a WT (top) and a TG mouse (bottom) under control conditions (C) and after i.p. injection of 0.02, 0.2 and 2 mg/kg dofetilide. For clarity, QRS peaks have been erased. (B) Effects of increasing doses of dofetilide on PP interval (top left), P wave duration (top right), PR interval (bottom left) and QTrc interval (bottom right). Open symbols: WT mice (n = 6); filled symbols: TG mice (n = 6). Each data point represent the mean of six different mice injected with a single dose of dofetilide. Mean data were compared using analysis of variance. If a statistically significant level was reached, a multiple comparison procedure (Fisher's PLSD test) was performed to determine which pair(s) of means were statistically different. The result of this test is indicated using letters a, b and c. b denotes a value statistically different from a and different from c.

 
Various drugs known for their ability to block the IKr current and also to prolong the QT interval in human were further evaluated in the TG mouse model (Fig. 3). In WT and TG mice, the effects of E4031 [14] (20 mg/kg) and of terikalant [15] (10 mg/kg) were similar to those produced by dofetilide. In particular, E4031 and terikalant did not prolong the QTrc duration either in WT or TG mice but induced a PP interval prolongation that was more pronounced in TG mice (+191% with E4031 and +96% with terikalant) than in WT mice (+59% and +19%, respectively; P = 0.0001). We also investigated the effects of sultopride [16] (200 mg/kg), haloperidol [17] (7 mg/kg), astemizole [18] (10 mg/kg), and cisapride [19] (20 mg/kg). Again, the effects induced by these drugs on WT and TG mice were comparable to those induced by more specific IKr blockers. The PP interval prolongation was also much greater in TG mice (+105%, +78%, +183% and +148%, with sultopride haloperidol, astemizole and cisapride, respectively) than in WT mice (+22%, +6%, +15% and +36%; P<0.003). However, at the tested dose, sultopride, haloperidol, astemizole, and cisapride did not decrease significantly the PR interval in TG or WT mice (not illustrated). No IKr blocking drug modified the P wave duration or the QTrc interval in WT or TG mice.


Figure 3
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  		Fig. 3 Effects of various IKr blockers on surface ECG in wild-type (WT) and transgenic (TG) mice. The left panel represents the effects of the vehicle and of IKr blockers (y axis) on the PP interval duration (x axis). Open bars: WT mice (n = 6); filled bars: transgenic mice (n = 6). ***, P<0.001 and ****, P<0.0001 versus WT with analysis of variance. The right panel shows corresponding ECG traces in lead I. For clarity, QRS peaks have been erased. Each data point represent the mean of six different mice injected with a single dose of drugs.

 
3.2 Effects of tedisamil
Tedisamil [20] is a potent inhibitor of the transient outward K+ current, Ito. As illustrated in Fig. 4, tedisamil lengthened the duration of the rapid phase of the T wave both in WT and TG mice. In WT mice, the shape of the T wave under tedisamil mimicked that recorded in TG mice under control conditions (Fig. 4A). In contrast to IKr blockers, tedisamil dose-dependently prolonged the QTrc interval in WT mice (from 19±2 ms with the vehicle to 39±4 ms with 50 mg/kg tedisamil; P = 0.0001), an effect not observed in TG mice (Fig. 4B). In addition, tedisamil dose-dependently prolonged the PP interval in both WT (P = 0.0001) and TG (P = 0.0001) mice. In contrast with the effects of IKr blockers, the PP lengthening produced by tedisamil was in the same order of magnitude in WT and TG mice: the PP interval increased from 112±15 ms (vehicle) to 283±57 ms (+153%; 50 mg/kg tedisamil) in WT mice, and from 136±21 ms (vehicle) to 374±97 ms (+175%) in TG mice. The P wave duration was slightly prolonged at the highest tedisamil dose in WT mice (P = 0.001) but not in TG mice. In TG mice, the tedisamil-induced lengthening in the sinus period did not associate with a PR interval shortening.


Figure 4
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  		Fig. 4 Effects of tedisamil on surface ECG in wild-type (WT) and transgenic (TG) mice. Same symbols and abbreviations as in Fig. 1.

 
3.3 Effects of Na+ channel block
As shown in Fig. 5, lidocaine dose-dependently shortened the QTrc interval in TG mice (from 45±3 ms with the vehicle to 30±3 ms with lidocaine 80 mg/kg; P = 0.003), whereas the drug produced no significant effects on the QTrc interval in WT mice. Lidocaine also prolonged the PP interval with a similar efficacy in WT (P = 0.0001) and TG (P = 0.0001) mice: the PP interval increased from 112±15 ms (vehicle) to 190±39 ms (+70%; 80 mg/kg lidocaine) in WT mice, and from 136±21 ms (vehicle) to 240±27 ms (+76%) in TG mice. It should be noted, however, that the effects of lidocaine on the PP interval essentially occurred at the highest drug dosage (Fig. 5). The most striking effect of lidocaine consisted in a dose-dependent P wave lengthening which was observed both in WT and TG mice. The PR interval was also dose-dependently prolonged by lidocaine in WT mice (P = 0.0001) whereas it was not significantly altered by the drug in TG mice.


Figure 5
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  		Fig. 5 Effects of lidocaine on surface ECG in wild-type (WT) and transgenic (TG) mice. Same symbols and abbreviations as in Fig. 1.

 
3.4 Effects of Ca2+ channel block
Data obtained with nicardipine [21] are depicted in Fig. 6. The most remarkable effect of nicardipine consisted of a sinus arrest often preceded by isorhythmic dissociation (Fig. 6A). In TG mice, sinus arrest occurred in most animals for every tested dose. In WT mice, sinus arrest occurred at the highest dosage (10 mg/kg) only. Sinus arrest under the effects of the drug was observed between 17 and 22 min after injection, so that the PP interval could be measured 15 min postinjection. Nicardipine dose-dependently prolonged the PP interval in both WT (P = 0.0001) and TG (P = 0.0001) mice. As with IKr blockers, the nicardipine-induced PP lengthening was more pronounced in TG than in WT mice: the PP interval increased from 136±21 ms (vehicle) to 448±124 ms (+229%; 10 mg/kg nicardipine) in TG mice, whereas it increased from 112±15 ms (vehicle) to 210±67 ms (+88%) only in WT mice. Finally, we observed a dose-dependent QTrc shortening in both WT (from 19±2 ms with the vehicle to 10±1 ms with 10 mg/kg nicardipine; P = 0.0001) and TG mice (from 45±3 ms to 23±6 ms; P = 0.0001). By contrast, the P wave duration and the PR interval were not significantly altered by the drug.


Figure 6
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  		Fig. 6 Effects of nicardipine on surface ECG in wild-type (WT) and transgenic (TG) mice. Same symbols and abbreviations as in Fig. 1.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
We have evaluated a KvLQT1-deficient transgenic mouse, as a model suitable to identifying IKr blocking drugs. Our results show that combined in vivo pharmacological investigation of wild-type and transgenic mice discriminates drugs that blocks IKr from drugs that block the transient outward current, Ito, the sodium current, INa, or the calcium current, ICa,L. Drugs that block IKr, Ito, INa or ICa,L all decreased the sinus rate (Table 1). However, IKr blockers and nicardipine produce bradycardia preferentially in TG mice, in contrast to Ito and INa blockers. Most importantly, IKr blockers do not prolong the QT duration either in WT or TG mice. In contrast, INa or ICa,L blockers reduce the QT duration whereas the Ito blocker prolongs the QT duration in WT mice. Finally, the INa blocker lidocaine markedly increases the P wave duration.


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  		Table 1 Summary of the effects of IKr, INa, and ICa,L blockers on surface ECG parameters in wild type (WT) and transgenic (TG) mice

 
In contrast to the human heart, IKr does not contribute substantially to repolarization in adult mice [22]. In line with this, adult transgenic mice over-expressing a dominant-negative HERG mutated gene exhibit normal QT duration [23]. Furthermore, dofetilide does not prolong the QTc interval in normal adult mice (Ref. [24] and present data). The contribution of IKr to the sinus node automaticity remains also modest in normal adult mice since dofetilide produces bradycardia at high doses (>0.5 mg/kg) only (Ref. [24] and present data). In our transgenic mice, we believe that functional suppression of IKs and/or remodeling of K+ channels [7] exacerbate the relative role of IKr in pacemaking and result in a markedly increased sensitivity of the sinus node to the bradycardic effects produced by IKr blockers.

In contrast to IKr, the transient outward current, Ito, is a dominant repolarising current in the adult mouse heart [25]. Functional suppression of Kv4.2 decreases the Ito current amplitude, and prolongs both action potential and QT interval durations in adult mice [26]. In normal mice, 4-aminopyridine, a blocker of transient outward current prolongs the QTc interval [24]. In our own experiments, tedisamil dose-dependently prolonged the QTrc in WT mice but not in TG mice suggesting that the current blocked by tedisamil was already down-regulated in TG mice. In line with this, in TG mice we reported down-expression of Kv 4.2 channels accompanied by a decreased Ito current density [7]. Ito, has been shown to contribute also to sinoatrial automaticity in other species including the rabbit [27] and the rat [28]. In human, clinical studies reported a bradycardic action of tedisamil [29–31].

A decreased INa window current is usually evoked to explain the action potential shortening as produced by lidocaine [32]. In our study, dose-dependent shortening of QTrc occurred in TG mice only, suggesting that INa current has a greater relative contribution to ventricular repolarization in TG than in WT mice. It is usually believed that INa plays little or no role in pacemaker cells. In the rabbit sinus node however, Kreitner [33] reported that pacemaker activity depends on two cell types having different pacemaker mechanisms, one of them being partly due to the INa current. In the present study, lidocaine prolonged the PP interval in WT and TG mice although this effect remained modest. A dose-dependent enlargement of the P wave duration was the main feature of lidocaine both in WT and TG mice. Reduction in the upstroke velocity of the action potential characterises INa blockers and is likely to account for the conduction slowing in atrial cells. In WT mice, prolongation of the PR interval could be related to prolongation in the intra-auricular conduction time as suggested by the parallelism between P wave and PR prolongation.

In the isolated rabbit heart, blocking the L-type Ca2+ current result in a significant shortening of the papillary muscle action potential and QTc interval [34]. We found a dose-dependent QTrc shortening in both WT and TG mice. In rabbit sinus node cells, ICa,L blockers reduce the rate of diastolic depolarisation and eventually abolish spontaneous activity [35]. A negative chronotropic effect of dihydropyridine has also been reported in various species whether on isolated sinus node or atrial tissues, or perfused hearts. In contrast, nicardipine shortens the sinus cycle length in humans [36] as a result of the adrenergic stimulation related to the drop in blood pressure. In our study performed under blockade of the autonomic nervous system, nicardipine caused a dose-dependent lengthening of the PP interval in TG mice, and to a lesser extent in WT mice. We propose that the ICa,L current contributes largely to the sinus node automaticity in mouse. Again, in TG mice, functional suppression of IKs and/or remodeling of K+ channels may exacerbate the relative role of ICa,L in pace-making and result in an increased sensitivity of the sinus node to the bradycardic effects produced by nicardipine.

The pharmacological profiles of IKr, INa, ICa,L and Ito blockers in mice profoundly differs from those reported in larger animals and in human. This is not surprising since the cellular electrophysiological characteristics of myocytes from small size rodents including mice and rats also markedly differ from those reported for larger animals and human. For example, IKr plays only a minor role during repolarization in the mouse [22] whereas this current is crucial for repolarization in the dog [37] and in the human heart [38]. In that setting, the cardiac repolarization of either normal or transgenic mice is not sensitive to QT prolonging drugs, in stark contrast with the dog or the human heart.

Time for primary review 27 days.


   Acknowledgements
 
We thank Sabine Erbibou, Franck Cosson and Pascal Gervier for expert technical assistance. We also thank Dr. Anne-Marie Le Ray for her help with molecule solubilisation. Supported by INSERM PROGRES and G.I.P. "Fonds de Recherche" Hoechst Marion Roussel grants.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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