© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Effects of ambasilide, quinidine, flecainide and verapamil on ultra-rapid delayed rectifier potassium currents in canine atrial myocytes
Department of Pharmacology and Therapeutics, McGill University, Department of Medicine, University of Montreal, and Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8
* Corresponding author. Tel.: +1-514-376-3330; fax: +1-514-376-1355 nattel{at}icm.umontreal.ca
Received 21 September 1999; accepted 16 December 1999
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Abstract |
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Objective: A dog atrial ultra-rapid delayed rectifier current (IKur.d) is involved in canine atrial repolarization and shares similarities with the human atrial ultra-rapid delayed rectifier (IKur). Almost no information is available about the actions of antiarrhythmic drugs on IKur.d. This study evaluated effects of ambasilide, quinidine, flecainide and verapamil on IKur.d in isolated canine atrial myocytes. Methods: Standard whole-cell patch clamp techniques were used to study the effects of multiple concentrations of each drug. Results: All drugs produced reversible concentration-, voltage- and time-dependent IKur.d inhibition. Significant effects of quinidine, flecainide and ambasilide were noted at atrial-effective antiarrhythmic concentrations in the dog. Upon the onset of a depolarizing pulse, block developed exponentially in relation to time, with the blocking rate-constant increasing with drug concentration, consistent with open-channel blockade and permitting the calculation of forward and reverse rate-constants. For all drugs, the 50% blocking concentration (EC50) showed significant voltage-dependence, decreasing at more positive potentials. The magnitude of voltage-dependent block was directly related to the degree of drug-induced shift in the voltage dependence of activation (r=0.97), pointing to open-channel block as a mechanism for voltage-dependent action. An additional component of voltage-dependence suggested that blocking sites were subjected to 17–21% of the transmembrane voltage field. Conclusions: Ambasilide, quinidine, flecainide and verapamil inhibit IKur.d, with preferential action on the open state. IKur.d inhibition may play a role in antiarrhythmic effects in canine atrial arrhythmia models. Comparisons between the effects of these drugs on IKur.d and previously studied effects on IKur suggest potential opportunities for investigating the molecular structural determinants of drug-blocking action on atrial-specific ultrarapid delayed rectifiers.
KEYWORDS Antiarrhythmic agents; Arrhythmia (mechanisms); Ion channels; K-channel; Supraventricular arrhythmia
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1 Introduction |
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Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice [1]. Treatment for AF, however, remains far from optimal. In order to improve therapeutic approaches to AF, wide use is being made of experimental models [2]. The most commonly-used species to study mechanisms of AF and of antiarrhythmic agents is the dog [2,3]. Since AF is predominantly a reentrant arrhythmia, tissue refractoriness (and its primary cellular determinant, action potential duration [APD]) is a major factor controlling arrhythmia occurrence [3].
Antiarrhythmic drugs alter refractoriness by modifying APD via changes in ionic currents. Several currents controlling canine atrial repolarization, such as the delayed rectifier (IK), the transient outward K+-current (Ito) and L-type Ca2+-current (ICa), have properties similar to corresponding currents in human atrium [4–7]. The human ultra-rapid delayed rectifier current (IKur) is important in human atrial repolarization [8] and, because of its atrial-specific distribution [9] is a potentially interesting target for antiarrhythmic drug therapy [10,11]. The canine counterpart, the dog ultra-rapid delayed rectifier IKur.d, also plays an important role in atrial repolarization [12]. It was therefore of interest to evaluate the effects of a variety of cardioactive drugs on IKur.d, and to compare these with previously evaluated effects on IKur. We elected to assess the widely used antiarrhythmic agents flecainide and quinidine, the investigational antiarrhythmic compound ambasilide and the L-type Ca2+-channel blocker verapamil, the effects of which on IKur or its molecular equivalent, Kv1.5 [9], have been reported [13–15]. The present study was therefore designed to evaluate the effects of ambasilide, quinidine, flecanide and verapamil on IKur.d.
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2 Methods |
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2.1 Cell isolation
Single canine atrial myocytes were isolated by a previously developed arterial perfusion method [7]. Adult mongrel dogs (n=32, 18–25 kg) were anesthetized with pentobarbital (30 mg/kg i.v.), their hearts removed and immersed in Tyrode solution containing 2 mM CaCl2. Animal handling procedures were approved by the Animal Research Ethics Committee of the Montreal Heart Institute according to the Canadian Council on Animal Care and the investigation conformed 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 solutions for dissection and perfusion were equilibrated with 100% O2. The right coronary artery was cannulated and the right atrium perfused with 2 mM Ca2+-containing Tyrode solution at 37°C until the effluent was clear of blood. Any leaks were ligated to assure adequate perfusion. The tissue was perfused at 12 ml/min with Ca2+-free Tyrode solution for 20 min, followed by 40-min perfusion with the same solution containing collagenase (100 Units/ml, CLS II, Worthington Biochemical, Freehold, NJ) and 1% bovine serum albumin. A small piece of tissue was minced and cells separated by trituration. Cells were kept at room temperature in a high-K+ storage solution before use.
Only quiescent rod-shaped cells showing clear cross-striations were used. Five minutes were allowed for cell adhesion to the bottom of the 1-ml chamber, and then cells were superfused at 3 ml/min. Experiments were performed at room temperature to resolve the very rapid activation of IKur.d [12].
2.2 Solutions
The high-K+ storage solution contained (mM): 20 KCl, 10 KH2PO4, 10 dextrose, 70 glutamic acid, 10 β-hydroxybutyric acid, 10 taurine, 10 ethyleneglycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA); albumin 1%, pH 7.4 (KOH). The Tyrode solution for cell isolation and extracellular solution for patch clamp studies contained (mM): 126 NaCl, 2 CaCl2, 5.4 KCl, 0.8 MgCl2, 0.33 NaH2 PO4, 10 dextrose, 10 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic (HEPES), pH 7.4 (adjusted with NaOH). The pipette solution for voltage-clamp studies contained (mM): 0.1 GTP, 110 K-aspartate, 20 KCl, 1 MgCl2, 5 Mg2ATP, 10 HEPES, 5 Na2-phosphocreatine, 10 EGTA; pH was adjusted to 7.4 with KOH. Ambasilide was obtained from Knoll Pharmaceuticals (Mississauga, ON). Quinidine, verapamil and flecainide were purchased from Sigma Chemicals (St. Louis, MO). For voltage-clamp recording, CdCl2 (200 µM) was added to the extracellular solution (to inhibit ICa and ICl.Ca) and dofetilide (1 µM) was used to prevent contamination by IKr.
2.3 Data acquisition
Borosilicate glass electrodes (outer diameter, 1.0 mm) were filled with pipette solution (resistance 2–3 M
) and connected to an Axopatch 1-D amplifier (Axon Instruments, Foster City, CA). Command pulses were generated by a 12-bit analog-to-digital converter controlled by pClamp software (Axon). Recordings were low-pass filtered (10 kHz) and series resistance compensated.
Junction potentials (2–8 mV) were zeroed before formation of the membrane-pipette seal. Seal resistance averaged 9.7±1.2 G. Several minutes after seal-formation, the membrane was ruptured to establish the whole-cell configuration. The series resistance (Rs) was electrically compensated to minimize the duration of the capacitive surge. Rs was estimated by dividing the capacitive time constant (
cap) by the membrane capacitance (the time-integral of the capacitive response to 5-mV hyperpolarizing steps from a holding potential [HP] of –60 mV, divided by the voltage difference). Before Rs compensation, cap was 537±26 µs (capacitance, 74.6±4.1 pF) and Rs 7.1±0.4 M. After compensation cap was reduced to 154±9 µs (cell capacitance, 75.7±4.5 pF) and Rs to 2.0±0.2 M. The mean maximum voltage drop across Rs did not exceed 3 mV. Cells with significant leak currents were rejected — leakage compensation was not applied.
2.4 Data analysis
IKur.d step current was measured at the end of a depolarizing pulse. Tail current was measured as the difference between initial current upon repolarization to –30 mV and the value at the end of the repolarizing step. All concentration–response analyses were based on tail currents, to avoid distortion by any non-specific component during depolarizing steps. Concentration–response curves were fitted by an equation of the form: E=Emax{1/[1+(EC50/C)n]}, where E is the effect at concentration C, Emax is maximal effect, EC50 is the concentration for half-maximal effect and n is the Hill coefficient. Group data are presented as mean±S.E.M. Statistical comparisons were made using two-way ANOVA and t-tests with Bonferroni correction. A two-tailed P<0.05 was taken to indicate statistical significance.
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3 Results |
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3.1 Effects of ambasilide on IKur.d
Fig. 1A shows typical IKur.d recordings elicited by 140-ms depolarizations at 0.1 Hz to potentials between –40 and +60 mV, followed by repolarization for 60 ms to –30 mV to record tail currents. A HP of –50 mV and an 80-ms prepulse to +30 mV 10 ms before the test pulse were used to suppress Ito and elicit selectively IKur.d as previously described [12]. This voltage protocol was used for all recordings in the study. The typical features of IKur.d, including rapid activation, slow inactivation, distinct tail currents and inward rectification at positive potentials were observed. Ambasilide decreased both step and tail currents (Fig. 1B and C), with effects reversed upon 20-min washout (Fig. 1D).
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The concentration-dependent effects of ambasilide were evaluated in six cells that were exposed to multiple concentrations of the drug, followed by washout. Mean current density–voltage relations under control conditions, in the presence of 10, 30, 100 µM ambasilide, and after washout are shown in Fig. 2A. Fig. 2B shows concentration-dependent changes upon depolarization to +30 mV. EC50 averaged 37.5±1.6 µM and the Hill coefficient 1.5±0.1. Fig. 2C shows mean percentage changes in IKur.d at each test potential. Drug-induced changes tended to be larger at more positive voltages, but the voltage dependence was not statistically significant. Fig. 2D shows activation voltage-dependence from normalized tail current–voltage relations under control conditions and in the presence of 30 µM ambasilide (the concentration studied that was closest to the EC50). The voltage for half-maximal activation (V1/2) and slope factor averaged 3.6±0.6 and 8.4±1.1 mV in six cells under control conditions, and 2.0±0.9 and 7.9±1.3 mV (P=NS) in the presence of ambasilide.
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Current inhibition during a pulse was time-dependent, as illustrated for pulses to +30 mV in Fig. 3A. Drug-induced current inhibition is expressed as a function of the outward current observed in the absence (ICtl) and in the presence (IAmb) of the drug at each time point following step depolarization, as ((ICtl–IAmb)/ICtlx100%). The current inhibition increased in an exponential manner and the rate of development of inhibition was concentration-dependent, pointing to possible state-dependent blocking mechanisms related to channel depolarization. The time-constants of block (
B) averaged 10.4±1.8, 7.2±1.2, 5.7±0.8, and 4.4±1.0 ms for 10, 30, 50, and 100 µM ambasilide, respectively.
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The decreasing time-constants of block with increasing drug concentration are consistent with a simple bimolecular interaction between drug molecules and channels when the cell is depolarized, with a forward (blocking) rate constant kon and a reverse (unblocking) rate constant koff. The dissociation constant (Kd) would then be koff/kon and
B at any concentration [D] would be given by koff/(kon[D]+koff), with the net blocking rate constant K being given by 1/B. Fig. 3B shows the relationship between K and ambasilide concentration, along with the best-fit regression line. Least-squares linear fitting of the relationship between K and [D] in each experiment gave values for kon and koff of 1.8±0.6 µM–1s–1 and 84.7±9.5 s–1, respectively, providing a mean Kd estimate of 43.9±5.1 µM, close to the independently estimated EC50 of 37.5±1.6 µM (Fig. 2B).
3.2 Effects of quinidine on IKur.d
The effects of quinidine on IKur.d in one cell are illustrated in Fig. 4. Mean current density–voltage relations in six cells before and after exposure to 1, 10, and 100 µM quinidine and after washout are shown in Fig. 5A. Quinidine decreased IKur.d density, with clear concentration-dependence. A concentration–response analysis for quinidine effects on IKur.d at +30 mV is illustrated in Fig. 5B. EC50 averaged 5.0±0.3 µM and the Hill coefficient 0.7±0.1.
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Quinidine produced significant voltage-dependent effects on IKur.d (Fig. 5C), with inhibitory effects increasing between –10 and +20 mV and reaching steady-state between +30 and +60 mV. Fig. 5D shows values for tail currents under control conditions and following 10 µM quinidine (the concentration studied that was closest to the EC50), normalized to values at the most positive step potentials. In six experiments, V1/2 averaged 5.5±0.5 mV (control) and –2.5±0.3 mV (quinidine, P<0.01), and slope factors were 8.4±0.6 (control) and 4.0±0.4 mV (quinidine, P<0.05).
To evaluate the time-dependence of quinidine block, we analyzed current inhibition by the drug as a function of time during a voltage step to +30 mV as illustrated in Fig. 6A. The blocking time-constants were 10.6, 3.6, and 1.6 ms with 1, 10, and 100 µM quinidine, respectively, in the example shown, resembling qualitatively the behavior of ambasilide in Fig. 3A. Fig. 6B shows a plot of the blocking rate constant vs. concentration of quinidine for data obtained in six experiments. The Kd obtained from this analysis (8.5±0.7 µM) is in agreement with the EC50 obtained from the concentration–response curve (Fig. 5B).
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3.3 Effects of flecainide on IKur.d
The response of one cell to flecainide is illustrated in Fig. 7. Mean current density–voltage relations in six cells before and after 1, 10, and 100 µM flecainide and after washout are shown in Fig. 8A. Fig. 8B shows concentration-dependent effects of flecainide on IKur.d evaluated in six cells at +30 mV. The EC50 of flecainide on IKur.d averaged 2.9±0.2 µM and the Hill coefficient 0.8±0.1. Fig. 8C shows percentage block as a function of voltage. The effect of flecainide increased significantly at more positive voltages. Fig. 8D shows the IKur.d activation curve fitted by a Boltzmann equation. The V1/2 and slope factor averaged 8.05±0.56 and 8.40±0.51 mV, respectively, under control conditions, and 3.09±0.46 and 8.07±0.41 mV in the presence of 5 µM flecainide (P<0.01 for change in V1/2).
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The time-dependent development of block during a depolarizing pulse in the presence of flecainide is shown in Fig. 9A. Inhibition increased in an exponential manner, with a
B of 24.1, 3.9, and 1.8 ms for 1, 10, and 100 µM flecainide in the example shown. Both maximum inhibition and the rate of development of inhibition were concentration-dependent. The average Kd obtained from Kd=koff/kon in six experiments was 6.5±0.8 µM, of the same order as the directly determined EC50 value of 2.9 µM shown in Fig. 8B.
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3.4 Effects of verapamil on IKur.d
Fig. 10 illustrates the concentration-dependent effects of verapamil on IKur.d in one cell, as well as their reversal by drug washout. Mean IKur.d density–voltage relations in six cells before and after 1, 5 and 10 µM verapamil and after washout are shown in Fig. 11A. Concentration-dependent effects of verapamil at +30 mV are shown in Fig. 11B. EC50 averaged 2.2±0.3 µM and Hill coefficient 1.5±0.2 (n=6). Fig. 11C shows percentage block at each concentration as a function of voltage. Verapamil-induced inhibition showed significant voltage-dependence. Fig. 11D shows mean normalized tail currents under control conditions and following 5 µM verapamil. V1/2 averaged 5.7±1.0 and –3.6±.6 mV (P<0.001), and slope factor 9.6±1.0 and 5.4±.5 (P<0.01) under control conditions and in the presence of verapamil, respectively.
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A kinetic analysis of verapamil block during a depolarizing pulse to +40 mV is shown in Fig. 12A. Fig. 12B presents a quantitative analysis of drug blocking and unblocking rate constants based on rates of block onset. Kd averaged 5.9±0.6 µM, of the same order as the directly estimated EC50 (2.2 µM).
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3.5 Possible role of open-channel block in voltage- and time-dependence of drug effects
The time-dependent block during a depolarizing pulse and the voltage-dependence of block are compatible with preferential drug interaction with the open state. To investigate further the voltage-dependence of drug action, we calculated the EC50 for each drug at each step voltage with the use of drug inhibition of tail currents following steps to the voltages indicated (Fig. 13A). The EC50 for each drug showed significant voltage-dependence. We noted that the shift in the activation V1/2 and the degree of voltage-dependent action varied among the compounds we studied. We therefore plotted the degree of voltage-dependence of inhibition ([% Inhib+60–% Inhib–10]/% Inhib+60x100%, where % Inhib+60, % Inhib–10=percentage current inhibition by the drug at +60, and –10 mV, respectively) as a function of the activation–voltage shift caused by the same drug concentration (Fig. 13B). The degree of voltage-dependent drug effect was directly related to the drug-induced shift in the voltage-dependence of activation (r=0.97), pointing to preferential open state block as a mechanism for voltage-dependent actions. However, for each drug, slight but perceptible voltage-dependent block was noted at voltages associated with full activation (positive to +20 mV). When these data were fitted to a Woodhull relation as in Ref. [16], we estimated fractional distances in the transmembrane electrical field of 0.17 (ambasilide), 0.21 (quinidine), 0.20 (flecainide) and 0.19 (verapamil), similar to previous reports for several drugs on IKur/Kv1.5 [15–17]. This finding points to an additional component to voltage-dependent block, over and above open-state blocking, due to an influence of the voltage field on the affinity of each drug for a binding site within the pore. Moreover, the similarity among drugs in the calculated electrical distances suggests that they may share a common binding site, or at least that the binding sites are in close physical proximity.
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4 Discussion |
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We have shown that ambasilide, quinidine, flecainide, and verapamil block IKur.d in a concentration, time and voltage-dependent manner. Furthermore, the nature of blocking actions suggest preferential interaction with the open channel state.
4.1 Comparison with previous studies of antiarrhythmic drug block of ultra-rapid delayed rectifier currents
All the drugs we evaluated have previously been studied for effects on human IKur or its cloned counterpart, cardiac Kv1.5 currents. The EC50 for ambasilide and quinidine inhibition of IKur are in the range of 35 and 5 µM, respectively [13,15]. These values are close to the results we obtained for the inhibitory actions of ambasilide and quinidine on IKur.d. Flecainide does not affect IKur [15], but inhibited IKur.d potently (EC50 of about 3 µM) in the present study. Similarly, verapamil inhibits Kv1.5 currents with an EC50 in the range of about 50 µM, an order of magnitude less potently than the effects observed on IKur.d in the present study [14]. These discrepancies may reflect the different molecular structure of IKur compared to IKur.d. Whereas Kv1.5 channel subunits underlie IKur [9], IKur.d appears to be formed by channel subunits of the Kv3.1 type [18]. Molecular differences in the sequences of the two clones are likely responsible for the differences in blocking profiles. This notion remains to be tested with the appropriate molecular electrophysiological methods.
All the drugs tested in the present series appeared to act via a preferential interaction with IKur.d channels in their open state. Similarly, IKur block by ambasilide, quinidine and the Ca2+ antagonist perhexiline appears to be open state-dependent [13,15,19]. Homomeric Kv1.5 channels also show open-channel block by quinidine [17], clofilium [20], nifedipine [21] and zatebridine [10]. Hydrophobic interactions appear to be important in stabilizing the drug-receptor complex [16], and key sites in the S6 transmembrane domain appear to be involved in these hydrophobic interactions [22].
Open-channel blockers of Kv1.5 produce a rapid decay in outward current after the initial activation-related current rise, with the resulting current–time profile resembling that of a rapidly inactivating channel [10,16,17,19–22]. Hints of this type of behaviour were seen in the present studies, and were most clear in the case of verapamil (Fig. 10). The degree by which various drugs accelerate Kv1.5 current decay varies, being more prominent for weakly hydrophobic drugs like clofilium and tetrapentylammonium and less marked for more hydrophobic compounds like quinidine [16]. One major difference between homomeric channels containing only one type of subunit in model systems and native ultra-rapid delayed rectifiers is the need for a prepulse to inhibit Ito in order to isolate the native currents (as in the present study). It is quite likely that time-dependent channel block of the native current occurs during the conditioning prepulse, and is therefore much less evident during the test pulse.
4.2 Potential limitations
One important limitation of studies of currents in native myocytes is the need to suppress potential contaminating currents. This requires the use of intracellular and extracellular constituents that are not identical to the normal physiological milieu, along with the application of specific voltage protocols like the prepulse used in the present study. These modifications are necessary to evaluate selectively drug effects on the current of interest, but may at the same time modify drug action. Studies of currents in native myocytes are therefore limited in their ability to define detailed biophysical mechanisms. On the other hand, studies of drug action on heterologously expressed channel subunits, which can define biophysical mechanisms more precisely, are limited in their relevance to effects on native currents, which may be affected by accessory proteins, heterotetramer formation, and multiple subunit composition. There is general agreement between blocking effects of drugs on native IKur [15,19] and Kv1.5 currents [17,19].
Studies of antiarrhythmic drug effects on currents carried by cardiac Kv3.1 would be interesting in order to compare actions on Kv3.1 with those on IKur.d.
4.3 Potential significance
The present studies are the first of which we are aware that evaluate the effects of a variety of antiarrhythmic drugs on IKur.d. The ability of compounds like quinidine to block IKur.d at therapeutically relevant concentrations suggest that IKur.d inhibition may play a role in mediating antiarrhythmic effects in canine atrial arrhythmia models. For example, significant effects on atrial refractoriness and arrhythmias are seen in dogs with flecainide concentrations of about 2.5 µM [23], ambasilide concentrations of 15 µM [24], and quinidine concentrations of 8–19 µM [25]. These concentrations correspond to concentrations with significant effects on IKur.d (Figs. 2, 5 and 8
), suggesting that IKur.d inhibition by these agents may contribute to their antiarrhythmic effects in dog models. Verapamil is not known to have a beneficial effect on reentrant atrial arrhythmias, despite its ability to inhibit IKur.d. Its lack of atrial antiarrhythmic action is likely due to inhibition of other currents, particularly L-type Ca2+ current, and to the reflex sympathetic enhancement it provokes. As far as we are aware, only one previous study has assessed the effects of a clinically available compound on IKur.d, and noted that the diuretic agent indapamide blocks IKur.d at supratherapeutic concentrations [26].
The drugs we evaluated in the present study had some consistent similarities in action (such as the occurrence of time-dependent block upon channel opening) and some important differences (like discrepancies in the voltage dependence of block and in the degree of shift in activation voltage dependence). These observations open up some potentially interesting opportunities to analyze the structural determinants of IKur.d block at the molecular level. We noted that quinidine and ambasilide block of IKur.d resemble their effects on IKur, whereas for flecainide and verapamil there were important differences in actions on the two native currents. These findings support the notion that IKur.d and human atrial IKur are carried by different molecular species. It remains to be determined whether effects on cardiac Kv1.5 and Kv3.1 parallel those on IKur and IKur.d, respectively, and whether the molecular basis for the similar actions of some compounds and different actions of others can be determined.
Time for primary review 27 days.
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Acknowledgements |
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The authors thank Nathalie Talbot for technical assistance, Luce Bégin, Christiane Calvé and Diane Campeau for expert secretarial help with the manuscript. Funding for the study was obtained from the Medical Research Council of Canada and the Quebec Heart Foundation. Dr Wang is a Heart and Stroke Foundation of Canada Research Scholar and Lixia Yue was supported by a studentship award from the HSFC.
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