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CARDIOVASCULAR

Propafenone and Its Metabolites Preferentially Inhibit I_Krin Rabbit Ventricular Myocytes

Department of Pediatrics and Child Health, University of Manitoba, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada

Received August 1, 2003; accepted September 18, 2003.

	Abstract

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Propafenone is an antiarrhythmic agent with recognized cardiac myocyte repolarizing K⁺ current inhibitory effects. It has two known electropharmacologically active metabolites, 5-hydroxy- and N-depropylpropafenone, whose K⁺ current inhibitory effects are less thoroughly elucidated than those of the parent compound. This study characterizes and directly compares the pharmacologic interaction of all three compounds with two key repolarizing K⁺ currents, the rapidly activating delayed rectifier I_Kr and the transient outward current I_to, using the whole-cell patch-clamp technique in isolated rabbit ventricular myocytes. All three agents potently inhibited I_Kr with IC₅₀ values of 0.80 ±0.14, 1.88 ±0.21, and 5.78 ±1.24 µM for propafenone, 5-hydroxypropafenone, andN-depropylpropafenone, respectively, based on reduction of peak tail current amplitude following repolarization from +50 mV to -30 mV. I_Kr inhibition was concentration- and weakly voltage-dependent, with a time course from channel activation that was well described by a single exponential model and consistent with open channel block. Propafenone and its 5-hydroxy and N-depropyl metabolites also blocked I_to with IC₅₀ values of 7.27 ±0.53, 40.29 ±7.55, and 44.26 ±5.73 µM, respectively, at +50 mV. No significant drug effects were observed with respect to I_to voltage dependence of steady-state inactivation or time course of recovery from inactivation. The preferential interaction of propafenone and its metabolites with I_Kr relative to I_to in ventricular myocytes sheds new light on the anti- and proarrhythmic activity of propafenone in vivo.

Clinical use of propafenone is associated with extensive hepatic transformation of the parent agent to two electropharmacologically active metabolites, 5-hydroxypropafenone and N-depropylpropafenone (Hege et al., 1984; Latini et al., 1987; Malfatto et al., 1988). Available studies with 5-hydroxypropafenone indicate potent I_to inhibition in cultured neonatal rat ventricular myocytes (Cahill et al., 2001) and electropharmacologic effects in intact organisms and in vitro preparations consistent with inhibition of a number of cardiac myocyte ionic currents (von Philipsborn et al., 1984; Delgado et al., 1987; Valenzuela et al., 1987, 1988; Malfatto et al., 1988; Rouet et al., 1989; Case et al., 1991; Haefeli et al., 1991; Boucher et al., 1996; Franqueza et al., 1998). The cardiac cellular electropharmacology of N-depropylpropafenone has not been previously studied, although limited data suggesting ionic current blockade are available from intact animals and tissue preparations (Malfatto et al., 1988; Rouet et al., 1989).

We used the whole-cell patch-clamp technique to directly compare the inhibitory effects of propafenone, 5-hydroxypropafenone, and N-depropylpropafenone on the repolarizing currents I_to and I_Kr in isolated rabbit ventricular myocytes.

	Materials and Methods

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This investigation conformed with the Guide to the Care and Use of Experimental Animals published by the Canadian Council on Animal Care (2nd edition, 1993) and was approved by the University of Manitoba Protocol Management and Review Committee.

Rabbit Ventricular Myocyte Isolation. Healthy male New Zealand White rabbits (2.5–3.5 kg) were anesthetized with inhaled isoflurane followed by intravenous heparinization (500 IU). After rapid cardiectomy, the aorta was cannulated (<2 min) and perfused retrogradely at 27 ml/min with nominally Ca²⁺-free HEPES-buffered saline (HBS) solution until the return was clear (10 min). The atria, excess connective tissue, and pericardium were trimmed off. Fresh Ca²⁺-free HBS containing 1 mg/ml collagenase (class 2; Worthington Biochemicals, Freehold, NJ) and 0.14 mg/ml protease (type XIV; Sigma-Aldrich, St. Louis, MO) was then substituted and recirculated until the ventricles softened (15–20 min), followed by a 4-min washout with enzyme- and Ca²⁺-free HBS. All perfusates were gassed with 100% O₂ and maintained at 37 ± 1°C. The ventricles were gently teased apart with forceps, dispersing the myocytes. The resulting suspension was filtered, then myocytes were resuspended in sequentially higher Ca²⁺ concentrations (0.05, 0.1, 0.2, 1.0, and 1.8 mM in HBS) and stored at room temperature for study within 10 h of isolation.

Electrophysiologic Recording. Conventional whole-cell patch clamp was performed as previously described (Hamill et al., 1981; Gross et al., 1995). Myocytes were allowed to settle to the bottom of a modified 35-mm culture dish mounted on the stage of an inverted microscope (Nikon Diaphot 300). The cells were superfused continuously at 1 to 2 ml/min. Only quiescent rod-shaped cells with clear striations were selected for study. Thin-walled borosilicate micropipettes were pulled and polished to a resistance of 1.5 to 3.0 M when filled with intracellular solution. Voltage-clamp protocols were controlled with a Pentium 133 MHz personal computer running pClamp 6.0.4 software interfaced to an Axopatch 200B amplifier via a Digidata 1200 A/D board (Axon Instruments Inc., Union City, CA). All experiments were carried out at room temperature (20–22°C). Holding potential was -80 mV except as otherwise indicated, and Na⁺ current was inactivated with a 100-ms conditioning step to -50 mV prior to each test pulse. L-type Ca²⁺ current was blocked with 2 mM CoCl₂ in the extracellular solution.

Solutions and Reagents. HBS used in ventricular myocyte isolation contained 132 mM NaCl, 4 mM KCl, 1.2 mM MgCl₂, 10 mM HEPES, 10 mM D-glucose, and 0.5% bovine serum albumin, pH 7.4 with NaOH. The extracellular solution used for whole-cell patchclamp recording included 135 mM NaCl, 5.4 mM KCl, 2.0 mM CoCl₂, 1.0 mM CaCl₂, 1.0 mM MgCl₂, 10 mM HEPES, and 10 mM D-glucose, pH 7.4 with NaOH. Pipette solution consisted of 145 mM KCl, 5 mM NaCl, 5 mM K₂EGTA, 10 mM HEPES, and 4 mM MgATP, pH 7.2 with KOH. Propafenone, 5-hydroxypropafenone, and N-depropylpropafenone (Knoll Pharma, Markham, ON, Canada) were kept as 10-mM stock solutions in dimethyl sulfoxide and serially diluted in control extracellular solution as required. E-4031 (Wako Pure Chemicals, Osaka, Japan) was stored as 5 mM stock solution dissolved in water then diluted to 5 µM in extracellular solution. All stock drug solutions were stored at -20°C until dilution to appropriate concentrations on the day of use. With any change in extracellular solution, at least 5 ml of the new solution were perfused through the bath to allow for equilibration prior to electrophysiologic recording.

Data Analysis. I_Kr was measured as peak tail current density at -30 mV following 3-s depolarizing voltage steps from a holding potential of -80 mV (Salata et al., 1996). To ensure that our measurements of I_Kr inhibition by propafenone and its metabolites were not confounded by I_Ks, we excluded data obtained from cells in which any of the following were observed: 1) evidence of multiple currents in an envelope of tails test; 2) the presence of a second deactivating tail current at 0 mV suggestive of I_Ks according to a protocol described by Carmeliet (1998); and/or 3) failure to observe complete tail-current inhibition with application of the dofetilide analog E-4031 at 5 µM (Follmer and Colatsky, 1990).

Transient outward current (I_to) and its inhibition were analyzed as previously described (Gross and Castle, 1998; Cahill et al., 2001). Briefly, I_to was measured as the time integral of spontaneously decaying outward current observed in response to depolarizing 800-ms voltage steps from a holding potential of -80 mV, adjusted for the "steady-state" current remaining at the end of the step.

Dose-response curves were generated using the Hill equation. I_to inactivation time constants were obtained using single or double exponential decay models fitted to the raw current tracings. Steady-state voltage dependence of I_to inactivation data were fitted with the Boltzmann equation, and the time course of recovery from inactivation with a single exponential equation. All curve-fitting procedures were performed using Origin 6.0 (OriginLab Corp., Northampton, MA), yielding time constants and midpoint potentials for pooled data where appropriate. Results are reported as mean ± S.E. except as otherwise indicated.

	Results

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I_Kr Inhibition by Propafenone and Its Metabolites. In response to 3-s depolarizing voltage steps from a holding potential of -80 mV followed by repolarization to -30 mV, we observed a time-dependent outward current followed by a deactivating tail current (Fig. 1). Although Salata and colleagues (1996) have shown evidence of the slowly activating component I_Ks in this preparation, the delayed rectifier current expressed in myocytes studied here featured characteristics consistent with those of pure I_Kr.

View larger version (22K): [in this window] [in a new window]   Fig. 1. Delayed rectifier current (IKr) in a rabbit ventricular myocyte. Representative illustration of family of tracings elicited with a series of 3-s depolarizing voltage steps from a holding potential of -80 to -40, -20, 0, +20, +40, and +60 mV (inset), followed in each case by repolarization to -30 mV to elicit outward tail current.

Propafenone and its metabolites potently inhibited I_Kr in a concentration-dependent fashion (Fig. 2). Based on reduction of peak tail current amplitude following repolarization from +50 mV to -30 mV, IC₅₀ values of 0.80 ± 0.14, 1.88 ± 0.21, and 5.78 ± 1.24 µM were calculated for propafenone, 5-hydroxypropafenone, and N-depropylpropafenone, respectively (Fig. 3A). Figure 3B illustrates I_Kr tail current density-voltage relations in the absence and presence of increasing concentrations of propafenone.

View larger version (28K): [in this window] [in a new window]   Fig. 2. Voltage-gated activating and tail currents elicited in the absence (left-hand panels) and presence (right-hand panels) of 30 µM propafenone (A), 5-hydroxypropafenone (5-OHpropaf; B), and N-depropylpropafenone (N-DPpropaf; C), using the same voltage-step protocol as in Fig. 1. Currents that persist after drug application in the depolarization phase of each tracing represent inwardly rectifying current (IK1) activated at voltages negative to 0 mV, which was not significantly inhibited by any of the agents tested.

View larger version (21K): [in this window] [in a new window]   Fig. 3. Concentration-dependent IKr inhibition by propafenone and its metabolites. A, dose-response curves for propafenone, 5-hydroxypropafenone, and N-depropylpropafenone generated from pooled peak tail current data elicited during repolarization to -30 mV from 3-s steps to +50 mV (n = 3–9 for each data point) fitted with the Hill equation. Each raw data point was generated by normalizing the observed peak tail current following depolarization to +50 mV in the presence of the drug, at the concentration indicated, to the current elicited in the same cell prior to drug application. B, current density-voltage relations for IKr peak tail currents in the absence (control, n = 14) and presence of 0.1 (n = 5), 1.0 (n = 9), and 10 (n = 4) µM propafenone.

Voltage-dependent I_Kr inhibition is consistent with open channel blockade and has previously been reported with dofetilide in rabbit and guinea pig (Carmeliet, 1992) and with propafenone in guinea pig (Delpón et al., 1995) ventricular myocytes. In the present study involving rabbit ventricular myocytes, tail current inhibition was mildly voltage-dependent with all three agents tested (Fig. 4A). Further evidence of open channel blockade was provided by estimation of the time course of I_Kr inhibition, through comparison of tail current amplitudes following depolarizations of varying duration in the absence and presence of drug. As can be seen in Fig. 4B, the time course of I_Kr inhibition was well described by a single exponential model. Furthermore, tail currents following relatively short depolarizations in the presence of drug were essentially the same as control currents, indicating lack of tonic I_Kr blockade by these agents.

View larger version (15K): [in this window] [in a new window]   Fig. 4. Voltage and time dependence of IKr block. A, voltage dependence of IKr block by 1 µM propafenone (Propaf, squares; n = 5), 3 µM 5-hydroxypropafenone (5-OHpropaf, circles; n = 5), and 10 µM N-depropylpropafenone (N-DPpropaf, triangles; n = 3). The IKr peak tail current amplitude in the presence of drug was divided by that recorded in the absence of drug to yield an estimate of residual current following 3-s steps to the voltages indicated. IKr block by all three drugs was voltage-dependent to a similar extent. B, time dependence of IKr block by 1 µM 5-hydroxypropafenone. Depolarizing steps to +50 mV of varying duration were applied in the presence of the drug, followed by repolarization to -30 mV to elicit tail current. For each cell (n = 3), peak tail-current density was divided by the value obtained with a full 3-s depolarizing step prior to drug application and then plotted against depolarizing step duration in presence of the drug. The resulting curve is well fitted by a single exponential decay model with time constant () as shown and is consistent with a requirement for the channel to open in order for drug interaction to take place.

I_to Inhibition by Propafenone and Its Metabolites. A rapidly activating, slowly inactivating current characteristic of I_to was elicited with 800-ms depolarizations from a holding potential of -80 mV. Although propafenone itself predictably inhibited this current in a concentration- and time-dependent fashion similar to that seen in other preparations (Duan et al., 1993; Slawsky and Castle, 1994; Gross and Castle, 1998) (Fig. 5A), both the 5-hydroxy and N-depropyl metabolites did so far less potently. The IC₅₀ for propafenone was 7.27 ± 0.53 µM at +50 mV, whereas 5-hydroxypropafenone and N-depropylpropafenone blocked I_to with IC₅₀ values of 40.29 ± 7.55 and 44.26 ± 5.73 µM, respectively, at +50 mV (Fig. 5B). Unlike propafenone inhibition of I_to, which was promptly and completely reversible upon washout (Fig. 6A), blockade by the metabolites was only partially reversible (Fig. 6B).

View larger version (20K): [in this window] [in a new window]   Fig. 5. Ito inhibition by propafenone and its metabolites. A, following a Na+ current-inactivating 100-ms step to -35 mV from holding potential -80 mV, an 800-ms step to +50 mV elicited Ito under control conditions (voltage protocol, inset). The myocyte was then sequentially superfused to presumed steady state (minimum 5 ml) with extracellular solution containing 1, 10, and 100 µM propafenone as shown, resulting in marked concentration- and time-dependent Ito block upon repetition of the voltage protocol. B, dose-response curves for propafenone, 5-hydroxypropafenone, and N-depropylpropafenone generated from pooled data at +50 mV (n = 3–8 for each data point) fitted with the Hill equation.

View larger version (20K): [in this window] [in a new window]   Fig. 6. Reversibility of Ito blockade by propafenone (A) and 5-hydroxypropafenone (5-OHP; B). Control current was elicited with a +50-mV depolarizing step in the absence of drug then repeated after extracellular drug application and equilibration at the concentration indicated. Drug-free extracellular solution (minimum 5 ml) was then applied to effect drug washout, resulting in nearly complete restoration of Ito after propafenone exposure but only partial recovery after perfusion with either metabolite (N-depropylpropafenone not shown).

Previous studies have shown no significant effect of propafenone on I_to voltage dependence of steady-state inactivation or time course of recovery from inactivation. In the present study, neither propafenone nor either of the metabolites studied had any apparent effect on these phenomena. None of the compounds studied showed use dependent I_to block.

	Discussion

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Clinical Significance of Repolarizing Current Blockade by Propafenone and Its Metabolites. Propafenone is effective in the medical therapy of a variety of supraventricular as well as ventricular tachyarrhythmias in children (Paul and Janousek, 1994) and adults (Grant, 1996). Although categorized as a sodium channel-blocking agent in the Vaughan Williams antiarrhythmic drug classification scheme, propafenone potently inhibits a number of repolarizing potassium currents in cardiac myocytes isolated from humans (Gross and Castle, 1998; Seki et al., 1999) as well as from animals (Duan et al., 1993; Slawsky and Castle, 1994; Delpón et al., 1995; Christé et al., 1999; Cahill et al., 2001). Most repolarizing current investigations have focused on I_to inhibition (Duan et al., 1993; Slawsky and Castle, 1994; Gross and Castle, 1998; Seki et al., 1999; Cahill et al., 2001). However, more recent studies involving heterologously expressed HERG channels, which mediate I_Kr, suggest that HERG is an important molecular target for propafenone (Mergenthaler et al., 2001; Paul et al., 2002). This supports the earlier demonstration of guinea pig ventricular myocyte I_Kr inhibition by Delpón et al. (1995) and is of great interest because I_Kr inhibition likely plays a key role in sometimes lethal proarrhythmic effects of antiarrhythmic drugs, including propafenone (Sanguinetti et al., 1995). Thus, a primary aim of the present study was to directly compare the I_to- and I_Kr-blocking effects of propafenone in an isolated ventricular myocyte model reliably expressing both currents.

Role of the Metabolites 5-Hydroxy- and N-Depropylpropafenone. Clinical use of propafenone is associated with extensive hepatic metabolism (Hege et al., 1984) to products that include two substances with recognized electropharmacologic activity in cardiac muscle preparations, namely 5-hydroxy- and N-depropylpropafenone (Malfatto et al., 1988; Thompson et al., 1988; Rouet et al., 1989). The extent of propafenone metabolism is phenotype-dependent (Siddoway et al., 1987) but can result in steady-state plasma concentrations of 5-hydroxy- and N-depropylpropafenone that are 18 and 23%, respectively, of that of the parent compound, with delayed metabolite clearance after discontinuation of propafenone administration (Kates et al., 1985). Moreover, Latini and colleagues (1989) demonstrated that 5-hydroxypropafenone accumulates in human atrial muscle with even greater affinity than does propafenone, resulting in cardiac tissue metabolite concentrations that can match or exceed those of the parent drug. Almost no information on the cardiac myocyte repolarizing current inhibitory effects of 5-hydroxy- and N-depropylpropafenone has thus far been available. Characterization of propafenone metabolite interaction with I_to and I_Kr was therefore the second major aim of this work.

Propafenone and Its Metabolites Preferentially Inhibit I_Kr Relative to I_to. A key finding of the present study is that all three substances assessed preferentially inhibit I_Kr relative to I_to, a phenomenon that is even more pronounced in the metabolites than in the parent compound. The IC₅₀ value of 0.80 ± 0.14 µM obtained for I_Kr tail-current blockade by propafenone in our freshly isolated rabbit ventricular myocytes is remarkably similar to the 0.44 ± 0.07 µM value documented by Paul and colleagues (2002) using cloned HERG channels stably expressed in mammalian HEK293 cells. Interestingly, these investigators found that propafenone was equipotent to quinidine in its inhibition of HERG currents and more potent than either flecainide or lidocaine, the other agents assessed in their study. Moreover, these values fall essentially within a clinically relevant therapeutic free plasma propafenone concentration range estimated at 0.15 to 0.7 µM (Slawsky and Castle, 1994). Mergenthaler et al. (2001) reported an IC₅₀ value of 13 to 15 µM from their conventional two-electrode voltage-clamp study using HERG channels expressed in Xenopus laevis oocytes but cited work from their own laboratory indicating that the oocyte expression system typically demands antiarrhythmic drug concentrations 5- to 10-fold higher than those applied to mammalian cell lines to yield comparable inhibitory effects (Rolf et al., 2000).

There are no published data with which to compare the I_Kr-blocking effects that we observed for 5-hydroxy- and N-depropylpropafenone with IC₅₀ values of 1.88 ± 0.21 µM and 5.78 ± 1.24 µM, respectively. Although suggesting slightly less HERG-blocking potency than that of propafenone itself, the clinical relevance of these results is difficult to assess because of scant data relating to variations in plasma and tissue accumulation already mentioned.

Although our findings indicate significantly less potent inhibition of cardiac myocyte I_to than of I_Kr by propafenone itself, they are consistent with previous observations of propafenone I_to inhibition in a variety of experimental models. The adult rabbit ventricular myocyte IC₅₀ value of 7.3 µM reported here compares with previously documented values of 5.9 µM in rabbit atrial myocytes (Duan et al., 1993), 4.8 (Gross and Castle, 1998) and 4.9 (Seki et al., 1999) µM in human atrial myocytes, 3.3 µM in adult rat ventricular myocytes (Slawsky and Castle, 1994), and 2.1 µM in neonatal rat ventricular myocytes (Cahill et al., 2001). It is noteworthy that the highest IC₅₀ values appear in rabbit, the only species in this group in which I_to is thought to be mediated primarily by Kv1.4 rather than Kv4.2/4.3 channels (Kääb et al., 1998; Wickenden et al., 1999).

Study Limitations. By restricting our study to ventricular myocytes that expressed I_Kr as the sole measurable component of delayed rectifier K⁺ current, we might have overlooked potentially important I_Ks-blocking activity by propafenone and its metabolites. However, I_Ks blockade is not associated with significantly altered repolarization in rabbit ventricle (Lengyel et al., 2001), and preferential propafenone inhibition of I_Kr relative to that of I_Ks has previously been demonstrated in a preparation that more readily accommodates study of both current components (Delpón et al., 1995). Rabbit ventricular myocytes were selected for this work because they prominently express I_Kr, the current most often implicated in drug-induced or "acquired" cases of QT interval prolongation and associated torsades des pointes (Camm et al., 2000), along with I_to, a well established repolarizing current target for antiarrhythmic agents.

Another potential limitation relates to performance of experiments at ambient rather than physiologic temperature, which affects the kinetics of K⁺ channel gating. We chose these conditions because they match those under which almost all benchmark data used for comparison were obtained (Slawsky and Castle, 1994; Delpón et al., 1995; Gross and Castle, 1998; Seki et al., 1999; Cahill et al., 2001).

	Conclusion

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This work significantly enhances preexisting knowledge of the cellular mechanisms of action of the antiarrhythmic agent propafenone and its electropharmacologically active metabolites. First, it establishes N-depropylpropafenone as a repolarizing K⁺ current blocker comparable in its effects to its sister metabolite 5-hydroxypropafenone. Secondly and more importantly, it indicates that both of these metabolites as well as their parent compound, propafenone, inhibit ventricular myocyte I_Kr more potently than I_to. Finally, it suggests that the combined in vivo effect of these three compounds may be even more preferentially selective for I_Kr, as evidenced by the metabolites' reduced affinity for I_to relative to that of propafenone.

	Acknowledgements

 
Propafenone, 5-hydroxypropafenone, and N-depropylpropafenone were graciously provided by Knoll Pharma Inc.

	Footnotes

 
This work was supported by an operating grant from the Manitoba Medical Service Foundation.

DOI: 10.1124/jpet.103.057844.

ABBREVIATIONS:HERG, human ether-à-go-go related gene; I_Kr, rapidly activating delayed rectifier potassium current; I_Ks, slowly activating delayed rectifier potassium current; I_to, transient outward potassium current; I_Kur, ultrarapidly activating delayed rectifier potassium current; HBS, HEPES-buffered saline.

Address correspondence to: Dr. Gil J. Gross, Cardiology Division, Room 1503F, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: ggross{at}sickkids.ca

	References

Top Abstract Materials and Methods Results Discussion Conclusion References

 

Boucher M, Chassaing C, Hamel JD, and Poirier JM (1996) Cardiac electrophysiological effects of propafenone and its 5-hydroxylated metabolite in the conscious dog. Eur J Pharmacol 315: 171-177.[CrossRef][Medline]

Cahill SA, Kirshenbaum LA, and Gross GJ (2001) Transient outward current inhibition by propafenone and 5-hydroxypropafenone in cultured neonatal rat ventricular myocytes. J Cardiovasc Pharmacol 38: 460-467.[CrossRef][Medline]

Camm AJ, Janse MJ, Roden DM, Rosen MR, Cinca J, and Cobbe SM (2000) Congenital and acquired long QT syndrome. Eur Heart J 21: 1232-1237.[Free Full Text]

Carmeliet E (1992) Voltage- and time-dependent block of the delayed K⁺ current in cardiac myocytes by dofetilide. J Pharmacol Exp Ther 262: 809-817.[Abstract/Free Full Text]

Carmeliet E (1998) Effects of cetirizine on the delayed K⁺ currents in cardiac cells: comparison with terfenadine. Br J Pharmacol 124: 663-668.[CrossRef][Medline]

Case CL, Ravin RR, Maheshwari R, Gillette PC, and Hewett KW (1991) Developmental electrophysiologic effects of propafenone and 5-hydroxypropafenone on the canine cardiac Purkinje fiber. Dev Pharmacol Ther 17: 24-34.[Medline]

Christé G, Tebbakh H, Simurdova M, Forrat R, and Simurda J (1999) Propafenone blocks ATP-sensitive K⁺ channels in rabbit atrial and ventricular cardiomyocytes. Eur J Pharmacol 373: 223-232.[CrossRef][Medline]

Delgado C, Tamargo J, Tejerina T, and Valenzuela C (1987) Effects of 5-hydroxypropafenone in guinea-pig atrial fibres. Br J Pharmacol 90: 575-582.[Medline]

Delpón E, Valenzuela C, Pérez O, Casis O, and Tamargo J (1995) Propafenone preferentially blocks the rapidly activating component of delayed rectifier K⁺ current in guinea pig ventricular myocytes. Voltage-independent and time-dependent block of the slowly activating component. Circ Res 76: 223-235.[Abstract/Free Full Text]

Duan D, Fermini B, and Nattel S (1993) Potassium channel blocking properties of propafenone in rabbit atrial myocytes. J Pharmacol Exp Ther 264: 1113-1123.[Abstract/Free Full Text]

Follmer CH and Colatsky TJ (1990) Block of delayed rectifier potassium current, I_K, by flecainide and E-4031 in cat ventricular myocytes. Circulation 82: 289-293.[Abstract/Free Full Text]

Franqueza L, Valenzuela C, Delpon E, Longobardo M, Caballero R, and Tamargo J (1998) Effects of propafenone and 5-hydroxy-propafenone on hKv1.5 channels. Br J Pharmacol 125: 969-978.[CrossRef][Medline]

Grant AO (1996) Propafenone: an effective agent for the management of supraventricular arrhythmias. J Cardiovasc Electrophysiol 7: 353-364.[Medline]

Gross GJ, Burke RP, and Castle NA (1995) Characterisation of transient outward current in young human atrial myocytes. Cardiovasc Res 29: 112-117.[CrossRef][Medline]

Gross GJ and Castle NA (1998) Propafenone inhibition of human atrial myocyte repolarizing currents. J Mol Cell Cardiol 30: 783-793.[CrossRef][Medline]

Haefeli WE, Vozeh S, Ha HR, Taeschner W, and Follath F (1991) Concentration-effect relations of 5-hydroxypropafenone in normal subjects. Am J Cardiol 67: 1022-1026.[CrossRef][Medline]

Hamill OP, Marty A, Neher E, Sakmann B, and Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflueg Arch 391: 85-100.[CrossRef][Medline]

Hege HG, Hollmann M, Kaumeier S, and Lietz H (1984) The metabolic fate of ²H-labelled propafenone in man. Eur J Drug Metab Pharmacokinet 9: 41-55.[Medline]

Kates RE, Yee YG, and Winkle RA (1985) Metabolite cumulation during chronic propafenone dosing in arrhythmia. Clin Pharmacol Ther 37: 610-614.[Medline]

Kääb S, Dixon J, Duc J, Ashen D, Näbauer M, Beuckelmann DJ, Steinbeck G, McKinnon D, and Tomaselli GF (1998) Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation 98: 1383-1393.[Abstract/Free Full Text]

Latini R, Barbieri E, Castello C, Marchi S, Sica A, Gerosa G, Rossi R, and Zardini P (1989) Propafenone and 5-hydroxypropafenone concentrations in the right atrium of patients undergoing heart surgery. Am Heart J 117: 497-498.[CrossRef][Medline]

Latini R, Marchi S, Riva E, Cavalli A, Cazzaniga MG, Maggioni AP, and Volpi A (1987) Distribution of propafenone and its active metabolite, 5-hydroxypropafenone, in human tissues. Am Heart J 113: 843-844.[CrossRef][Medline]

Lengyel C, Iost N, Virág L, Varró A, Lathrop DA, and Papp JG (2001) Pharmacological block of the slow component of the outward delayed rectifier current (I_Ks) fails to lengthen rabbit ventricular muscle QT_c and action potential duration. Br J Pharmacol 132: 101-110.[CrossRef][Medline]

Malfatto G, Zaza A, Forster M, Sodowick B, Danilo PJ, and Rosen MR (1988) Electrophysiologic, inotropic and antiarrhythmic effects of propafenone, 5-hydroxypropafenone and N-depropylpropafenone. J Pharmacol Exp Ther 246: 419-426.[Abstract/Free Full Text]

Mergenthaler J, Haverkamp W, Huttenhofer A, Skryabin BV, Musshoff U, Borggrefe M, Speckmann EJ, Breithardt G, and Madeja M (2001) Blocking effects of the antiarrhythmic drug propafenone on the HERG potassium channel. Naunyn-Schmiedeberg's Arch Pharmacol 363: 472-480.[CrossRef][Medline]

Paul AA, Witchel HJ, and Hancox JC (2002) Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine. Br J Pharmacol 136: 717-729.[CrossRef][Medline]

Paul T and Janousek J (1994) New antiarrhythmic drugs in pediatric use: propafenone. Pediatr Cardiol 15: 190-197.[CrossRef][Medline]

Rolf S, Haverkamp W, Borggrefe M, Musshoff U, Eckardt L, Mergenthaler J, Snyders DJ, Pongs O, Speckmann EJ, Breithardt G, et al. (2000) Effects of antiarrhythmic drugs on cloned cardiac voltage-gated potassium channels expressed in Xenopus oocytes. Naunyn-Schmiedeberg's Arch Pharmacol 362: 22-31.[CrossRef][Medline]

Rouet R, Libersa CC, Broly F, Caron JF, Adamantidis MM, Honore E, Wajman A, and Dupuis BA (1989) Comparative electrophysiological effects of propafenone, 5-hydroxypropafenone and N-depropylpropafenone on guinea pig ventricular muscle fibers. J Cardiovasc Pharmacol 14: 577-584.[CrossRef][Medline]

Salata JJ, Jurkiewicz NK, Jow B, Folander K, Guinosso PJJ, Raynor B, Swanson R, and Fermini B (1996) I_K of rabbit ventricle is composed of two currents: evidence for I_Ks. Am J Physiol 271: H2477-H2489.

Sanguinetti MC, Jiang C, Curran ME, and Keating MT (1995) A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the I_Kr potassium channel. Cell 81: 299-307.[CrossRef][Medline]

Seki A, Hagiwara N, and Kasanuki H (1999) Effects of propafenone on K currents in human atrial myocytes. Br J Pharmacol 126: 1153-1162.[CrossRef][Medline]

Siddoway LA, Thompson KA, McAllister CB, Wang T, Wilkinson GR, Roden DM, and Woosley RL (1987) Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 75: 785-791.[Abstract/Free Full Text]

Slawsky MT and Castle NA (1994) K⁺ channel blocking actions of flecainide compared with those of propafenone and quinidine in adult rat ventricular myocytes. J Pharmacol Exp Ther 269: 66-74.[Abstract/Free Full Text]

Thompson KA, Iansmith DH, Siddoway LA, Woosley RL, and Roden DM (1988) Potent electrophysiologic effects of the major metabolites of propafenone in canine Purkinje fibers. J Pharmacol Exp Ther 244: 950-955.[Abstract/Free Full Text]

Valenzuela C, Delgado C, and Tamargo J (1987) Electrophysiological effects of 5-hydroxypropafenone on guinea pig ventricular muscle fibers. J Cardiovasc Pharmacol 10: 523-529.[Medline]

Valenzuela C, Delpon E, and Tamargo J (1988) Tonic and phasic Vmax block induced by 5-hydroxypropafenone in guinea pig ventricular muscles. J Cardiovasc Pharmacol 12: 423-431.[Medline]

von Philipsborn G, Gries J, Hofmann HP, Kreiskott H, Kretzschmar R, Muller CD, Raschack M, and Teschendorf HJ (1984) Pharmacological studies on propafenone and its main metabolite 5-hydroxypropafenone. Arzneim-Forsch 34: 1489-1497.[Medline]

Wickenden AD, Tsushima RG, Losito VA, Kaprielian R, and Backx PH (1999) Effect of Cd²⁺ on Kv4.2 and Kv1.4 expressed in Xenopus oocytes and on the transient outward currents in rat and rabbit ventricular myocytes. Cell Physiol Biochem 9: 11-28.[CrossRef][Medline]

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