AJP - Heart Calcium Transients and Cell-Sarcomere
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 294: H793-H800, 2008. First published November 30, 2007; doi:10.1152/ajpheart.01229.2007
0363-6135/08 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/2/H793    most recent
01229.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tsujimae, K.
Right arrow Articles by Kurachi, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsujimae, K.
Right arrow Articles by Kurachi, Y.

In silico study on the effects of IKur block kinetics on prolongation of human action potential after atrial fibrillation-induced electrical remodeling

Kenji Tsujimae,1 Shingo Murakami,1,2 and Yoshihisa Kurachi1,2

1Division of Molecular and Cellular Pharmacology, Department of Pharmacology, Graduate School of Medicine, and 2The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan

Submitted 23 October 2007 ; accepted in final form 30 November 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Pharmacological treatment with various antiarrhythmic agents for the termination or prevention of atrial fibrillation (AF) is not yet satisfactory. This is in part because the drugs may not be sufficiently selective for the atrium, and they often cause ventricular arrhythmias. The ultrarapid-delayed rectifying potassium current (IKur) is found in the atrium but not in the ventricle, and it has been recognized as a potentially promising target for anti-AF drugs that would be without ventricular proarrhythmia. Several new agents that specifically block IKur have been developed. They block IKur in a voltage- and time-dependent manner. Here we use mathematical models of normal and electrically remodeled human atrial action potentials to examine the effects of the blockade kinetics of IKur on atrial action potential duration (APD). It was found that after AF remodeling, an IKur blocker with fast onset can effectively prolong APD at any stimulus frequency, whereas a blocker with slow onset prolongs APD in a frequency-dependent manner only when the recovery is slow. The results suggest that the voltage and time dependence of IKur blockade should be taken into account in the testing of anti-AF drugs. This modeling study suggests that a simple voltage-clamp protocol with a short pulse of ~10 ms at 1 Hz may be useful to identify the effective anti-AF drugs among various IKur blockers.

ultrarapid-delayed rectifying potassium current; atrial action potential; computer simulation

THE TREATMENT OF atrial fibrillation (AF) is complicated by the fact that "AF begets AF" (26), where chronic high-frequency fibrillation causes remodeling of atrial electrophysiology with reduced action potential (AP) duration (APD) and refractory period leading to an enhanced propensity for reentry and circus movement for arrhythmogenesis. Recently, the ultrarapid-delayed rectifier current (IKur) has been recognized as a potential target for anti-AF drugs (17). IKur is carried by Kv1.5 subunits and contributes toward the repolarization of the AP in the human atrium. Since there is either little or no IKur in human ventricular myocytes (11, 15, 24), selective IKur blockers may not have the adverse effects common to many potassium channel blockers that prolong APD in the ventricle and cause life-threatening ventricular arrhythmias, including Torsades de pointes (17).

A number of IKur blockers that demonstrate high atrial selectivity are under development and/or in clinical testing (17). They show different effects on effective refractory period (ERP), QT interval, and rate dependence. XEN-D0101 increased atrial ERP in a positive rate- and dose-dependent manner without producing significant changes in ventricular ERP, QT intervals, or spontaneous sinus cycle length in a canine model (21). AZD7009 induced concentration-dependent but rate-independent increases in atrial ERP in dogs, whereas ventricular ERP and QT interval increased slightly (5). AVE0118 dose dependently caused reverse frequency-dependent prolongation of atrial ERP in goat with no effect on QT interval (1). NIP-142 prolonged atrial APD independently of stimulus frequency but shortened ventricular APD in guinea pig (16). These different phenotypes of the effects of drugs on atrial ERP are thought to result from their diverse effects on the atrial AP.

Experimentally, IKur blockade by drugs exhibits diverse voltage and time dependence (13, 14, 16, 19). Previously, we have shown that various voltage- and time-dependent blockade of the rapid-delayed rectifier potassium current (IKr) differently affects APD prolongation in the atrium (22). Therefore, different kinetics of IKur blockade might be responsible for their distinct effects on the atrial AP. In this study we test this hypothesis by incorporating various kinetics of voltage- and time-dependent block of IKur into in silico models of the human atrial AP. This study used not only a normal atrial AP model (7, 22) but also the one that incorporated the characteristics of AF remodeling (10).

Simulation study with both models showed that voltage- and time-independent block of IKur reproduced experimental APD prolongation behavior. The incorporation of voltage- and time-dependent block of IKur in the AF model showed that fast onset at depolarization effectively prolonged APD at any stimulus frequency, whereas slow onset and slow recovery at diastolic potentials prolonged APD in a frequency-dependent manner. These results suggest that the voltage and time dependence of the block of IKur may be an important element in the action of effective anti-AF drugs. Therefore, we looked for a simple experimental protocol to screen IKur blockers and found that the voltage-clamp experiment using short steps (~10 ms) at a frequency of 1 Hz is useful to identify the IKur blockers effective as anti-AF drugs.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
AP simulation. To simulate the human atrial AP with voltage- and time-dependent block of IKur, we used the mathematical model developed by Courtemanche et al. (7, 8) and modified by Tsujimae et al. (22). Briefly, this model has passive properties (e.g., membrane capacitance and membrane resistance) and 12 voltage-dependent and carrier-mediated ionic currents as follows: fast sodium current (INa), inward rectifier potassium current (IK1), transient-outward potassium current (Ito), IKur, IKr, slow-delayed rectifier potassium current (IKs), L-type calcium current (ICa,L), sarcolemmal calcium pump current (Ip,Ca), sodium-potassium pump current (INaK), sodium-calcium exchanger current (INaCa), background sodium current (Ib,Na), and background calcium current (Ib,Ca). Hodgkin-Huxley type equations are used to calculate the forward and backward kinetics of the activation and inactivation processes of each voltage-gated ion channel. The program was coded in C/C++, and simulations were run on an IBM-compatible computer with a C++ compiler. The stimulus frequency was set to 1 Hz unless otherwise stated. Thirty APs were calculated in each simulation. The last AP in each run was used for analysis. The APD was measured at –70 mV (APD–70 mV); this closely approximates to APD at 90% repolarization.

AF-modified AP simulation. Electrical remodeling was implemented by modifying the maximum conductance of particular ion channels in the human atrial AP model (normal model) according to experimental data; thus the AF-modified AP model (AF model) showed a 70% reduction in the maximum conductance of ICa,L (2, 3), a 50% reduction in the maximum conductance of Ito, (4, 23), a 50% reduction in the maximum conductance of IKur (4, 23), and a 100% increase in the maximum conductance of IK1 (3, 9, 23).

Formulation of kinetic properties of types of IKur blockade. To incorporate the effects of the voltage- and time-dependent IKur blockade, we modified the formulation of IKur given by Courtemanche et al. (7) as follows:

Formula 1(Eq.1)
where yKur is the fraction of IKur that is not blocked by a drug, gKur is the maximum conductance, ua is the activation gate variable, ui is the inactivation gate variable, V is the membrane potential, and EK is the reverse potential.

The nonblocked IKur fraction, yKur, was calculated with the following first order differential equation:

Formula 2(Eq.2)
where y{infty},Kur is the steady-state value of yKur and {tau}yKur is the time constant for yKur. The y{infty},Kur and {tau}yKur were expressed as functions of V as follows.

Formula 3(Eq.3)

Formula 4(Eq.4)
where {tau}onset,yKur is the time constant for yKur at large depolarized potential, {tau}recovery,yKur is the time constant for yKur at large hyperpolarized potential, and the values for the half value and slope of the Boltzmann function are –40 and 5, respectively.

In this study, the voltage dependence of the steady state of IKur blockade was fixed to isolate and examine only the effects of the time constant. Most IKur blockers are known to exhibit voltage-dependent blockade in steady state, but their blockade at the resting potential is weak even at high drug concentrations (12, 19, 20). In contrast, the time constant for IKur blockade at large depolarized potential ranges from <10 ms (14) to >200 ms (20). Similarly, the time constant for recovery from block at large hyperpolarized potential ranges from <100 ms to >4 s (14). Therefore, to examine APD prolongation with maximum block effect, we used Eq. 3, which corresponds to a form of blockade where IKur is not blocked at all at large hyperpolarized potential and where 90% of IKur is blocked at large depolarized potential (Fig. 1A) and the voltage dependence of the time constant was changed by adjusting the time constant at large depolarized potential ({tau}onset,yKur, from 5 to 160 ms) and time constant at large hyperpolarized potential ({tau}recovery,yKur, from 250 to 40 s). An example of different values of {tau}recovery and {tau}onset is shown in Fig. 1B. A simulation of a voltage-clamp pulse with a step from –80 to +40 mV for 200 ms upon IKur showed that the changes of the time constants affected the time course of IKur (Fig. 1C) and the development of IKur blockade and the recovery from IKur blockade (Fig. 1D).


Figure 1
View larger version (15K):
[in this window]
[in a new window]

  		Fig. 1. Parameters of voltage- and time-dependent blockade of ultrarapid-delayed rectifying current (IKur). A: the steady-state unblocked fraction of IKur is expressed as a Boltzmann function with a half-maximum block voltage of –40 mV and a slope of 5 mV between an upper limit of 1 and a lower limit of 0.1. B: the effects of time dependence on the nonblocked IKur fraction. The solid line represents a {tau}onset of 10 ms and a {tau}recovery of 1,000 ms. The dashed line represents a {tau}onset of 160 ms and a {tau}recovery of 500 ms. C: IKur simulated by a voltage-clamp step from –80 to +40 mV for 200 ms. The fine-dotted line presents control conditions. The effects of time-dependent block are shown by the dashed and solid lines representing the time constants shown in B. D: the fraction of nonblocked IKur recorded during the voltage-clamp step shown in C.

 

   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
We first validated our normal and remodeled human atrial myocyte AP models. The maximum conductance of IKur was decreased stepwise from the control level so that the effect of voltage- and time-independent IKur blockade on the AP could be analyzed (Fig. 2). As IKur block increased, the "dome" of the AP in the normal atrial myocyte model was augmented (Fig. 2A, normal), whereas the APD at –70 mV remained almost constant (Fig. 2B, normal). On the other hand, IKur blockade in the remodeled atrial myocyte AP model (AF model) progressively prolonged APD as the blockade was enhanced (Fig. 2A, AF; Fig. 2B, AF). These characteristics are consistent with experimental (25) and previous model results (8), and this shows that IKur blockade has potential as an anti-AF target because of its capability to prolong APD and ERP in the remodeled atrium under chronic AF. The rest of this study concentrates on the AF model.


Figure 2
View larger version (10K):
[in this window]
[in a new window]

  		Fig. 2. Action potential (AP) duration (APD) prolongation by voltage- and time-independent block of IKur in normal and atrial fibrillation (AF) remodeled atrial myocytes. A: simulated APs resulting from the reduction of the conductance of IKur to 90%, 70%, 50%, 30%, and 10% (thin lines, reading from left to right) of the control level (shown by the thick line) in the normal atrial myocyte model (normal group) and the AF remodeled atrial myocyte model (AF group). B: the relationship between APD at –70 mV (APD–70 mV) and the fraction of blocked IKur in the normal atrial myocyte (normal group) and the AF-remodeled myocyte (AF group).

 
Voltage- and time-dependent blockade was introduced into IKur kinetics in the AF model, and the effects of varying onset and recovery time constants of block on the remodeled AP were examined (Fig. 3). The maximum block of IKur was fixed at 90% (Eq. 3). Figure 3, A and B, illustrates the effect of block-onset time constant with a fixed recovery time constant of 1,000 ms at the resting potential. The stimulus frequency was 1 Hz. The onset time constant was altered from 10 to 160 ms. APD was most enhanced at the shortest onset time constant. As the time constant was increased, the form of the AP gradually evolved toward the control (Fig. 3A). The APD prolongation peaked at the shortest onset time constant, and the value of APD decreased to that in control as the onset time constant was increased (Fig. 3B).


Figure 3
View larger version (17K):
[in this window]
[in a new window]

  		Fig. 3. The effects of voltage- and time-dependent IKur blockade on the AP in the AF-remodeled atrial myocyte. A: the effects of the onset time constant of IKur blockade on the AP. The onset time constant is 5, 10, 20, 40, 80, and 160 ms reading from right to left. The control AP, without any IKur blockade, is shown by the thick line, and AP under equivalent but voltage- and time-independent blockade is shown by the dotted line. B: the relationship between APD–70 mV and onset time constant (thin line) compared with control (thick line) and voltage-independent blockade (dashed line). C: the effect of recovery time constant on the APs (thin lines). C, left: a 10-ms onset time constant with recovery time constants, reading from left to right, of 250, 1,000, 4,000, and 16,000 ms. C, right: a 160-ms onset time constant with recovery time constants, reading from left to right, of 500, 1,000, 2,000, 4,000, 8,000, 16,000, and 32,000 ms. Control APs are shown by the thick lines, and APs under equivalent voltage-independent blockade are shown by the dashed lines. D: the relationship between APD–70 mV and recovery time constant (thin lines) compared shown with control (thick line) and voltage-independent blockade (dashed line).

 
When the onset time constant was fixed at 10 ms, altering the recovery time constant from 250 ms to 40 s had little effect on APD (10 ms; Fig. 3, C and D). Actually, even when the recovery time constant was set to the fastest value (250 ms), the APD was 170 ms (cf. 132 ms in the control). On the other hand, with an onset time constant of 160 ms, APD was only slightly prolonged (137 ms) with the recovery time constant of 250 ms. As the recovery time constant was increased, APD was gradually prolonged (160 ms; Fig. 3, C and D), and it reached 176 ms at the recovery time constant of 40 s.

These different effects on APD prolongation were accounted for by the different kinetics of the nonblocked IKur fraction, yKur (Fig. 4). An analysis of yKur showed that IKur blockade during phase 0 of AP depends on the recovery time constant (Fig. 4A). Under blockade with fast recovery kinetics of 250 ms, the recovery from block could be complete during phase 4 of AP with any onset time constant from 5 to 160 ms and the subsequent IKur blockade during phase 0 of AP was small. But under blockade with slow recovery kinetics, the recovery from block may not be complete during phase 4 and the IKur blockade accumulated. Actually, as the recovery time constant was increased to 1,000 or 4,000 ms, the IKur blockade at phase 0 increased. This increase was more pronounced as the onset time kinetics was slower. However, when the onset time constant was short (~5–40 ms), the maximum IKur blockade developed during the AP did not alter significantly. In contrast, when the onset kinetics was slow (80 and 160 ms), not only the IKur blockade at phase 0 but also the maximum IKur blockade during the AP increased as the recovery kinetics became slower. Thus the stimulus frequency affected the consequences of the recovery from IKur blockade when the onset time constant was slow (Fig. 4B). A long phase 4 between APs allowed IKur blockade to recover completely, whereas a short cycle length led to incomplete recovery. Irrespective of the recovery time constant, a fast onset of block completed the development of IKur blockade. Therefore, it was predicted that whereas IKur blockers with fast onset kinetics prolong APD rate independently, those with slow onset and recovery kinetics do so rate dependently.


Figure 4
View larger version (20K):
[in this window]
[in a new window]

  		Fig. 4. The effects of onset and recovery time constants and stimulus frequency on IKur. A: the effects of different onset and recovery time constants on APs and the fraction of the nonblocked IKur. A, top: APs with onset time constant of 5, 10, 20, 40, 80, and 160 ms (thin lines reading from right to left) at recovery time constants of 250, 1,000, and 4,000 ms. For comparison, control APs are shown as thick lines, and APs with voltage- and time-independent blockade are shown with dashed lines. A, bottom: the corresponding fraction of nonblocked IKur. B: APs and nonblocked fraction of IKur (onset time constants as for A) with a constant recovery time constant (1,000 ms) at different stimulus frequencies (0.5, 1, and 2 Hz).

 
In vitro studies of potassium channel blockers routinely use heterologous expression systems and voltage-clamp protocols to determine the effects of drugs on target ion channels. But it is difficult to directly translate results from classical voltage-clamp protocols to the dynamic changes that occur in potential and currents during an AP. The final section of this study was therefore dedicated to determining whether it was possible to design a voltage-clamp protocol that would reflect the effect of IKur blockers on APD and which could then be used to identify IKur blockers with fast onset and/or slow recovery kinetics. Figure 5A, left, shows the results of simulating IKur within the AF-atrial myocyte model with a voltage-clamp step protocol (200 ms in duration). Running the simulation of IKur block with different onset time constants clearly shows that at anything but the slowest onset rates (80 and 160 ms), IKur block achieved saturation before the end of the 200-ms voltage step. Therefore, it was not possible to relate the relative amount of current recorded at the end of the voltage step (13, 16, 19) to the effect of equivalent block on APD (Fig. 5B; open squares). On the other hand, repeating these simulations with a 10-ms-duration voltage step (Fig. 5A, right) gave information that provided a more predictive relationship between the amount of current remaining at the end of the voltage step and the effect of this time course of the onset of block on APD (Fig. 5B; asterisks). These results indicate that the length of a step must be carefully set if voltage- and time-dependent blockade is involved in drug action.


Figure 5
View larger version (26K):
[in this window]
[in a new window]

  		Fig. 5. Simulation of IKur in voltage clamp. A: a voltage-clamp step from –80 to 0 mV for 200 (left) and 10 (right) ms was added to the AF atrial myocyte model, and IKur is shown with various block onset time constants (reading traces from bottom to top; voltage- and time-independent blockade, then time constants of 5, 10, 20, 40, 80 and 160 ms, and, finally, the control current). B: the relationship between APD prolongation and voltage-clamp current recorded at the end of 200 ({square}) or 10 (*) ms duration voltage steps. Symbols represent block on rate time constants from 160 to 5 ms (reading from right to left). The effect of voltage- and time-independent blockade (x) is indicated. C: traces of IKur simulated as above at different stimulus frequencies (columns) with different recovery from block time-constants (rows). D: the relationship between APD and voltage-clamp currents recorded at the end of 10-ms voltage step after repetitive 200-ms steps. Simulations run with an onset time constant of 10 ms ({circ}) and onset time constant of 160 ms ({triangleup}) are shown. The symbols represent recovery times constants of 250, 1,000, 4,000, and 16,000 ms (reading from right to left).

 
The next step was to identify protocols that could decorticate the effects of the kinetics of recovery from block. Figure 5C illustrates the effects of simulating voltage-clamp step stimulation of IKur at different stimulus frequencies and with different time constants for recovery from block. The duration (200 ms) and holding voltage (0 mV) were selected to correspond to those of plateau in human atrial AP after electrical remodeling. The onset time constants of IKur block were those shown in Fig. 5A. It is clear that increasing stimulus frequency and/or recovery time constant lead to the accumulation of IKur block with successive stimuli. We then changed the duration of the last step to 10 ms and calculated its step end current. Figure 5D exhibits the relationship between relative-step end currents and APD for two block-onset time constants (10 ms, open triangles; and 160 ms, open circles) while varying recovery time constant. In both cases the reduction in voltage-clamp current associated with longer recovery from block reflected an increase in APD in the AP simulation. In conclusion, a short-duration voltage-clamp step is able to identify the various kinetic parameters of block of IKur that might be useful to screen pharmaceutically interesting compounds.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This study used an AF-remodeled human atrial AP mathematical model to examine the effects of voltage- and time-dependent kinetics of IKur block on atrial AP configuration to identify the characteristics required for effective anti-AF drugs. In this simulation, IKur blockers with fast onset would prolong APD rate independently and those with slow onset are expected to prolong APD rate dependently, when the recovery is slow recovery. To aid fast and effective screening for compounds with these characteristics, a voltage-clamp protocol with a 10-ms step is more useful than the conventional 200–500-ms step.

Advantages of model studies. In silico studies are not intended to replace either in vitro or clinical trials during drug development, but they can reduce the number of animal and human experiments and orientate screening methods toward identifying compounds with maximally effective characteristics. For example, it is generally accepted that the quantity and the quality of human atrial tissue available for in vitro studies are extremely limited, and this situation is even worse when samples of AF-remodeled material are required. Advances in the therapeutic treatment of AF are also hindered by the absence of a clinically relevant animal model of this pathology (6). Although the shortening of APD in sinus rhythm due to an indirect enhancement of ICa during the profoundly elevated plateau was not reproduced in this study (25), the normal and AF atrial myocyte models used in this study reproduced experimental effects of IKur block on the human atrial AP (Fig. 2), and further in silico studies of drug effects on these simulations of the human atrial AP may reduce the need for a number of in vitro experiments. Furthermore, with in silico studies, it is possible to examine hypothetical effects of drugs, both good and bad. Thus IKur blockers with slow onset and fast recovery can be excluded from further consideration.

Optimal anti-AF drug profile predicted from the model study: fast onset and slow recovery. This study suggests that conventional voltage-clamp experiments with a long step (~200 ms) may fail to capture the properties of IKur blockers, which indicate their potential as effective anti-AF drugs. In previous in vitro experiments, long voltage-clamp steps were used to emphasize the IKur blocking potency of different compounds (13, 14, 16, 19). However, the results of this study suggest that for IKur blockers to effectively treat chronic AF, they should exhibit fast onset kinetics during systole or both slow onset during systole and slow recovery during diastole. Although this point has not been considered in previous studies, IKur blockers under trial for AF (e.g., AVE0118) do show fast development of block and thus fit at least part of this profile (13). Short voltage-clamp steps of 10-ms duration detect this particular property of anti-AF IKur blockers.

The recovery time constant of IKur blockade is not usually considered as a factor in the development of an anti-AF drug. However, it clearly plays a role in the frequency dependence of APD prolongation by a drug. Most strategies for the development of selective IKur blockers as anti-AF drugs do not aim to be effective within a specific AP frequency band; rather, the same drug is expected to terminate AF and to prevent the reoccurrence of AF after the return to sinus rhythm. The fast onset time constant may fit into this strategy. On the other hand, a frequency-dependent elongation of APD due to slow recovery from block may be a desirable characteristic for a compound to prevent fibrillation. Because of the major overlap of IKur and Ito for the repolarization reserve in atrial AP, the frequency dependence of APD elongation in native human AF atrium caused by IKur blockers with different blocking and recovery kinetics would be more complicated than that proposed in this study. Although Ito is known to be less sensitive to IKur blockers (e.g., Ref. 18), it is possible to examine the effects on APD and its frequency dependence of possible overlapped Ito and IKur blockades with our human atrial AF model by further introducing Ito blockade into the model. However, for the final conclusion, it is needed to confirm the feasibility of this concept in native AF human atrial myocytes or tissue.

Different effects of IKur blockade on atrial AP in human and animals. Different potassium channels contribute differently to cardiac AP repolarization in different species, in different parts of the heart, and during or following different pathologies. The combination of the potassium currents (e.g., IKr, IKs) and calcium currents contributing to AP repolarization is known as its repolarization reserve. Thus blockade of IKur did not induce significant APD prolongation in the model of the normal human atrial AP because strong activation of IK during normal APD conceals the effect of IKur blockade. AF remodeling reduced ICa,L and shortened APD, and weak activation of IK due to shortened APD could not compensate for blockade of IKur, which then prolonged APD. In a similar manner the effects of IKur block on APD in animals will depend on the particular combination of potassium currents and the physiological conditions regulating the repolarization reserve. In animals with short APDs, APD prolongation due to IKur blockade could be overestimated and drug efficacy may not reflect the situation in human. Models of the human heart can assist to resolve such problems in drug development.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by the Leading Project for Biosimulation "Development of Heart and Lung models for in silico prediction of drug action and clinical treatment" from the Ministry of Education, Culture, Sports, Science and Technology in Japan (to Y. Kurachi).


   ACKNOWLEDGMENTS
 
We thank Dr. I. Findlay for a critical reading of this manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Y. Kurachi, Div. of Molecular and Cellular Pharmacology, Dept. of Pharmacology, Graduate School of Medicine, Osaka Univ., 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan (e-mail: ykurachi{at}pharma2.med.osaka-u.ac.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Blaauw Y, Gogelein H, Tieleman RG, van Hunnik A, Schotten U, Allessie MA. "Early" class III drugs for the treatment of atrial fibrillation: efficacy and atrial selectivity of AVE0118 in remodeled atria of the goat. Circulation 110: 1717–1724, 2004.[Abstract/Free Full Text]
  2. Bosch RF, Zeng X, Grammer JB, Popovic K, Mewis C, Kuhlkamp V. Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc Res 44: 121–131, 1999.[Abstract/Free Full Text]
  3. Brundel BJ, van Gelder IC, Henning RH, Tuinenburg AE, Deelman LE, Tieleman RG, Grandjean JG, van Gilst WH, Crijns HJ. Gene expression of proteins influencing the calcium homeostasis in patients with persistent and paroxysmal atrial fibrillation. Cardiovasc Res 42: 443–454, 1999.[Abstract/Free Full Text]
  4. Brundel BJ, Van Gelder IC, Henning RH, Tuinenburg AE, Wietses M, Grandjean JG, Wilde AA, Van Gilst WH, Crijns HJ. Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: differential regulation of protein and mRNA levels for K+ channels. J Am Coll Cardiol 37: 926–932, 2001.[Abstract/Free Full Text]
  5. Carlsson L, Chartier D, Nattel S. Characterization of the in vivo and in vitro electrophysiological effects of the novel antiarrhythmic agent AZD7009 in atrial and ventricular tissue of the dog. J Cardiovasc Pharmacol 47: 123–132, 2006.[CrossRef][Web of Science][Medline]
  6. Chen PS. Douglas P. Zipes Lecture. Neural mechanisms of atrial fibrillation. Heart Rhythm 3: 1373–1377, 2006.[CrossRef][Web of Science][Medline]
  7. Courtemanche M, Ramirez RJ, Nattel S. Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. Am J Physiol Heart Circ Physiol 275: H301–H321, 1998.[Abstract/Free Full Text]
  8. Courtemanche M, Ramirez RJ, Nattel S. Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model. Cardiovasc Res 42: 477–489, 1999.[Abstract/Free Full Text]
  9. Dobrev D, Graf E, Wettwer E, Himmel HM, Hala O, Doerfel C, Christ T, Schuler S, Ravens U. Molecular basis of downregulation of G-protein-coupled inward rectifying K+ current (IK,ACh) in chronic human atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced IK,ACh and muscarinic receptor-mediated shortening of action potentials. Circulation 104: 2551–2557, 2001.[Abstract/Free Full Text]
  10. Dobrev D, Ravens U. Remodeling of cardiomyocyte ion channels in human atrial fibrillation. Basic Res Cardiol 98: 137–148, 2003.[Web of Science][Medline]
  11. Feng J, Wible B, Li GR, Wang Z, Nattel S. Antisense oligodeoxynucleotides directed against Kv1.5 mRNA specifically inhibit ultrarapid delayed rectifier K+ current in cultured adult human atrial myocytes. Circ Res 80: 572–579, 1997.[Abstract/Free Full Text]
  12. Franqueza L, Valenzuela C, Delpon E, Longobardo M, Caballero R, Tamargo J. Effects of propafenone and 5-hydroxy-propafenone on hKv1.5 channels. Br J Pharmacol 125: 969–978, 1998.[CrossRef][Web of Science][Medline]
  13. Gogelein H, Brendel J, Steinmeyer K, Strubing C, Picard N, Rampe D, Kopp K, Busch AE, Bleich M. Effects of the atrial antiarrhythmic drug AVE0118 on cardiac ion channels. Naunyn Schmiedebergs Arch Pharmacol 370: 183–192, 2004.[Web of Science][Medline]
  14. Lagrutta A, Wang J, Fermini B, Salata JJ. Novel, potent inhibitors of human Kv1.5 K+ channels and ultrarapidly activating delayed rectifier potassium current. J Pharmacol Exp Ther 317: 1054–1063, 2006.[Abstract/Free Full Text]
  15. Li GR, Feng J, Yue L, Carrier M, Nattel S. Evidence for two components of delayed rectifier K+ current in human ventricular myocytes. Circ Res 78: 689–696, 1996.[Abstract/Free Full Text]
  16. Matsuda T, Masumiya H, Tanaka N, Yamashita T, Tsuruzoe N, Tanaka Y, Tanaka H, Shigenoba K. Inhibition by a novel anti-arrhythmic agent, NIP-142, of cloned human cardiac K+ channel Kv1.5 current. Life Sci 68: 2017–2024, 2001.[CrossRef][Web of Science][Medline]
  17. Nattel S, Carlsson L. Innovative approaches to anti-arrhythmic drug therapy. Nat Rev Drug Discov 5: 1034–1049, 2006.[CrossRef][Web of Science][Medline]
  18. Nattel S, Matthews C, De Blasio E, Han W, Li D, Yue L. Dose-dependence of 4-aminopyridine plasma concentrations and electrophysiological effects in dogs: potential relevance to ionic mechanisms in vivo. Circulation 101: 1179–1184, 2000.[Abstract/Free Full Text]
  19. Persson F, Carlsson L, Duker G, Jacobson I. Blocking characteristics of hKv1.5 and hKv43/hKChIP22 after administration of the novel antiarrhythmic compound AZD7009. J Cardiovasc Pharmacol 46: 7–17, 2005.[CrossRef][Web of Science][Medline]
  20. Rampe D, Murawsky MK. Blockade of the human cardiac K+ channel Kv1.5 by the antibiotic erythromycin. Naunyn Schmiedebergs Arch Pharmacol 355: 743–750, 1997.[CrossRef][Web of Science][Medline]
  21. Rivard L, Takeshita AS, Maltais C, Ford J, Pinnock R, Madge D, Nattel S.Electrophysiological and atrial antiarrhythmic effects of a novel IKur/Kv1.5 blocker in dogs (Abstract). Heart Rhythm, Suppl 2: S180, 2005.
  22. Tsujimae K, Suzuki S, Murakami S, Kurachi Y. Frequency dependent effects of various IKr blockers on cardiac action potential duration in a human atrial model. Am J Physiol Heart Circ Physiol 293: H660–H669, 2007.[Abstract/Free Full Text]
  23. Van Wagoner DR, Pond AL, McCarthy PM, Trimmer JS, Nerbonne JM. Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation. Circ Res 80: 772–781, 1997.[Abstract/Free Full Text]
  24. Wang Z, Fermini B, Nattel S. Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K+ current similar to Kv15 cloned channel currents. Circ Res 73: 1061–1076, 1993.[Abstract/Free Full Text]
  25. Wettwer E, Hala O, Christ T, Heubach JF, Dobrev D, Knaut M, Varro A, Ravens U. Role of IKur in controlling action potential shape and contractility in the human atrium: influence of chronic atrial fibrillation. Circulation 110: 2299–2306, 2004.[Abstract/Free Full Text]
  26. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92: 1954–1968. 1995.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Phil Trans R Soc AHome page
S. Severi, C. Corsi, and E. Cerbai
From in vivo plasma composition to in vitro cardiac electrophysiology and in silico virtual heart: the extracellular calcium enigma
Phil Trans R Soc A, June 13, 2009; 367(1896): 2203 - 2223.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/2/H793    most recent
01229.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tsujimae, K.
Right arrow Articles by Kurachi, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsujimae, K.
Right arrow Articles by Kurachi, Y.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.