Atrial-selective sodium channel block for the treatment of atrial fibrillation

Burashnikov, Alexander; Antzelevitch, Charles

doi:10.1517/14728210902997939

Cited by 33 publications

(68 citation statements)

References 116 publications

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“…One possible explanation for this effect is the state-dependent inhibition of Na + channels by amiodarone, which means that the binding of the drug is increased when the channel is in its inactivated state. As the resting membrane potential in atria is more depolarized than in ventricles, amiodarone is considered to block atrial Na + channels more potently than ventricular ones (Burashnikov et al 2008;Burashnikov and Antzelevitch 2009). One aim of the present study was to investigate whether dronedarone displays a similar atrial-selective inhibition of the fast Na + channel as amiodarone.…”

Section: Introductionmentioning

confidence: 94%

Effect of dronedarone on Na+, Ca2+ and HCN channels

Bogdan

Goegelein

Ruetten

2011

Naunyn-Schmied Arch Pharmacol

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Previous studies showed that amiodarone causes state-dependent inhibition of Na(+) channels thereby mediating an atrial-selective drug effect. The aim of the present study was to investigate the impact of the new antiarrhythmic compound dronedarone on Na(+), Ca(2+) and hyperpolarization-activated cyclic nucleotide-gated ion channels. Monophasic action potentials (MAP) and effective refractory period (ERP) were studied in arterially perfused left atria and ventricular wedge preparations of the pig. Fast Na(+) and Ca(2+) currents in isolated guinea pig ventricular myocytes as well as human HCN4 channels expressed in Chinese hamster ovary (CHO) cells were investigated with the patch-clamp technique. In left atrial epicardial tissue, dronedarone (3 μM) had no effect on the MAP duration, but the drug caused a significant prolongation of the ERP from 145 ± 9 to 184 ± 17 ms (n = 6; p < 0.05). In guinea pig ventricular myocytes, dronedarone exhibited a state-dependent inhibition of the fast Na(+) channel current with an IC(50) of 0.7 ± 0.1 μM, when the holding potential (V (hold)) was -80 mV. The maximal block at the highest concentration used was 77 ± 8%. In contrast, when V (hold) was -100 mV, inhibition with 10 μM dronedarone was only 9 ± 3% (n = 7). Dronedarone blocked Ca(2+) currents elicited by rectangular pulses at V (hold) = -40 mV with an IC(50) value of 0.4 ± 0.1 μM (maximal block by 10 μM dronedarone, 80 ± 6%), whereas at V (hold) = -80 mV, 10 μM dronedarone blocked only 20 ± 6% (n = 4) of the current. Applying an action potential clamp (V (hold) = -80 mV) yielded an IC(50) of 0.4 ± 0.3 μM. Human HCN4 channels expressed in CHO cells were blocked by dronedarone with an IC(50) of 1.0 ± 0.1 μM. Inhibition of fast Na(+) and Ca(2+) channels by dronedarone depends on the cell's resting membrane potential (state-dependent block) favouring an atrial-selective mode of action. Besides fast Na(+) and Ca(2+) channels, dronedarone also inhibits HCN4 currents. This might contribute to the clinically observed reduction in heart rate seen in patients in sinus rhythm after dronedarone treatment.

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Section: Introductionmentioning

confidence: 94%

Effect of dronedarone on Na+, Ca2+ and HCN channels

Bogdan

Goegelein

Ruetten

2011

Naunyn-Schmied Arch Pharmacol

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“…[1, 33, 34] The more negative half-inactivation voltage and more positive RMP importantly reduce the fraction of resting channels in atria vs. ventricles at RMP. Because recovery from sodium channel block generally occurs predominantly during the resting state of the channel, accumulation of sodium channel block is expected to be greater in atria than in the ventricles.…”

Section: Discussionmentioning

confidence: 99%

“…[33–35] Available data suggest that binding affinity of the I Na blocker for a given state of the channel (i.e., open, inactivated, or resting) does not determine the drug’s atrial-selectivity. [33] The rate of dissociation of the drug from the sodium channel, however, appears to be a key factor. I Na blockers possessing rapid vs. slow unbinding kinetics tend to be highly atrial-selective (e.g., ranolazine, vernakalant, amiodarone).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms underlying atrial-selective block of sodium channels by Wenxin Keli: Experimental and theoretical analysis

Barajas-Martínez

Burashnikov

et al. 2016

International Journal of Cardiology

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Introduction Atrial-selective inhibition of cardiac sodium channel current (INa) and INa-dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation. The present study was designed to examine the basis for the atrial-selective actions of Wenxin Keli. Methods Whole cell INa was recorded at rroom temperature in canine atrial and ventricular myocytes. Trains of 40 pulses were elicited over a range of pulse durations and interpulse intervals to determine tonic and use-dependent block. A Markovian model for INa that incorporates interaction of Wenxin Keli with different states of the channel was developed to examine the basis for atrial selectivity of the drug. Results Our data indicate that Wenxin Keli does not bind significantly to either closed or open states of the sodium channel, but binds very rapidly to the inactivated state of the channel and dissociates rapidly from the closed state. Action potentials recorded from atrial and ventricular preparations in the presence of 5g/L Wenxin Keli were introduced into the computer model in current clamp mode to simulate the effects on maximum upstroke velocity (Vmax). The model predicted much greater inhibition of Vmax in atrial vs. ventricular cells at rapid stimulation rates. Conclusion Our findings suggest that atrial selectivity of Wenxin Keli to block INa is due to more negative steady-state inactivation, less negative resting membrane potential, and shorter diastolic intervals in atrial vs. ventricular cells at rapid activation rates. These actions of Wenxin Keli account for its relatively safe and effective suppression of atrial fibrillation.

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“…Ranolazine is predominantly an open state blocker, whereas amiodarone and dronedarone are predominantly inactivate state block. Other drugs, such as quinidine or disopyramide, may inhibit both open and inactivated sodium channels to a similar extent but are not as safe as they dissociate from the sodium channels slowly, thus adding to the development of ventricular arrhythmias [59]. These ventricular arrhythmias are not observed in combination therapy with dronedarone or amiodarone and ranolazine because these drugs present rapid dissociation from the sodium channel thereby causing a predominantly atrial-selective sodium-channel inhibition [60].…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

Ranolazine for the treatment of atrial fibrillation

Rosa

Dorighi

Ferrero

et al. 2015

Expert Opinion on Investigational Drugs

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Although ranolazine is considered an anti-angina drug, it may also be, according to the available data, used in patients with AF. Ranolazine has anti-AF efficacy, both alone or in combination with other drugs such as amiodarone and dronedarone. Indeed, its efficacy has been demonstrated in various settings such as the termination of paroxysmal AF, the facilitation of AF electrical cardioversion, and postoperative AF prevention. Although there is a great deal of evidence from pioneering experimental studies, the clinical evidence of the AF-suppressing effect of ranolazine is derived from studies with small sample size or from secondary analyses. A better understanding of the role of ranolazine as an anti-AF drug will be obtained through larger, prospective, placebo-controlled clinical trials in different populations.

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Atrial-selective sodium channel block for the treatment of atrial fibrillation

Cited by 33 publications

References 116 publications

Effect of dronedarone on Na+, Ca2+ and HCN channels

Effect of dronedarone on Na+, Ca2+ and HCN channels

Mechanisms underlying atrial-selective block of sodium channels by Wenxin Keli: Experimental and theoretical analysis

Ranolazine for the treatment of atrial fibrillation

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