Frequency-Dependent Electrophysiological Effects of Flecainide, Nifekalant and &lt;i&gt;d,l&lt;/i&gt;-Sotalol on the Human Atrium

Watanabe, Hiromi; Watanabe, Ichiro; Nakai, Toshiko; Oshikawa, Naohiro; Kunimoto, Satoshi; Masaki, Riko; Kojima, Toshiaki; Saito, Satoshi; Ozawa, Yukio; Kanmatuse, Katsuo

doi:10.1253/jcj.65.1

Cited by 26 publications

(18 citation statements)

References 21 publications

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“…Previous clinical studies have demonstrated that class I antiarrhythmic drugs have 'frequency-dependent effects' on the atrial conduction and effective refractory period, and that most of the class III antiarrhythmic drugs have 'reverse frequencydependent effects' on the atrial effective refractory period. 6) In this study, oseltamivir as well as pilsicainide decreased the atrial conduction velocity in a frequency-dependent manner, confirming that oseltamivir can inhibit atrial Na + channels similarly to class Ic antiarrhythmic drugs. Also, 10 µM of pilsicainide increased the atrial effective refractory period in a frequency-dependent manner as reported previously.…”

Section: )supporting

confidence: 74%

Electrophysiological Effects of an Anti-influenza Drug Oseltamivir on the Guinea-Pig Atrium: Comparison with Those of Pilsicainide

Takahara

Suzuki

Hagiwara

et al. 2013

Biological & Pharmaceutical Bulletin

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We assessed the effects of oseltamivir on the conduction velocity and effective refractory period in the guinea-pig atrium in comparison with those of a class Ic antiarrhythmic drug pilsicainide. The recording and stimulating electrodes were attached on the epicardium close to the sinus nodal region and on the left atrial appendage. Oseltamivir (10-100 µM) as well as pilsicainide (1-10 µM) decreased the atrial conduction velocity in a frequency-dependent manner. Both drugs also increased the effective refractory period in both atria; but the frequency-dependent property of oseltamivir was lacking in the left atrium, and it was less obvious in the right atrium compared with that of pilsicainide. These results suggest that oseltamivir can directly modify the electrophysiological functions in the guinea-pig atrium possibly via combination of Na and K channel-blocking actions.Key words oseltamivir; pilsicainide; atrium; conduction velocity; effective refractory period A neuraminidase inhibitor oseltamivir is one of the most effective drugs against influenza virus infection.1) In a recent study using the halothane-anesthetized dog, we found a supratherapeutic dose of oseltamivir (30 mg/kg, intravenous (i.v.)) can exert the negative chronotropic, inotropic and dromotropic actions on the heart.2) More interestingly, the lower dose (3 mg/kg, i.v.), which is still 10 times higher than therapeutic dose range as an anti-influenza drug, increased the P-wave duration without affecting the other electrocardiographic variables. Since the P-wave duration reflects the intra-atrial conduction time, this observation may evoke a new category of drugs showing atrio-selective actions. However, since oseltamivir is known to be metabolized to the active form inhibiting neuraminidase (Ro64-0802), it is unknown whether oseltamivir itself affects the atrial impulse conduction. Our previous study using the isolated guinea-pig atrium electrically driven at 1 Hz demonstrated that 10-100 µM of oseltamivir can decrease the upstroke velocity of the phase 0 depolarization, but prolong the action potential duration, suggesting that the drug may affect ionic channels in the atrium such as Na + and K + channels.2) Using the isolated atrium of the guinea pig, in this study we assessed the effects of oseltamivir on the conduction velocity and effective refractory period at pacing cycle lengths of 150-250 ms in comparison with those of a class Ic antiarrhythmic drug pilsicainide to better understand electrophysiological profiles of oseltamivir in the atrium. MATERIALS AND METHODSAll experiments were performed according to the Guidelines for Animal Experiments for Toho University. The Hartley guinea pigs of either sex weighing 350-450 g were used in this study.The isolated atrial preparation consists of the entire right and left atrium of a guinea pig, which was incubated with the Krebs-Henseleit solution of the following composition (in mM): NaCl 118.4, KCl 4.7, CaCl 2 2.5, MgSO 4 1.2, KH 2 PO 4 1.2, NaHCO 3 24.9, glucose 11.1, gassed with 95% O 2 /5%...

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Section: )supporting

confidence: 74%

Electrophysiological Effects of an Anti-influenza Drug Oseltamivir on the Guinea-Pig Atrium: Comparison with Those of Pilsicainide

Takahara

Suzuki

Hagiwara

et al. 2013

Biological & Pharmaceutical Bulletin

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“…Depending on the model, flecainide has been reported to have variable effects on aERP in vivo 16, 17, 18, 19, 20. In humans, some reported a slight but not significant flecainide‐induced increase in aERP, whereas others reported significant and use‐dependent increases 20, 34. A flecainide‐induced reduction in aERP accommodation to atrial activation rates, which may be important in suppressing AF, has been demonstrated by others 18, 34, 35, 36.…”

Section: Discussionmentioning

confidence: 99%

“…In humans, some reported a slight but not significant flecainide‐induced increase in aERP, whereas others reported significant and use‐dependent increases 20, 34. A flecainide‐induced reduction in aERP accommodation to atrial activation rates, which may be important in suppressing AF, has been demonstrated by others 18, 34, 35, 36. However, this mechanism of rate‐dependency and increased drug action at rapid atrial activation rates could not be proven by the present study.…”

Section: Discussionmentioning

confidence: 99%

Antiarrhythmic and Electrophysiologic Effects of Flecainide on Acutely Induced Atrial Fibrillation in Healthy Horses

Haugaard

Pehrson

Carstensen

et al. 2014

Veterinary Internal Medicne

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BackgroundOnly few pharmacologic compounds have been validated for treatment of atrial fibrillation (AF) in horses. Studies investigating the utility and safety of flecainide to treat AF in horses have produced conflicting results, and the antiarrhythmic mechanisms of flecainide are not fully understood.ObjectivesTo study the potential of flecainide to terminate acutely induced AF of short duration (≥15 minutes), to examine flecainide‐induced changes in AF duration and AF vulnerability, and to investigate the in vivo effects of flecainide on right atrial effective refractory period, AF cycle length, and ventricular depolarization and repolarization.AnimalsNine Standardbred horses. Eight received flecainide, 3 were used as time‐matched controls, 2 of which also received flecainide.MethodsProspective study. The antiarrhythmic and electrophysiologic effects of flecainide were based on 5 parameters: ability to terminate acute pacing‐induced AF (≥15 minutes), and drug‐induced changes in atrial effective refractory period, AF duration, AF vulnerability, and ventricular depolarization and repolarization times. Parameters were assessed at baseline and after flecainide by programmed electrical stimulation methods.ResultsFlecainide terminated all acutely induced AF episodes (n = 7); (AF duration, 21 ± 5 minutes) and significantly decreased the AF duration, but neither altered atrial effective refractory period nor AF vulnerability significantly. Ventricular repolarization time was prolonged between 8 and 20 minutes after initiation of flecainide infusion, but no ventricular arrhythmias were detected.Conclusions and Clinical ImportanceFlecainide had clear antiarrhythmic properties in terminating acute pacing‐induced AF, but showed no protective properties against immediate reinduction of AF. Flecainide caused temporary prolongation in the ventricular repolarization, which may be a proarrhythmic effect.

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“…19) As in patients without AF, 20) nifekalant did not affect IACT at any pacing CL (Table IV). Amiodarone blocks multiple channel currents (I Na , I ca, L , I to , I Kr , and I Ks ).…”

Section: Effects Of Class III Antiarrhythmic Drugs In the Remodeled Hmentioning

confidence: 78%

Rate-Dependent Electrophysiologic Effects of the Class III Antiarrhythmic Drugs Nifekalant, Amiodarone, and Ibutilide on the Atrium in Patients With Persistent Atrial Fibrillation

et al. 2013

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SummaryPersistent atrial fibrillation (AF) is characterized by electrical remodeling, ie, marked decreases in the atrial effective refractory period (ERP), ERP rate adaptation, and atrial conduction velocity. Little information is available on the effects of class III antiarrhythmic drugs on the remodeled atrium. We studied the effects of the class III antiarrhythmic drugs nifekalant, ibutilide, and amiodarone on rate-dependent changes in atrial action potential duration in patients with persistent AF. Right atrial (RA) monophasic action potential duration (MAPD) and intra-atrial conduction time (IACT) were measured at pacing cycle lengths (CLs) of 800, 700, 600, 500, 400, 350, 300, and 250 ms before and after administration of nifekalant (0.4 mg/kg + 0.3 mg/kg/hr, iv), amiodarone (5 mg/kg, iv), or ibutilide (0.01 mg/kg, iv) in 31 patients after successful internal cardioversion of chronic AF of > 2 months duration. Nifekalant and ibutilide significantly increased RA MAPD and the ERP at each CL in a reverse rate-dependent manner. Amiodarone did not affect RA MAPD. Nifekalant did not affect IACT, whereas amiodarone increased IACT at each CL in a rate-dependent manner, and ibutilide increased IACT at CLs ≤ 350 ms. The atrial electrophysiologic effects of the class III antiarrhythmic drugs nifekalant, amiodarone, and ibutilide differ, depending on the degree of electrical and structural remodeling and the effects of the drugs on the depolarizing and repolarizing currents. 2) A better understanding of the mechanisms determining antiarrhythmic drug efficacy would help to improve therapy. Under awareness of the risks of potent class I antiarrhythmic drugs made apparent by the Cardiac Arrhythmia Suppression Trial and subsequent analysis, developers shifted to class III antiarrhythmic agents.2-4) Clinical trials have shown class III drugs to be relatively ineffective in terminating AF but effective in preventing its recurrence.5) Experimental studies in vagotonic and atrial tachycardia-related models of sustained AF have shown limited capacity of clinically-relevant doses of class III rapid delayed rectifier (I Kr )-selective blocking agents to terminate AF.6-8) Wang, et al 6) showed that reverse use-dependent actions may limit class III drug efficacy at the rapid rates characteristic of AF but permit these drugs to prevent AF induction by premature complexes at slower resting sinus rates. Furthermore, recent experimental studies have shown that persistent AF causes progressive electrophysiologic changes in the atrial myocardium that make the atria more vulnerable to fibrillation.9,10) Thus, it is plausible to assume that this process of electrical remodeling during persistent AF also influences the efficacy of antiarrhythmic drugs. We therefore designed the present study to investigate the electrophysiologic effects of the different class III agents nifekalant, 11) amiodarone, and ibutilide on the remodeled atrium in patients with sustained AF. MethodsPatients: The subjects were 31 consecutive patients (26 men, 5 wom...

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Frequency-Dependent Electrophysiological Effects of Flecainide, Nifekalant and <i>d,l</i>-Sotalol on the Human Atrium

Cited by 26 publications

References 21 publications

Electrophysiological Effects of an Anti-influenza Drug Oseltamivir on the Guinea-Pig Atrium: Comparison with Those of Pilsicainide

Electrophysiological Effects of an Anti-influenza Drug Oseltamivir on the Guinea-Pig Atrium: Comparison with Those of Pilsicainide

Antiarrhythmic and Electrophysiologic Effects of Flecainide on Acutely Induced Atrial Fibrillation in Healthy Horses

Rate-Dependent Electrophysiologic Effects of the Class III Antiarrhythmic Drugs Nifekalant, Amiodarone, and Ibutilide on the Atrium in Patients With Persistent Atrial Fibrillation

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