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Hikaru Tanaka - One of the best experts on this subject based on the ideXlab platform.

  • electrophysiological effects of the Antiarrhythmic Drug bepridil on the guinea pig pulmonary vein myocardium
    Biological & Pharmaceutical Bulletin, 2013
    Co-Authors: Akira Takahara, Mihoko Hagiwara, Kiyoshi Takeda, Hikaru Tanaka
    Abstract:

    We compared effects of the Antiarrhythmic Drug bepridil on the electrophysiological parameters in the isolated pulmonary vein preparation from guinea pigs with those in the left atrium. Three pairs of bipolar electrodes were attached to the left atrium, pulmonary vein and junctional region of left atrium and pulmonary vein to measure intra-atrial and intra-pulmonary vein conduction velocity and effective refractory period. Bepridil at 10 µM prolonged the effective refractory period with little effect on the conduction velocity in the pulmonary vein, whereas the Drug failed to affect the electrophysiological parameters in the left atrium. Using the conventional microelectrode technique, action potential of the isolated pulmonary vein preparation and left atrium were measured. Bepridil prolonged the action potential duration of the pulmonary vein more potently than that of the left atrium. These results suggest that Antiarrhythmic effects of bepridil on reentry within the pulmonary vein are estimated to be greater than within the left atrium, which may be one of the key considerations to understand its Antiarrhythmic mechanisms.

  • electrophysiological effects of the class ic Antiarrhythmic Drug pilsicainide on the guinea pig pulmonary vein myocardium
    Journal of Pharmacological Sciences, 2012
    Co-Authors: Akira Takahara, Iyuki Namekata, Mihoko Hagiwara, Kiyoshi Takeda, Yayoi Tsuneoka, Hikaru Tanaka
    Abstract:

    The pulmonary vein is known as an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation. We compared effects of the class Ic Antiarrhythmic Drug pilsicainide on the electrophysiological parameters in the isolated pulmonary vein preparation from guinea pigs with those in the left atrium. Three pairs of bipolar electrodes were attached to the left atrium, pulmonary vein, and junctional region of the left atrium and pulmonary vein to measure intra-atrial and intra-pulmonary vein conduction velocity and effective refractory period. Pilsicainide (10 μM) decreased the conduction velocity in the pulmonary vein as well as the left atrium, whose effect on the pulmonary vein was relatively greater than that on the left atrium. The Drug prolonged the effective refractory period in the pulmonary vein as well as the left atrium, and the effect of the Drug on the pulmonary vein was less than that on the left atrium. The currently observed electrophysiological property of pilsicainide suggests that its effects on reentry within the pulmonary vein are estimated to be weaker than within the left atrium, which may be one of the key considerations for understanding its Antiarrhythmic mechanisms in the atrium and pulmonary vein.

  • analysis of arrhythmogenic profile in a canine model of chronic atrioventricular block by comparing in vitro effects of the class iii Antiarrhythmic Drug nifekalant on the ventricular action potential indices between normal heart and atrioventricular block heart
    Journal of Pharmacological Sciences, 2007
    Co-Authors: Akira Takahara, Hideki Nakamura, Hideaki Nouchi, Takeshi Tamura, Toshikazu Tanaka, Hideaki Shimada, Miku Tamura, Noriko Tsuruoka, Kentaro Takeda, Hikaru Tanaka
    Abstract:

    The chronic atrioventricular block dog is a useful model for predicting the future onset of Drug-induced long QT syndrome in clinical practice. To better understand the arrhythmogenic profile of this model, we recorded the action potentials of the isolated ventricular tissues in the presence and absence of the class III Antiarrhythmic Drug nifekalant. The action potential durations of the Purkinje fiber and free wall of the right ventricle were longer in the chronic atrioventricular block dogs than in the dogs with normal sinus rhythm. Nifekalant in concentrations of 1 and 10 μM prolonged the action potential durations of Purkinje fiber and the free wall in a concentration-dependent manner. The extent of prolongation was greater in the chronic atrioventricular block dogs than in the normal dogs. However, increase of temporal dispersion of ventricular repolarization including early afterdepolarization was not detected by nifekalant in either group of dogs, indicating lack of potential to trigger arrhythmias in vitro. These results suggest that the ventricular repolarization delay in the chronic atrioventricular block model by nifekalant may largely depend on the decreased myocardial repolarization reserve, whereas the trigger for lethal arrhythmia was not generated in the in vitro condition in contrast to the in vivo experiment.

Leonid V Rosenshtraukh - One of the best experts on this subject based on the ideXlab platform.

  • a new class iii Antiarrhythmic Drug niferidil prolongs action potentials in guinea pig atrial myocardium via inhibition of rapid delayed rectifier
    Cardiovascular Drugs and Therapy, 2017
    Co-Authors: V S Kuzmin, Denis V. Abramochkin, Leonid V Rosenshtraukh
    Abstract:

    A new class III Antiarrhythmic Drug niferidil (RG-2) has been introduced as a highly effective therapy for cases of persistent atrial fibrillation, but ionic mechanisms of its action are poorly understood. In the present study, the effects of niferidil on action potential (AP) waveform and potassium currents responsible for AP repolarization were investigated in guinea pig atrial myocardium. APs were recorded with sharp glass microelectrodes in multicellular atrial preparations. Whole-cell patch-clamp technique was used to measure K+ currents in isolated myocytes. In multicellular atrial preparations, 10−8 M niferidil effectively prolonged APs by 15.2 ± 2.8% at 90% repolarization level. However, even the highest tested concentrations, 10−6 M and 10−5 M failed to prolong APs more than 32.5% of control duration. The estimated concentration of niferedil for half-maximal AP prolongation was 1.13 × 10−8 M. Among the potassium currents responsible for AP repolarization phase, I K1 was found to be almost insensitive to niferidil. However, another inward rectifier, I KACh, was effectively suppressed by micromolar concentrations of niferidil with IC50 = 9.2 × 10−6 M. I KATP was much less sensitive to the Drug with IC50 = 2.26 × 10−4 M. The slow component of delayed rectifier, I Ks, also demonstrated low sensitivity to niferidil—the highest used concentration, 10−4 M, decreased peak I Ks density to 46.2 ± 5.5% of control. Unlike I Ks, the rapid component of delayed rectifier, I Kr, appeared to be extremely sensitive to niferidil. The IC50 was 1.26 × 10−9 M. I Kr measured in ventricular myocytes was found to be less sensitive to niferidil with IC50 = 3.82 × 10−8 M. Niferidil prolongs APs in guinea pig atrial myocardium via inhibition of I Kr.

  • Effects of new class III Antiarrhythmic Drug niferidil on electrical activity in murine ventricular myocardium and their ionic mechanisms
    Naunyn-Schmiedeberg's Archives of Pharmacology, 2015
    Co-Authors: Denis V. Abramochkin, Vladislav S. Kuzmin, Leonid V Rosenshtraukh
    Abstract:

    A new class III Antiarrhythmic Drug niferidil has been recently introduced as a highly effective therapy cure for cases of persistent atrial fibrillation, but ionic mechanisms of its action are still unknown. Effects of niferidil on action potential (AP) waveform and major ionic currents were studied in mouse ventricular myocardium. APs were recorded with glass microelectrodes in multicellular preparations of right ventricular wall. Whole-cell patch-clamp technique was used to measure K^+, Ca^2+, and Na^+ currents in isolated mouse ventricular myocytes. While 10^−7 M niferidil failed to alter the AP configuration, 10^−6 M tended to prolong APs (by 12.05 ± 1.8 % at 50 % of repolarization) and 10^−5 M induced significant slowing of repolarization (32.1 ± 4.9 % at 50 % of repolarization). Among the potassium currents responsible for AP repolarization phase, I _K1 was found to be almost insensitive to niferidil. I _to demonstrated low sensitivity to niferidil with IC50 = 2.03 × 10^−4 M. I _Kur, which was previously hypothesized to be the main target of the Drug, was more sensitive with IC50 = 6 × 10^−5 M. However, sustained delayed rectifier potassium current I _ss was inhibited with even lower IC50 = 2.8 × 10^−5 M. Therefore, suppression of I _ss and, second, I _Kur by niferidil seems to underlie the AP prolongation in mouse ventricular tissue. Niferidil also produced a modest decrease in I _CaL peak amplitude (IC50≈10^−4 M), but failed to alter I _Na significantly. Niferidil prolongs APs in mouse ventricular myocardium mainly by inhibiting I _ss and I _Kur K^+ currents, but not exclusively I _Kur, as was proposed earlier. Further investigations are required to reveal the mechanisms of niferidil action in human myocardium, where I _Kr is strongly expressed instead of I _ss.

  • effects of a new class iii Antiarrhythmic Drug nibentan in a canine model of vagally mediated atrial fibrillation
    Journal of Cardiovascular Pharmacology, 2000
    Co-Authors: Vadim V Fedorov, G G Beloshapko, Oleg F Sharifov, Anna V Yushmanova, Leonid V Rosenshtraukh
    Abstract:

    Nibentan, a new class III Antiarrhythmic Drug, is highly effective in patients with atrial flutter and fibrillation. However, its mechanism of action remains unclear. The aim of this study was to investigate the effects of nibentan using a canine model of vagally sustained atrial fibrillation (AF). Nibentan was intravenously infused to anesthetized open-chest dogs during vagally induced AF. Cumulative doses of nibentan (0.063, 0.125, and 0.250 mg/kg) successfully terminated AF in 78, 88, and 100% as well as prevented AF reinduction in 11, 63, and 90% of cases, respectively. All doses of nibentan significantly and rate-independently increased atrial effective refractory period (AERP) with and without vagal stimulation. Activation mapping (224 epicardial electrodes) during AF showed that nibentan reduced the number of simultaneously occurring reentrant wavelets. Herewith the atrial excitation slowed down until conduction failure of reentrant wavelets led to arrhythmia termination. These changes in activation patterns can be accounted for by nibentan-induced increase of AERP (55 +/- 9%, 82 +/- 12%, and 90 +/- 6%; p < 0.01) and wavelength for reentry (47 +/- 7%, 68 +/- 12%, and 72 +/- 4%; p < 0.01) at rapid atrial rates in the presence of vagal stimulation. In conclusion, the high efficacy of nibentan against AF was associated with significant rate-independent increase in AERP and in wavelength, and might be in part explained by block of both delayed rectifier (I(K)) and muscarinic I(K,ACh) currents.

Akira Takahara - One of the best experts on this subject based on the ideXlab platform.

  • electrophysiological effects of the Antiarrhythmic Drug bepridil on the guinea pig pulmonary vein myocardium
    Biological & Pharmaceutical Bulletin, 2013
    Co-Authors: Akira Takahara, Mihoko Hagiwara, Kiyoshi Takeda, Hikaru Tanaka
    Abstract:

    We compared effects of the Antiarrhythmic Drug bepridil on the electrophysiological parameters in the isolated pulmonary vein preparation from guinea pigs with those in the left atrium. Three pairs of bipolar electrodes were attached to the left atrium, pulmonary vein and junctional region of left atrium and pulmonary vein to measure intra-atrial and intra-pulmonary vein conduction velocity and effective refractory period. Bepridil at 10 µM prolonged the effective refractory period with little effect on the conduction velocity in the pulmonary vein, whereas the Drug failed to affect the electrophysiological parameters in the left atrium. Using the conventional microelectrode technique, action potential of the isolated pulmonary vein preparation and left atrium were measured. Bepridil prolonged the action potential duration of the pulmonary vein more potently than that of the left atrium. These results suggest that Antiarrhythmic effects of bepridil on reentry within the pulmonary vein are estimated to be greater than within the left atrium, which may be one of the key considerations to understand its Antiarrhythmic mechanisms.

  • electrophysiological effects of the class ic Antiarrhythmic Drug pilsicainide on the guinea pig pulmonary vein myocardium
    Journal of Pharmacological Sciences, 2012
    Co-Authors: Akira Takahara, Iyuki Namekata, Mihoko Hagiwara, Kiyoshi Takeda, Yayoi Tsuneoka, Hikaru Tanaka
    Abstract:

    The pulmonary vein is known as an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation. We compared effects of the class Ic Antiarrhythmic Drug pilsicainide on the electrophysiological parameters in the isolated pulmonary vein preparation from guinea pigs with those in the left atrium. Three pairs of bipolar electrodes were attached to the left atrium, pulmonary vein, and junctional region of the left atrium and pulmonary vein to measure intra-atrial and intra-pulmonary vein conduction velocity and effective refractory period. Pilsicainide (10 μM) decreased the conduction velocity in the pulmonary vein as well as the left atrium, whose effect on the pulmonary vein was relatively greater than that on the left atrium. The Drug prolonged the effective refractory period in the pulmonary vein as well as the left atrium, and the effect of the Drug on the pulmonary vein was less than that on the left atrium. The currently observed electrophysiological property of pilsicainide suggests that its effects on reentry within the pulmonary vein are estimated to be weaker than within the left atrium, which may be one of the key considerations for understanding its Antiarrhythmic mechanisms in the atrium and pulmonary vein.

  • analysis of arrhythmogenic profile in a canine model of chronic atrioventricular block by comparing in vitro effects of the class iii Antiarrhythmic Drug nifekalant on the ventricular action potential indices between normal heart and atrioventricular block heart
    Journal of Pharmacological Sciences, 2007
    Co-Authors: Akira Takahara, Hideki Nakamura, Hideaki Nouchi, Takeshi Tamura, Toshikazu Tanaka, Hideaki Shimada, Miku Tamura, Noriko Tsuruoka, Kentaro Takeda, Hikaru Tanaka
    Abstract:

    The chronic atrioventricular block dog is a useful model for predicting the future onset of Drug-induced long QT syndrome in clinical practice. To better understand the arrhythmogenic profile of this model, we recorded the action potentials of the isolated ventricular tissues in the presence and absence of the class III Antiarrhythmic Drug nifekalant. The action potential durations of the Purkinje fiber and free wall of the right ventricle were longer in the chronic atrioventricular block dogs than in the dogs with normal sinus rhythm. Nifekalant in concentrations of 1 and 10 μM prolonged the action potential durations of Purkinje fiber and the free wall in a concentration-dependent manner. The extent of prolongation was greater in the chronic atrioventricular block dogs than in the normal dogs. However, increase of temporal dispersion of ventricular repolarization including early afterdepolarization was not detected by nifekalant in either group of dogs, indicating lack of potential to trigger arrhythmias in vitro. These results suggest that the ventricular repolarization delay in the chronic atrioventricular block model by nifekalant may largely depend on the decreased myocardial repolarization reserve, whereas the trigger for lethal arrhythmia was not generated in the in vitro condition in contrast to the in vivo experiment.

Denis V. Abramochkin - One of the best experts on this subject based on the ideXlab platform.

  • a new class iii Antiarrhythmic Drug niferidil prolongs action potentials in guinea pig atrial myocardium via inhibition of rapid delayed rectifier
    Cardiovascular Drugs and Therapy, 2017
    Co-Authors: V S Kuzmin, Denis V. Abramochkin, Leonid V Rosenshtraukh
    Abstract:

    A new class III Antiarrhythmic Drug niferidil (RG-2) has been introduced as a highly effective therapy for cases of persistent atrial fibrillation, but ionic mechanisms of its action are poorly understood. In the present study, the effects of niferidil on action potential (AP) waveform and potassium currents responsible for AP repolarization were investigated in guinea pig atrial myocardium. APs were recorded with sharp glass microelectrodes in multicellular atrial preparations. Whole-cell patch-clamp technique was used to measure K+ currents in isolated myocytes. In multicellular atrial preparations, 10−8 M niferidil effectively prolonged APs by 15.2 ± 2.8% at 90% repolarization level. However, even the highest tested concentrations, 10−6 M and 10−5 M failed to prolong APs more than 32.5% of control duration. The estimated concentration of niferedil for half-maximal AP prolongation was 1.13 × 10−8 M. Among the potassium currents responsible for AP repolarization phase, I K1 was found to be almost insensitive to niferidil. However, another inward rectifier, I KACh, was effectively suppressed by micromolar concentrations of niferidil with IC50 = 9.2 × 10−6 M. I KATP was much less sensitive to the Drug with IC50 = 2.26 × 10−4 M. The slow component of delayed rectifier, I Ks, also demonstrated low sensitivity to niferidil—the highest used concentration, 10−4 M, decreased peak I Ks density to 46.2 ± 5.5% of control. Unlike I Ks, the rapid component of delayed rectifier, I Kr, appeared to be extremely sensitive to niferidil. The IC50 was 1.26 × 10−9 M. I Kr measured in ventricular myocytes was found to be less sensitive to niferidil with IC50 = 3.82 × 10−8 M. Niferidil prolongs APs in guinea pig atrial myocardium via inhibition of I Kr.

  • Effects of new class III Antiarrhythmic Drug niferidil on electrical activity in murine ventricular myocardium and their ionic mechanisms
    Naunyn-Schmiedeberg's Archives of Pharmacology, 2015
    Co-Authors: Denis V. Abramochkin, Vladislav S. Kuzmin, Leonid V Rosenshtraukh
    Abstract:

    A new class III Antiarrhythmic Drug niferidil has been recently introduced as a highly effective therapy cure for cases of persistent atrial fibrillation, but ionic mechanisms of its action are still unknown. Effects of niferidil on action potential (AP) waveform and major ionic currents were studied in mouse ventricular myocardium. APs were recorded with glass microelectrodes in multicellular preparations of right ventricular wall. Whole-cell patch-clamp technique was used to measure K^+, Ca^2+, and Na^+ currents in isolated mouse ventricular myocytes. While 10^−7 M niferidil failed to alter the AP configuration, 10^−6 M tended to prolong APs (by 12.05 ± 1.8 % at 50 % of repolarization) and 10^−5 M induced significant slowing of repolarization (32.1 ± 4.9 % at 50 % of repolarization). Among the potassium currents responsible for AP repolarization phase, I _K1 was found to be almost insensitive to niferidil. I _to demonstrated low sensitivity to niferidil with IC50 = 2.03 × 10^−4 M. I _Kur, which was previously hypothesized to be the main target of the Drug, was more sensitive with IC50 = 6 × 10^−5 M. However, sustained delayed rectifier potassium current I _ss was inhibited with even lower IC50 = 2.8 × 10^−5 M. Therefore, suppression of I _ss and, second, I _Kur by niferidil seems to underlie the AP prolongation in mouse ventricular tissue. Niferidil also produced a modest decrease in I _CaL peak amplitude (IC50≈10^−4 M), but failed to alter I _Na significantly. Niferidil prolongs APs in mouse ventricular myocardium mainly by inhibiting I _ss and I _Kur K^+ currents, but not exclusively I _Kur, as was proposed earlier. Further investigations are required to reveal the mechanisms of niferidil action in human myocardium, where I _Kr is strongly expressed instead of I _ss.

  • effects of a new Antiarrhythmic Drug ss 68 on electrical activity in working atrial and ventricular myocardium of mouse and their ionic mechanisms
    Journal of Pharmacological Sciences, 2015
    Co-Authors: Saida K Bogus, Denis V. Abramochkin, Pavel A Galenkoyaroshevsky, K F Suzdalev
    Abstract:

    SS-68 is a derivative of indole, which demonstrated strong Antiarrhythmic effects not associated with significant QT prolongation in dog models of atrial fibrillation. Therefore, SS-68 was proposed as a new Antiarrhythmic Drug and the present study is the first describing its effects on action potentials (APs) configuration and elucidating the ionic mechanisms of these effects. Sharp microelectrodes were used to record APs in isolated preparations of mouse atrial and ventricular myocardium. In both types of myocardium 10(-6) M SS-68 produced reduction of AP duration, 3 × 10(-6) M failed to alter AP waveform and 10(-5) - 3 × 10(-5) M prolonged APs. Sensitivity of main ionic currents to SS-68 was determined using whole-cell patch clamp. Transient potassium current Ito was slightly inhibited by SS-68 with IC50 = 1.43 × 10(-4) M. IKur was more sensitive with IC50 = 1.84 × 10(-5) M. Background inward rectifier showed very low sensitivity to SS-68 - only 10(-4) M SS-68 caused significant reduction of IK1. ICaL was significantly inhibited by 10(-6)M - 3 × 10(-5) M SS-68. The IC50 value for the ICaL was 1.84 × 10(-6) M. Thus, main ionic currents of mouse cardiomyocytes are inhibited by SS-68 in the following order of potency: ICaL > IKur > Ito > IK1. While lower concentration of SS-68 shorten APs via suppression of ICaL, higher concentrations inhibit K(+)-currents leading to APs prolongation.

Michael Knaut - One of the best experts on this subject based on the ideXlab platform.

  • the new Antiarrhythmic Drug vernakalant ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation
    Cardiovascular Research, 2013
    Co-Authors: Erich Wettwer, John K Gibson, Joseph J Lynch, Marc Pourrier, Torsten Christ, Sebastian Endig, Nadiia Rozmaritsa, K Matschke, David Fedida, Michael Knaut
    Abstract:

    AIMS: Vernakalant is a newly developed Antiarrhythmic Drug against atrial fibrillation (AF). However, its electrophysiological actions on human myocardium are unknown. METHODS AND RESULTS: Action potentials (APs) and ion currents were recorded in right atrial trabeculae and cardiomyocytes from patients in sinus rhythm (SR) and chronic AF. Vernakalant prolonged early repolarization in SR and AF, but late only in AF. AP amplitude (APA) and dV/dtmax were reduced in a concentration- and frequency-dependent manner with IC50 3 Hz. Effective refractory period was increased more than action potential duration (APD) in SR and AF. INa was blocked with IC50s of 95 and 84 µM for SR and AF, respectively (0.5 Hz). Vernakalant did not reduce outward potassium currents compared with time-matched controls. However, area under the current-time curve was reduced due to acceleration of current decline with IC50s of 19 and 12 µM for SR and AF, respectively. Vernakalant had less effect on APD than the IKr blocker E-4031, blocked IK,ACh, and had a small inhibitory effect on IK1 at 30 µM. L-Type Ca(2+) currents (SR) were reduced with IC50 of 84 µM. CONCLUSION: Rate-dependent block of Na(+) channels represents the main Antiarrhythmic mechanism of vernakalant in the fibrillating atrium. Open channel block of early transient outward currents and IK,ACh could also contribute.

  • the new Antiarrhythmic Drug vernakalant ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation
    Cardiovascular Research, 2013
    Co-Authors: Erich Wettwer, John K Gibson, Joseph J Lynch, Marc Pourrier, Torsten Christ, Sebastian Endig, Nadiia Rozmaritsa, K Matschke, David Fedida, Michael Knaut
    Abstract:

    Aims Vernakalant is a newly developed Antiarrhythmic Drug against atrial fibrillation (AF). However, its electrophysiological actions on human myocardium are unknown. Methods and results Action potentials (APs) and ion currents were recorded in right atrial trabeculae and cardiomyocytes from patients in sinus rhythm (SR) and chronic AF. Vernakalant prolonged early repolarization in SR and AF, but late only in AF. AP amplitude (APA) and d V /d t max were reduced in a concentration- and frequency-dependent manner with IC50 3 Hz. Effective refractory period was increased more than action potential duration (APD) in SR and AF. INa was blocked with IC50s of 95 and 84 µM for SR and AF, respectively (0.5 Hz). Vernakalant did not reduce outward potassium currents compared with time-matched controls. However, area under the current–time curve was reduced due to acceleration of current decline with IC50s of 19 and 12 µM for SR and AF, respectively. Vernakalant had less effect on APD than the IKr blocker E-4031, blocked IK,ACh, and had a small inhibitory effect on IK1 at 30 µM. L-Type Ca2+ currents (SR) were reduced with IC50 of 84 µM. Conclusion Rate-dependent block of Na+ channels represents the main Antiarrhythmic mechanism of vernakalant in the fibrillating atrium. Open channel block of early transient outward currents and IK,ACh could also contribute.