Effects of bepridil on ventricular depolarization and repolarization of rabbit isolated hearts with particular reference to its possible proarrhythmic properties

Osaka, Toshiyuki; Kodama, Itsuo; Toyama, Junji; Yamada, Kazuo

doi:10.1111/j.1476-5381.1988.tb11462.x

Cited by 19 publications

(9 citation statements)

References 24 publications

(26 reference statements)

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“…34 In line with this regional difference in the APD prolongation on the apexbase axis, the present study on the human heart has demonstrated that bepridil causes a greater prolongation of the MAPDs in the RVOT than in the RVA. In voltage-clamp experiments on rabbit LV myocytes, Chen et al showed higher IKr and lower IKs densities in the apex than those in the base.…”

Section: Inhomogeneous Mapd Prolongation By Bepridilsupporting

confidence: 81%

Opposing Effects of Bepridil on Ventricular Repolarization in Humans Inhomogeneous Prolongation of the Action Potential Duration vs Flattening of Its Restitution Kinetics

Osaka

Yokoyama

Kushiyama

et al. 2009

Circ J

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Background: Bepridil is highly effective in the treatment of atrial fibrillation, but its clinical usefulness is limited by a potential risk for the drug-induced Torsades de pointes (TdP) in association with its Class III action. Methods and Results: Monophasic action potentials (MAPs) were recorded from the right ventricular outflow tract (RVOT) and apex (RVA) in 9 patients treated with bepridil (172±26 mg/day) and 10 control patients. Bepridil significantly increased the steady-state MAP durations at 90% repolarization (MAPD90s) in a rate-independent manner at pacing cycle lengths ranging from 330 to 750 ms. The bepridil-induced prolongation of the MAPD90 was greater in RVOT (~13%) than RVA (~8%). Bepridil flattened the MAPD90 restitution slope estimated by an S1-S2 protocol in both the RVOT (0.65±0.22 vs 0.95±0.38) and RVA (0.65±0.14 vs 0.94±0.29). The Tpeak-end interval in the ECG was increased by bepridil for S1 but not S2 at the shortest diastolic interval to produce a ventricular response. Conclusions: Bepridil produces an inhomogeneous prolongation of the MAPDs, but flattens their restitution kinetics in the human ventricle. The former effect would favor the functional reentry predisposing to TdP, whereas the latter one would counteract that by reducing the dynamic instability of the repolarization. (Circ J 2009; 73: 1612 -1618

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Section: Inhomogeneous Mapd Prolongation By Bepridilsupporting

confidence: 81%

Opposing Effects of Bepridil on Ventricular Repolarization in Humans Inhomogeneous Prolongation of the Action Potential Duration vs Flattening of Its Restitution Kinetics

Osaka

Yokoyama

Kushiyama

et al. 2009

Circ J

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“…A schematic diagram of a typical preparation is shown in Fig. 1 (Veenstra, Joyner & Rawling, 1984;Osaka, Kodama, Toyama & Yamada, 1988 Fig. 1A, the time of activation of other sites with respect to the time of initiation of the action potential at the primary pacemaker site is shown as a series of isochrones (dashed lines) at 5 ms intervals.…”

Section: Methods Preparationmentioning

confidence: 99%

Regional differences in the response of the isolated sino‐atrial node of the rabbit to vagal stimulation.

Kodama

Boyett

Suzuki

et al. 1996

The Journal of Physiology

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1. The effects of brief postganglionic vagal nerve stimulation on electrical activity in different regions of the rabbit sino-atrial node and surrounding atrial muscle were recorded. 2. At the centre of the node (the leading pacemaker site), the brief stimulation resulted in a large hyperpolarization followed by a depolarization and a shortening of the action potential. All effects were short lasting (time to 90% recovery of membrane potential, 0 8 s). 3. At other sites within the node and in the surrounding atrial muscle, although there was still a substantial action potential shortening, the hyperpolarization was smaller and the depolarization was small or absent. All effects were longer lasting (time to 90 % recovery in atrial muscle, 11 4 s). 4. The depolarization in the centre of the node was abolished by block of the hyperpolarizationactivated current (if) by Cs+ or zatebradine (UL-FS 49). It could, therefore, result from the activation of if during the preceding hyperpolarization. 5. Block of acetylcholinesterase by eserine greatly slowed recovery from vagal stimulation at all sites, demonstrating that recovery is dependent on acetylcholinesterase. The longer lasting effects of vagal stimulation in atrial muscle, therefore, result from lower acetylcholinesterase activity. 6. Vagal stimulation resulted in a short-lasting initial slowing of spontaneous action potentials followed by a long-lasting secondary slowing. Whereas the initial slowing coincided with the effects of vagal stimulation on the centre of the node, the secondary slowing coincided with the slower effects of vagal stimulation on the surrounding atrial muscle. The secondary slowing was reduced by 68 + 11 % (n = 5) by cutting the atrial muscle away from the node. 7. It is concluded that the short-lasting initial slowing of spontaneous action potentials is the direct effect of vagal stimulation on the centre of the sino-atrial node, whereas the secondary slowing is the result of the longer lasting effects of vagal stimulation on the surrounding atrial muscle and the electrotonic suppression of the node by the muscle.

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“…We recorded nique is, however, limited by large far-field potentials of extracellular potentials from the endocardial surface of atrial muscle close to the SA node [8,9]. isolated rabbit right atria including the whole SA node using custom-made modified bipolar electrodes [10,11], since the proximity of the indifferent and active poles of time. Each pair of MBEs was positioned using a calibrated the electrodes is expected to provide a high level of X,Y,Z-micromanipulator with 0.1 mm precision.…”

Section: Introductionmentioning

confidence: 99%

Low-frequency extracellular potentials recorded from the sinoatrial node

Yamamoto

Honjo

Niwa

et al. 1998

Cardiovascular Research

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Objective: To study the morphology of small extracellular potentials localized to the sinoatrial (SA) node and to elucidate its potential usefulness in evaluating SA node dysfunction. Methods: Extracellular potentials were recorded from the endocardial surface of the SA node in isolated right atrial preparations of rabbits through custom-made modified bipolar electrodes with high-gain amplification and a low-frequency (0.5-30 Hz) filter setting. Results: The potentials in and around the SA node under control conditions showed a variety of morphologies. In a small area near the leading pacemaker site, slow primary negative deflections were preceded by a gradual increase of the negativity (73.565.6 mV in amplitude, n512). In the periphery of the SA node cranial and caudal to the leading pacemaker site, slow positive / negative deflections were recorded. In the septal side of the SA node showing very slow conduction, the electrograms showed slow primary positive deflections. Transient pacemaker shifts induced by atrial stimulation or vagal nerve stimulation were reflected well in morphologies of the extracellular potentials. In the presence of 20 mM TTX, wide and slow negative deflections were observed in the center and periphery of the SA node in association with extremely slow conduction restricted to a corridor-like area along the crista terminalis, whereas the atrial muscle surrounding the area was made inexcitable. In the presence of 1 mM nifedipine, the leading pacemaker site was shifted to the periphery of the SA node close to the crista terminalis. The negative deflection in the center and septal side of the SA node disappeared reflecting no excitation of the area. Conclusion: The endocardial extracellular electrograms recorded in and around the SA node under appropriate conditions reflect two dimensional activation sequences. They would provide useful information in recognizing the leading pacemaker site and alterations of the conductivity and excitability.

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Effects of bepridil on ventricular depolarization and repolarization of rabbit isolated hearts with particular reference to its possible proarrhythmic properties

Cited by 19 publications

References 24 publications

Opposing Effects of Bepridil on Ventricular Repolarization in Humans Inhomogeneous Prolongation of the Action Potential Duration vs Flattening of Its Restitution Kinetics

Opposing Effects of Bepridil on Ventricular Repolarization in Humans Inhomogeneous Prolongation of the Action Potential Duration vs Flattening of Its Restitution Kinetics

Regional differences in the response of the isolated sino‐atrial node of the rabbit to vagal stimulation.

Low-frequency extracellular potentials recorded from the sinoatrial node

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