Effects of Bepridil Versus E-4031 on Transmural Ventricular Repolarization and Inducibility of Ventricular Tachyarrhythmias in the Dog

Izumi, Daisuke; Chinushi, Masaomi; Iijima, Kenichi; Ahara, M T Shizue; Komura, Satoru; Furushima, Hiroshi; Hosaka, Yukio; Sanada, Akiko; Yagihara, Nobue; Aizawa, Yoshifusa

doi:10.1111/j.1540-8159.2010.02768.x

Cited by 9 publications

(10 citation statements)

References 39 publications

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“…In our previous study using the same model, bradycardia-dependent QT interval prolongation and repolarization dispersion increment were less apparent with bepridil as compared to a pure IKr blocker. 29) These results from our present and pre-vious studies may suggest that bepridil, up to a medium dosage, could be safely used for the treatment of ventricular arrhythmias. While greater amounts, of course, have a potential risk of polymorphic ventricular arrhythmias, this drug was deemed to have been used in a safe therapeutic range in this experiment.…”

Section: Safe Usage Of This Drugsupporting

confidence: 55%

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Bepridil Inhibits Premature Ventricular Complexes Induced by Cardio-Sympathetic Nerve Stimulation in a Canine Experimental Model

et al. 2020

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Sympathetic nerve activity has arrhythmogenic potential for ventricular arrhythmias associated with structural heart diseases. However, a sufficient amount of beta-blockers occasionally cannot be prescribed in some patients. An experimental study was performed to clarify the therapeutic effects of bepridil, a multiple ionic current inhibitor that does not affect beta-adrenergic receptors, for premature beats occurring during enhanced sympathetic nerve activity. Cardio-sympathetic nerve activity was augmented via stellate-ganglion (SG) stimulation in a canine model (n = 8), and the arrhythmogenic potential and anti-arrhythmic effects of bepridil (2 and 4 mg/kg intravenously) were assessed. For safe use, vagal-stimulation-induced slow HR and programmed electrical stimulation were applied to evaluate possible pro-arrhythmic effects of the drug. Heart rate variability (HRV) indexes were used to estimate cardio-autonomic nerve activity. Either side of the SG-stimulation increased BP and HR. Premature beats were induced in 10/16 SGstimulations and it was more frequent in left (8/8) rather than right stimulation (2/8). Following 2 mg/kg drug administration, premature beats were still inducible in 8/16 stimulations (7/8 in left and 1/8 in right), but burden of the premature beats decreased from 87.1 ± 46.8 to 62.1 ± 42.6 beats. After 4 mg/kg administration, premature beats were inducible in one SG-stimulation. Proarrhythmic effects were not observed in all experiments. Steady-state HRV indexes and percent increases in SG-stimulation-induced BP-elevation and HR-acceleration were similar among the 3 periods (before, 2 and 4 mg/kg of the drug). Bepridil may be an option for ventricular arrhythmias developed during enhanced cardio-sympathetic nerve activity with minimal effect on autonomic nerve responses.

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Section: Safe Usage Of This Drugsupporting

confidence: 55%

“…However, the drug's effects on the myocardium had already been examined in several previous studies by ourselves and other researchers. 13,14,29) Therefore, we focused on the triggered premature beats in this study.…”

Section: Safe Usage Of This Drugmentioning

confidence: 99%

Bepridil Inhibits Premature Ventricular Complexes Induced by Cardio-Sympathetic Nerve Stimulation in a Canine Experimental Model

et al. 2020

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“…thiopental-anethetized open-chest dogs (Izumi et al, 2010) and chloralose-anesthetized dogs (Wallace et al, 1991). Moreover, E-4031 in doses of 0.1 to 0.4 µg/kg did not affect the heart rate in humans (Katritsis et al, 1997), suggesting that the halothane-anesthetized model can mimic the chronotropic response in humans.…”

Section: Cardiohemodynamic Effectsmentioning

confidence: 95%

Effects of selective IKr channel blockade by E-4031 on ventricular electro-mechanical relationship in the halothane-anesthetized dogs

Izumi-Nakaseko

Nakamura

Cao

et al. 2014

European Journal of Pharmacology

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An inversion of electro-mechanical coupling: namely, mechanical relaxation which precedes electrical repolarization, has been proposed as a surrogate marker to predict the occurrence of drug-induced arrhythmias. The present study was designed to qualitatively and quantitatively clarify the effects of rapidly activating delayed rectifier K+ current (IKr)-selective blockade by E-4031 on the electro-mechanical relationship in vivo. We adopted the halothane-anesthetized canine model (n=4). E-4031 in doses of 0.01 and 0.1 mg/kg that can provide the plasma concentrations effectively to inhibit IKrin vitro significantly delayed the repolarization beyond the initiation of diastole, resulting in the inversion of electro-mechanical coupling, which provides an ideal proarrhythmic substrate, while the durations of left ventricular systole and diastole remained the same. Since these observed changes were solely caused by the repolarization delay, the inversion of electro-mechanical coupling may have a similar extent of sensitivity to QT-interval prolongation as a surrogate marker in predicting the onset of IKr inhibitor-induced arrhythmias.

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“…The vast proportion of experimental data, primarily from studies in the dog, indicates that slowing of rate, by pacing or autonomic nerve stimulation, acts to magnify regional differences in APD. [22][23][24][25][26][27][28][29][30][31][32][33][34] This observation may be best explained by the RRepol-APD relationship.…”

Section: Rate Dependency Of Dispersion Of Repolarizationmentioning

confidence: 99%

Geometrical considerations in cardiac electrophysiology and arrhythmogenesis

Winter¹,

Shattock²

2015

Europace

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The rate of repolarization (RRepol) and so the duration of the cardiac action potential are determined by the balance of inward and outward currents across the cardiac membrane (net ionic current). Plotting action potential duration (APD) as a function of the RRepol reveals an inverse non-linear relationship, arising from the geometric association between these two factors. From the RRepol-APD relationship, it can be observed that a longer action potential will exhibit a greater propensity to shorten, or prolong, for a given change in the RRepol (i.e. net ionic current), when compared with one that is initially shorter. This observation has recently been used to explain why so many interventions that prolong the action potential exert a greater effect at slow rates (reverse rate-dependence). In this article, we will discuss the broader implications of this simple principle and examine how common experimental observations on the electrical behaviour of the myocardium may be explained in terms of the RRepol-APD relationship. An argument is made, with supporting published evidence, that the non-linear relationship between the RRepol and APD is a fundamental, and largely overlooked, property of the myocardium. The RRepol-APD relationship appears to explain why interventions and disease with seemingly disparate mechanisms of action have similar electrophysiological consequences. Furthermore, the RRepol-APD relationship predicts that prolongation of the action potential, by slowing repolarization, will promote conditions of dynamic electrical instability, exacerbating several electrophysiological phenomena associated with arrhythmogenesis, namely, the rate dependence of dispersion of repolarization, APD restitution, and electrical alternans.

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Effects of Bepridil Versus E-4031 on Transmural Ventricular Repolarization and Inducibility of Ventricular Tachyarrhythmias in the Dog

Abstract: Unlike the pure I(kr) blocker, E-4031, bepridil exhibited weak properties of reverse use-dependency and protected against sympathetic stimulation-induced VTA. It may be an effective supplemental treatment for recipients of implantable cardioverter defibrillator.

Cited by 9 publications

References 39 publications

Bepridil Inhibits Premature Ventricular Complexes Induced by Cardio-Sympathetic Nerve Stimulation in a Canine Experimental Model

Bepridil Inhibits Premature Ventricular Complexes Induced by Cardio-Sympathetic Nerve Stimulation in a Canine Experimental Model

Effects of selective IKr channel blockade by E-4031 on ventricular electro-mechanical relationship in the halothane-anesthetized dogs

Geometrical considerations in cardiac electrophysiology and arrhythmogenesis

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