Bepridil Facilitates Early Termination of Spiral-Wave Reentry in Two-Dimensional Cardiac Muscle Through an Increase of Intercellular Electrical Coupling

Takanari, Hiroki; Honjo, Haruo; Takemoto, Yoshio; Suzuki, Tomoyuki; Kato, S.; Harada, Masafumi; Ashihara, Takashi; Opthof, Tobias; Sakuma, Ichiro; Kamiya, Kaichiro; Kodama, Itsuo

doi:10.1254/jphs.10233fp

Cited by 15 publications

(21 citation statements)

References 38 publications

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“…These data suggest that the effect of class IV anti-arrhythmic drugs is beneficial to the stabilization of conduction [24]. Decades ago, verapamil was shown to have anti-arrhythmic properties against ischemia infarction-induced ventricular tachycardia [25].…”

Section: Discussionmentioning

confidence: 95%

Anti-Arrhythmic Effect of Verapamil Is Accompanied by Preservation of Cx43 Protein in Rat Heart

et al. 2013

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The present study was to test the hypothesis that anti-arrhythmic properties of verapamil may be accompanied by preserving connexin43 (Cx43) protein via calcium influx inhibition. In an in vivo study, myocardial ischemic arrhythmia was induced by occlusion of the left anterior descending (LAD) coronary artery for 45 min in Sprague-Dawley rats. Verapamil, a calcium channel antagonist, was injected i.v. into a femoral vein prior to ischemia. Effects of verapamil on arrhythmias induced by Bay K8644 (a calcium channel agonist) were also determined. In an ex vivo study, the isolated heart underwent an initial 10 min of baseline normal perfusion and was subjected to high calcium perfusion in the absence or presence of verapamil. Cardiac arrhythmia was measured by electrocardiogram (ECG) and Cx43 protein was determined by immunohistochemistry and western blotting. Administration of verapamil prior to myocardial ischemia significantly reduced the incidence of ventricular arrhythmias and total arrhythmia scores, with the reductions in heat rate, mean arterial pressure and left ventricular systolic pressure. Verapamil also inhibited arrhythmias induced by Bay K8644 and high calcium perfusion. Effect of verapamil on ischemic arrhythmia scores was abolished by heptanol, a Cx43 protein uncoupler and Gap 26, a Cx43 channels inhibitor. Immunohistochemistry data showed that ischemia-induced redistribution and reduced immunostaining of Cx43 were prevented by verapamil. In addition, diminished expression of Cx43 protein determined by western blotting was observed following myocardial ischemia in vivo or following high calcium perfusion ex vivo and was preserved after verapamil administration. Our data suggest that verapamil may confer an anti-arrhythmic effect via calcium influx inhibition, inhibition of oxygen consumption and accompanied by preservation of Cx43 protein.

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Section: Discussionmentioning

confidence: 95%

Anti-Arrhythmic Effect of Verapamil Is Accompanied by Preservation of Cx43 Protein in Rat Heart

et al. 2013

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“…Many theoretical and experimental studies (11,23) have revealed that spiral-wave (SW) reentry rotating around a functional obstacle (rotor) is the major organization mechanism to maintain VT/VF. As to the influence of GJ conductance (either increase or decrease) on the dynamics of SW reentry in the heart, however, information available is still limited, and much remains to be clarified (22).…”

Section: Takemoto Y Takanari H Honjo H Ueda N Harada M Kato Smentioning

confidence: 99%

“…In the present study, we investigated the electrophysiological effects of carbenoxolone (CBX) and rotigaptide (RG), which are known to decrease and increase cardiac GJ coupling, respectively (8,25), in a two-dimensional (2D) subepicardial layer of rabbit ventricular muscle by using a high-resolution optical action potential mapping system (9,10,22,26,27). We have found that CBX stabilizes the SW reentry circuits, whereas RG destabilizes them in favor of early self-termination of the reentry.…”

Section: Takemoto Y Takanari H Honjo H Ueda N Harada M Kato Smentioning

confidence: 99%

Inhibition of intercellular coupling stabilizes spiral-wave reentry, whereas enhancement of the coupling destabilizes the reentry in favor of early termination

Takemoto

Takanari

Honjo

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Spiral-wave (SW) reentry is a major organizing principle of ventricular tachycardia/fibrillation (VT/VF). We tested a hypothesis that pharmacological modification of gap junction (GJ) conductance affects the stability of SW reentry in a two-dimensional (2D) epicardial ventricular muscle layer prepared by endocardial cryoablation of Langendorff-perfused rabbit hearts. Action potential signals were recorded and analyzed by high-resolution optical mapping. Carbenoxolone (CBX; 30 μM) and rotigaptide (RG, 0.1 μM) were used to inhibit and enhance GJ coupling, respectively. CBX decreased the space constant (λ) by 36%, whereas RG increased it by 22-24% (n = 5; P < 0.01). During centrifugal propagation, there was a linear relationship between the wavefront curvature (κ) and local conduction velocity (LCV): LCV = LCV(0) - D·κ (D, diffusion coefficient; LCV(0), LCV at κ = 0). CBX decreased LCV(0) and D by 27 ± 3 and 57 ± 3%, respectively (n = 5; P < 0.01). RG increased LCV(0) and D by 18 ± 3 and 54 ± 5%, respectively (n = 5, P < 0.01). The regression lines with and without RG crossed, resulting in a paradoxical decrease of LCV with RG at κ > ~60 cm(-1). SW reentry induced after CBX was stable, and the incidence of sustained VTs (>30 s) increased from 38 ± 4 to 85 ± 4% after CBX (n = 18; P < 0.01). SW reentry induced after RG was characterized by decremental conduction near the rotation center, prominent drift and self-termination by collision with the anatomical boundaries, and the incidence of sustained VTs decreased from 40 ± 5 to 17 ± 6% after RG (n = 13; P < 0.05). These results suggest that decreased intercellular coupling stabilizes SW reentry in 2D cardiac muscle, whereas increased coupling facilitates its early self-termination.

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“…Approaches to eliminate this life threatening event include increasing refractoriness 2-3 (with the consequent threat of long Q-T syndrome), converting unidirectional block to bidirectional block by blocking excitatory sodium current 4-6 and more recently the conversion of slow conduction to more rapid conduction 7-9 thereby increasing the wavelength of the propagating wave reducing the potential for reentrant events.…”

Section: Introductionmentioning

confidence: 99%

Improving Cardiac Conduction With a Skeletal Muscle Sodium Channel by Gene and Cell Therapy

Liang

Wang

Jia

et al. 2012

Journal of Cardiovascular Pharmacology

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The voltage-gated Na+ channel is a critical determinant of the action potential upstroke. Increasing Na+ conductance may speed action potential propagation. Here we propose use of the skeletal muscle Na+ channel SkM1 as a more favorable gene than the cardiac isoform SCN5A to enhance conduction velocity in depolarized cardiac tissue. We used cells which electrically coupled with cardiac myocytes as a delivery platform to introduce the Na+ channels. HEK293 cells were stably transfected with SkM1 or SCN5A. SkM1 had a more depolarized (18mV shift) inactivation curve than SCN5A. We also found that SkM1 recovered faster from inactivation than SCN5A. When coupled with SkM1 expressing cells, cultured myocytes showed an increase in the dV/dtmax of the action potential. Expression of SCN5A had no such effect. In an in vitro cardiac syncytium, coculture of neonatal cardiac myocytes with SkM1 expressing but not SCN5A expressing cells significantly increased the conduction velocity under both normal and depolarized conditions. In an in vitro re-entry model induced by high frequency stimulation, expression of SkM1 also enhanced angular velocity of the induced re-entry. These results suggest that cells carrying a Na+ channel with a more depolarized inactivation curve can improve cardiac excitability and conduction in depolarized tissues.

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Bepridil Facilitates Early Termination of Spiral-Wave Reentry in Two-Dimensional Cardiac Muscle Through an Increase of Intercellular Electrical Coupling

Cited by 15 publications

References 38 publications

Anti-Arrhythmic Effect of Verapamil Is Accompanied by Preservation of Cx43 Protein in Rat Heart

Anti-Arrhythmic Effect of Verapamil Is Accompanied by Preservation of Cx43 Protein in Rat Heart

Inhibition of intercellular coupling stabilizes spiral-wave reentry, whereas enhancement of the coupling destabilizes the reentry in favor of early termination

Improving Cardiac Conduction With a Skeletal Muscle Sodium Channel by Gene and Cell Therapy

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