Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations

Sicouri, Serge; Glass, Aaron; Belardinelli, Luiz; Antzelevitch, Charles

doi:10.1016/j.hrthm.2008.03.018

Cited by 108 publications

(121 citation statements)

References 28 publications

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“…Previous studies have shown that DAD-and latephase EAD-induced TA can be easily induced in canine PV sleeve preparations after the addition of isoproterenol, ACh, and high calcium alone or in combination (Patterson et al, 2005(Patterson et al, , 2006Sicouri et al, 2008aSicouri et al, , 2009, in canine-and rabbitisolated single PV myocytes (Chen et al, 2000;Chen and Chen, 2006) and in canine coronary perfused right atrial preparations Antzelevitch, 2003, 2006). Conditions permitting intracellular calcium loading facilitate the development of DADs and late phase 3 EADs (Burashnikov and Antzelevitch, 2006).…”

Section: Discussionmentioning

confidence: 99%

Electrophysiologic and Antiarrhythmic Effects of AZD1305 in Canine Pulmonary Vein Sleeves

Sicouri

Carlsson²,

Antzelevitch³

2010

J Pharmacol Exp Ther

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The objective of this study was to examine the electrophysiologic and antiarrhythmic effects of the new antiarrhythmic agent tert-butyl (2-{7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non3-yl}ethyl)carbamate (AZD1305) in canine pulmonary vein (PV) sleeve preparations isolated from untreated and long-term amiodarone-treated animals. Ectopic activity arising from PV sleeves plays a prominent role in the development of atrial fibrillation (AF). Delayed afterdepolarizations (DADs) and late phase 3 early afterdepolarizations (EADs), originating from the PV have been proposed as potential triggers in initiation of AF. Action potentials were recorded from canine superfused PV sleeves using standard microelectrode techniques. Acetylcholine (1 M), isoproterenol (1 M), or their combination was used to induce EADs, DADs, and triggered activity (TA). The effects of AZD1305 (0.1-10 M) were evaluated in PV sleeve preparations isolated from untreated and amiodarone-treated (40 mg/kg daily for 6 weeks) dogs. AZD1305 (0.1-10 M, 30 min) significantly prolonged action potential duration and reduced excitability. Abbreviating basic cycle length from 1000 to 300 ms resulted in a decrease of V max from 314 Ϯ 79 to 251 Ϯ 55 V/s (⌬ ϭ Ϫ20%) in control and from 177 Ϯ 53 to 76.5 Ϯ

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Section: Discussionmentioning

confidence: 99%

Electrophysiologic and Antiarrhythmic Effects of AZD1305 in Canine Pulmonary Vein Sleeves

Sicouri

Carlsson²,

Antzelevitch³

2010

J Pharmacol Exp Ther

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“…Isolated myocytes and dynamic-clamp experiments have shown that an isolated increase of either of these two late inward currents promotes cellular early and delayed afterdepolarizations (EADs and DADs respectively) causing rapid triggered activity [16,17]. Indeed inhibition of the I Na-L with the highly potent (IC 50 =0.143 μM) and selective inhibitor GS-967 [18] suppresses EADs in isolated atrial myocytes [18,19]. The purpose of this study is to test the following two hypotheses; 1) oxidative stress-mediated activation of CaMKII signaling with hydrogen peroxide (H 2 O 2 ) in structurally remodeled atria characterized with increased atrial tissue fibrosis promotes AF by the mechanism of EAD and DAD-mediated triggered activity; and 2) selective inhibition of the enzymatic activity of CaMKII or its distal target, the I Na-L with the specific I Na-L blocker, GS-967, [18] suppresses the oxidative AF.…”

Section: Introductionmentioning

confidence: 99%

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

Pezhouman¹,

Cao

Fishbein

et al. 2018

J Hear Health

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Background The mechanism of Atrial Fibrillation (AF) that emerges spontaneously during acute oxidative stress is poorly defined and its drug therapy remains suboptimal. We hypothesized that oxidative activation of Ca-calmodulin dependent protein kinase (CaMKII) promotes Early Afterdepolarization-(EAD)-mediated triggered AF in aged fibrotic atria that is sensitive to late Na current (INa-L) blockade. Method and Results High-resolution voltage optical mapping of the Left and Right Atrial (LA & RA) epicardial surfaces along with microelectrode recordings were performed in isolated-perfused male Fisher 344 rat hearts in Langendorff setting. Aged atria (23–24 months) manifested 10-fold increase in atrial tissue fibrosis compared to young/adult (2–4 months) atria (P<0001. Spontaneous AF arose in 39 out of 41 of the aged atria but in 0 out of 12 young/adult hearts (P<001) during arterial perfusion of with 0.1 mm of hydrogen peroxide (H2O2). Optical Action Potential (AP) activation maps showed that the AF was initiated by a focal mechanism in the LA suggestive of EAD-mediated triggered activity. Cellular AP recordings with glass microelectrodes from the LA epicardial sites showing focal activity confirmed optical AP recordings that the spontaneous AF was initiated by late phase 3 EAD-mediated triggered activity. Inhibition of CaMKII activity with KN-93 (1 μM) (N=6) or its downstream target, the enhanced INa-L with GS-967 (1 μM), a specific blocker of INa-L (N=6), potently suppressed the AF and prevented its initiation when perfused 15 min prior to H2O2 (n=6). Conclusions Increased atrial tissue fibrosis combined with acute oxidative activation of CaMK II Initiate AF by EAD-mediated triggered activity. Specific block of the INa-L with GS-967 effectively suppresses the AF. Drug therapy of oxidative AF in humans with traditional antiarrhythmic drugs remains suboptimal; suppressing INa-L offers a potential new strategy for effective suppression of oxidative human AF that remains suboptimal.

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“…22 Another study tested ranolazine with dronedarone in treatment of AF in animal models and found that the combined use results in better rhythm control. 23 Moreover, ranolazine helped with dronedarone to decrease ischemia-induced vulnerability to AF as well as ventricular arrhythmias.…”

Section: Ranolazine In the Management Of Atrial Fibrillation Experimementioning

confidence: 99%

Ranolazine in Cardiac Arrhythmia

Saad

Mahmoud

Elgendy

et al. 2015

Clinical Cardiology

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Ranolazine utilization in the management of refractory angina has been established by multiple randomized clinical studies. However, there is growing evidence showing an evolving role in the field of cardiac arrhythmias. Multiple experimental and clinical studies have evaluated the role of ranolazine in prevention and management of atrial fibrillation, with ongoing studies on its role in ventricular arrhythmias. In this review, we will discuss the pharmacological, experimental, and clinical evidence behind ranolazine use in the management of various cardiac arrhythmias.

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Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations

Abstract: Objectives-To determine the electrophysiologic effects of ranolazine in canine pulmonary veins (PV) sleeve preparations.Background-Ectopic activity arising from the PV plays a prominent role in the development of atrial fibrillation (AF).

Cited by 108 publications

References 28 publications

Electrophysiologic and Antiarrhythmic Effects of AZD1305 in Canine Pulmonary Vein Sleeves

Electrophysiologic and Antiarrhythmic Effects of AZD1305 in Canine Pulmonary Vein Sleeves

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

Ranolazine in Cardiac Arrhythmia

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