Effects of K201 on repolarization and arrhythmogenesis in anesthetized chronic atrioventricular block dogs susceptible to dofetilide-induced torsade de pointes

Stams, Thom R G; Oros, Avram; Nagel, Roel van der; Beekman, Jet D.M.; Chamberlin, Paul; Dittrich, Howard C.; Vos, Marc A.

doi:10.1016/j.ejphar.2011.09.180

Cited by 13 publications

(20 citation statements)

References 40 publications

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“…JTV‐519 has multiple sites of action and exerts profound effects upon Na + , Ca2 + and K + homeostasis. It produces the inhibition of INa, ICa, IKr, IKAch and IK 1 , and exerts blocking actions on the α 1 receptors . The IC50 value is between 1.2 and 2 μmol/L for INa, 3 μmol/L for ICa, 5 μmol/L for IK 1 , and 1.2 μmol/L for IKr .…”

Section: Discussionmentioning

confidence: 99%

“…It inhibits Ca 2+ release from the sarcoplasmic reticulum, and has multichannel effects, including inhibition of the Na + current (INa), Ca 2+ current (ICa), rapidly‐activating delayed rectifier current (IKr), muscarinic acetylcholine receptor‐operated K current (IKAch), and inwardly rectifying K + current (IK 1 ). In addition, the drug exerts blocking actions upon the α 1 receptors and intracellular Ca 2+ pathways . Its effects on Ca 2+ handling include stabilization of the closed state of the ryanodine receptor (RyR 2 ) and the prevention of Ca 2+ leaks, spontaneous Ca 2+ sparks and Ca 2+ waves.…”

Section: Introductionmentioning

confidence: 99%

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Effects of JTV‐519 on stretch‐induced manifestations of mechanoelectric feedback

Canto¹,

Such-Miquel

Brines³

et al. 2016

Clin Exp Pharma Physio

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JTV-519 is a 1,4-benzothiazepine derivative with multichannel effects that inhibits Ca release from the sarcoplasmic reticulum and stabilizes the closed state of the ryanodine receptor, preventing myocardial damage and the induction of arrhythmias during Ca overload. Mechanical stretch increases cellular Na inflow, activates the reverse mode of the Na /Ca exchanger, and modifies Ca handling and myocardial electrophysiology, favoring arrhythmogenesis. This study aims to determine whether JTV-519 modifies the stretch-induced manifestations of mechanoelectric feedback. The ventricular fibrillation (VF) modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts using epicardial multiple electrodes under control conditions (n=9) or during JTV-519 perfusion: 0.1 μmol/L (n=9) and 1 μmol/L (n=9). Spectral and mapping techniques were used to establish the baseline, stretch and post-stretch VF characteristics. JTV-519 slowed baseline VF and decreased activation complexity. These effects were dose-dependent (baseline VF dominant frequency: control=13.9±2.2 Hz; JTV 0.1 μmol/L=11.1±1.1 Hz, P<.01; JTV 1 μmol/L=6.6±1.1 Hz, P<.0001). The stretch-induced acceleration of VF (control=38.8%) was significantly reduced by JTV-519 0.1 μmol/L (19.8%) and abolished by JTV 1 μmol/L (-1.5%). During stretch, the VF activation complexity index was reduced in both JTV-519 series (control=1.60±0.15; JTV 0.1 μmol/L=1.13±0.3, P<.0001; JTV 1 μmol/L=0.57±0.21, P<.0001), and was independently related to VF dominant frequency (R=.82; P<.0001). The fifth percentile of the VF activation intervals, conduction velocity and wavelength entered the multiple linear regression model using dominant frequency as the dependent variable (R=-.84; P<.0001). In conclusion, JTV-519 slowed and simplified the baseline VF activation patterns and abolished the stretch-induced manifestations of mechanoelectric feedback.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of JTV‐519 on stretch‐induced manifestations of mechanoelectric feedback

Canto¹,

Such-Miquel

Brines³

et al. 2016

Clin Exp Pharma Physio

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“…In the CAVB (chronic AV block) dog, K201 was not able to decrease the incidence nor the severity of dofetilide-induced TdP. In addition, K201 prolonged repolarisation and slowed heart rate, although no negative inotropic effects were observed [48]. These divergent results are in contrast with the well-established molecular role of RyR in the incidence of Ca 2+ sparks and DADs and its suppression by K201.…”

Section: New Targets For Antiarrhythmic Treatmentmentioning

confidence: 99%

“…In the mentioned dog study, our group showed that at a relatively high dose (1.5–2 μM), even proarrhythmic effects of the drug were observed [48]. Although K201 has already been used in clinical trials for treatment of atrial fibrillation (AF), the results seem disappointing: only one has been completed without publication of the results, and two other trials were prematurely terminated.…”

Section: New Targets For Antiarrhythmic Treatmentmentioning

confidence: 99%

New antiarrhythmic targets to control intracellular calcium handling

et al. 2014

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Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca2+/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (INa-Late), all related to intracellular calcium (Ca2+) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

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“…K201 is a multichannel blocking (I K,Ach , I Kr , I Na , I CaL , and I K1 ) drug, which mainly stabilizes ryanodine receptors, therefore limiting the incidence of EADs and DADs by prevention of calcium sparks. 34 AVE0118, an atrial-specific agent inhibiting the potassium currents I Kur and I KAch , prolongs atrial but not ventricular repolarization. 35 Based on its pharmacological profile, it could have been anticipated that AVE0118 would not have antiarrhythmic properties against dofetilide-induced arrhythmias.…”

Section: Antiarrhythmic Strategies Studied In the Cavb Dog Modelmentioning

confidence: 99%

Short-term Variability of Repolarization Is Superior to Other Repolarization Parameters in the Evaluation of Diverse Antiarrhythmic Interventions in the Chronic Atrioventricular Block Dog

Bossu

Varkevisser²,

Beekman³

et al. 2017

Journal of Cardiovascular Pharmacology

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Effects of K201 on repolarization and arrhythmogenesis in anesthetized chronic atrioventricular block dogs susceptible to dofetilide-induced torsade de pointes

Cited by 13 publications

References 40 publications

Effects of JTV‐519 on stretch‐induced manifestations of mechanoelectric feedback

Effects of JTV‐519 on stretch‐induced manifestations of mechanoelectric feedback

New antiarrhythmic targets to control intracellular calcium handling

Short-term Variability of Repolarization Is Superior to Other Repolarization Parameters in the Evaluation of Diverse Antiarrhythmic Interventions in the Chronic Atrioventricular Block Dog

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