ArticleHeart rhythm2012
Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2.
Article in Heart rhythm, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
37 citing papers in PubMed, 75 citations in OpenAlex.
- Cisd2 delays atrial aging via a modulation of calcium homeostasis that mitigates atrial myopathy.Cell communication and signaling : CCS · 2025Article
- Unraveling the pharmacological and therapeutic potential of Ranolazine beyond antianginal drug use: a new insight.Experimental biology and medicine (Maywood, N.J.) · 2025Review
- Ranolazine Unveiled: Rediscovering an Old Solution in a New Light.Journal of clinical medicine · 2024Review
- Mechanisms of torsades de pointes: an update.Frontiers in cardiovascular medicine · 2024Review
- Emerging Antiarrhythmic Drugs for Atrial Fibrillation.International journal of molecular sciences · 2022Review
- Rotors anchored by refractory islands drive torsades de pointes in an experimental model of electrical storm.Heart rhythm · 2022Article
- Cardiomyocyte NaBasic research in cardiology · 2021Article
- Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db/db mice with acute regional ischemia-reperfusion injury.Scientific reports · 2020Article
- Tetrodotoxin-Sensitive Neuronal-Type NaJournal of the American Heart Association · 2020Article
- Transgenic Rabbit Models in Proarrhythmia Research.Frontiers in pharmacology · 2020Review
- Ranolazine prevents pressure overload-induced cardiac hypertrophy and heart failure by restoring aberrant NaJournal of cellular physiology · 2019Article
- Article
- BlindedFrontiers in pharmacology · 2019Article
- Multiple Dynamical Mechanisms of Phase-2 Early Afterdepolarizations in a Human Ventricular Myocyte Model:Frontiers in physiology · 2019Article
- NCX-Mediated Subcellular CaBiophysical journal · 2018Article
- Late sodium current inhibitors to treat exercise-induced obstruction in hypertrophic cardiomyopathy: an in vitro study in human myocardium.British journal of pharmacology · 2018Article
- Selective late sodium current inhibitor GS-458967 suppresses Torsades de Pointes by mostly affecting perpetuation but not initiation of the arrhythmia.British journal of pharmacology · 2018Article
- CaHeart rhythm · 2018Review
- Impact of ranolazine on ventricular arrhythmias - A systematic review.Journal of arrhythmia · 2018Review
- Altered CaFrontiers in physiology · 2018Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundRanolazine (Ran) is known to inhibit multiple targets, including the late Na(+)current, the rapid delayed rectifying K(+)current, the L-type Ca(2+)current, and fatty acid metabolism. Functionally, Ran suppresses early afterdepolarization (EADs) and torsades de pointes (TdP) in drug-induced long QT type 2 (LQT2) presumably by decreasing intracellular [Na(+)](i) and Ca(2+)overload. However, simulations of EADs in LQT2 failed to predict their suppression by Ran.
objectiveTo elucidate the mechanism(s) whereby Ran alters cardiac action potentials (APs) and cytosolic Ca(2+)transients and suppresses EADs and TdP in LQT2.
methodsThe known effects of Ran were included in simulations (Shannon and Mahajan models) of rabbit ventricular APs and Ca(2+)transients in control and LQT2 models and compared with experimental optical mapping data from Langendorff rabbit hearts treated with E4031 (0.5 μM) to block the rapid delayed rectifying K(+)current. Direct effects of Ran on cardiac ryanodine receptors (RyR2) were investigated in single channels and changes in Ca(2+)-dependent high-affinity ryanodine binding.
resultsRan (10 μM) alone prolonged action potential durations (206 ± 4.6 to 240 ± 7.8 ms; P <0.05); E4031 prolonged action potential durations (204 ± 6 to 546 ± 35 ms; P <0.05) and elicited EADs and TdP that were suppressed by Ran (10 μM; n = 7 of 7 hearts). Simulations (Shannon but not Mahajan model) closely reproduced experimental data except for EAD suppression by Ran. Ran reduced open probability (P(o)) of RyR2 (half maximal inhibitory concentration = 10 ± 3 μM; n = 7) in bilayers and shifted half maximal effective concentration for Ca(2+)-dependent ryanodine binding from 0.42 ± 0.02 to 0.64 ± 0.02 μM with 30 μM Ran.
conclusionsRan reduces P(o) of RyR2, desensitizes Ca(2+)-dependent RyR2 activation, and inhibits Ca(i) oscillations, which represents a novel mechanism for its suppression of EADs and TdP.
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