ArticleMolecular pharmacology2014
Multiple modes of ryanodine receptor 2 inhibition by flecainide.
Article in Molecular pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 39 citations in OpenAlex.
- Computational approaches for identifications of altered ion channels in keratoconus.Eye (London, England) · 2025Article
- Flecainide Specifically Targets the Monovalent Countercurrent Through the Cardiac Ryanodine Receptor, While a Dominant Opposing CaInternational journal of molecular sciences · 2024Article
- Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.Circulation · 2023Article
- FKBP12 binds to the cardiac ryanodine receptor with negative cooperativity: implications for heart muscle physiology in health and disease.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Article
- How does flecainide impact RyR2 channel function?The Journal of general physiology · 2022Article
- Article
- Therapeutic Approaches of Ryanodine Receptor-Associated Heart Diseases.International journal of molecular sciences · 2022Review
- The Antiarrhythmic Mechanisms of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia.Frontiers in physiology · 2022Review
- Review
- Mechanisms of flecainide induced negative inotropy: An in silico study.Journal of molecular and cellular cardiology · 2021Article
- Article
- Flecainide How and When: A Practical Guide in Supraventricular Arrhythmias.Journal of clinical medicine · 2021Review
- RYR2 Channel Inhibition Is the Principal Mechanism of Flecainide Action in CPVT.Circulation research · 2021Article
- Pharmacology of A-Type KHandbook of experimental pharmacology · 2021Article
- The Unpaceable Heart: Flecainide Toxicity?JACC. Case reports · 2020Article
- The cardiac work-loop technique: An in vitro model for identifying and profiling drug-induced changes in inotropy using rat papillary muscles.Scientific reports · 2020Article
- The Effect of Antiarrhythmic Drugs on the Beat Rate Variability of Human Embryonic and Human Induced Pluripotent Stem Cell Derived Cardiomyocytes.Scientific reports · 2019Article
- Calcium signals that determine vascular resistance.Wiley interdisciplinary reviews. Systems biology and medicine · 2019Review
- A unique triadin exon deletion causing a null phenotype.HeartRhythm case reports · 2018Article
- Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients.American journal of medical genetics. Part A · 2018Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) causes sudden cardiac death due to mutations in cardiac ryanodine receptors (RyR2), calsequestrin, or calmodulin. Flecainide, a class I antiarrhythmic drug, inhibits Na(+) and RyR2 channels and prevents CPVT. The purpose of this study is to identify inhibitory mechanisms of flecainide on RyR2. RyR2 were isolated from sheep heart, incorporated into lipid bilayers, and investigated by single-channel recording under various activating conditions, including the presence of cytoplasmic ATP (2 mM) and a range of cytoplasmic [Ca(2+)], [Mg(2+)], pH, and [caffeine]. Flecainide applied to either the cytoplasmic or luminal sides of the membrane inhibited RyR2 by two distinct modes: 1) a fast block consisting of brief substate and closed events with a mean duration of ∼1 ms, and 2) a slow block consisting of closed events with a mean duration of ∼1 second. Both inhibition modes were alleviated by increasing cytoplasmic pH from 7.4 to 9.5 but were unaffected by luminal pH. The slow block was potentiated in RyR2 channels that had relatively low open probability, whereas the fast block was unaffected by RyR2 activation. These results show that these two modes are independent mechanisms for RyR2 inhibition, both having a cytoplasmic site of action. The slow mode is a closed-channel block, whereas the fast mode blocks RyR2 in the open state. At diastolic cytoplasmic [Ca(2+)] (100 nM), flecainide possesses an additional inhibitory mechanism that reduces RyR2 burst duration. Hence, multiple modes of action underlie RyR2 inhibition by flecainide.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.