ArticleAmerican journal of physiology. Heart and circulatory physiology2011
Mechanisms of atrial-selective block of Na⁺ channels by ranolazine: II. Insights from a mathematical model.
Article in American journal of physiology. Heart and circulatory physiology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Mechanisms of Chemical Atrial Defibrillation by Flecainide and Ibutilide.JACC. Clinical electrophysiology · 2024Article
- Eugenol and lidocaine inhibit voltage-gated NaFrontiers in pharmacology · 2024Article
- Ranolazine: An Old Drug with Emerging Potential; Lessons from Pre-Clinical and Clinical Investigations for Possible Repositioning.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Rate-dependent effects of lidocaine on cardiac dynamics: Development and analysis of a low-dimensional drug-channel interaction model.PLoS computational biology · 2021Article
- Inhibition of voltage-gated NaHeart rhythm O2 · 2020Article
- Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers.Frontiers in physiology · 2020Article
- Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels.Frontiers in pharmacology · 2019Article
- Validation and Trustworthiness of Multiscale Models of Cardiac Electrophysiology.Frontiers in physiology · 2018Review
- Atrial-ventricular differences in rabbit cardiac voltage-gated NaHeart rhythm · 2017Article
- Mechanisms underlying atrial-selective block of sodium channels by Wenxin Keli: Experimental and theoretical analysis.International journal of cardiology · 2016Article
- Uncertainty quantification of fast sodium current steady-state inactivation for multi-scale models of cardiac electrophysiology.Progress in biophysics and molecular biology · 2015Review
- Mathematical approaches to understanding and imaging atrial fibrillation: significance for mechanisms and management.Circulation research · 2014Review
- The role of late I Na in development of cardiac arrhythmias.Handbook of experimental pharmacology · 2014Review
- Role of late sodium channel current block in the management of atrial fibrillation.Cardiovascular drugs and therapy · 2013Review
- Computational cardiology: how computer simulations could be used to develop new therapies and advance existing ones.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2012Review
- Computational approaches to understand cardiac electrophysiology and arrhythmias.American journal of physiology. Heart and circulatory physiology · 2012Review
- Crystal structure of a voltage-gated sodium channel in two potentially inactivated states.Nature · 2012Article
- In silico optimization of atrial fibrillation-selective sodium channel blocker pharmacodynamics.Biophysical journal · 2012Article
- Left-shifted nav channels in injured bilayer: primary targets for neuroprotective nav antagonists?Frontiers in pharmacology · 2012Article
- Computational cardiology: the heart of the matter.ISRN cardiology · 2012Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Block of Na(+) channel conductance by ranolazine displays marked atrial selectivity that is an order of magnitude higher that of other class I antiarrhythmic drugs. Here, we present a Markovian model of the Na(+) channel gating, which includes activation-inactivation coupling, aimed at elucidating the mechanisms underlying this potent atrial selectivity of ranolazine. The model incorporates experimentally observed differences between atrial and ventricular Na(+) channel gating, including a more negative position of the steady-state inactivation curve in atrial versus ventricular cells. The model assumes that ranolazine requires a hydrophilic access pathway to the channel binding site, which is modulated by both activation and inactivation gates of the channel. Kinetic rate constants were obtained using guarded receptor analysis of the use-dependent block of the fast Na(+) current (I(Na)). The model successfully reproduces all experimentally observed phenomena, including the shift of channel availability, the sensitivity of block to holding or diastolic potential, and the preferential block of slow versus fast I(Na.) Using atrial and ventricular action potential-shaped voltage pulses, the model confirms significantly greater use-dependent block of peak I(Na) in atrial versus ventricular cells. The model highlights the importance of action potential prolongation and of a steeper voltage dependence of the time constant of unbinding of ranolazine from the atrial Na(+) channel in the development of use-dependent I(Na) block. Our model predictions indicate that differences in channel gating properties as well as action potential morphology between atrial and ventricular cells contribute equally to the atrial selectivity of ranolazine. The model indicates that the steep voltage dependence of ranolazine interaction with the Na(+) channel at negative potentials underlies the mechanism of the predominant block of I(Na) in atrial cells by ranolazine.
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