ArticleMolecular pharmacology2008
State- and use-dependent block of muscle Nav1.4 and neuronal Nav1.7 voltage-gated Na+ channel isoforms by ranolazine.
Article in Molecular pharmacology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 1 of them a synthesis that pooled it.
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Who cites it
42 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine.Journal of neuromuscular diseases · 2021Pooled it
- The Plant Alkaloid Harmaline Blocks the Voltage-Gated Sodium Channel NaInternational journal of molecular sciences · 2025Article
- Ranolazine Attenuates Brain Inflammation in a Rat Model of Type 2 Diabetes.International journal of molecular sciences · 2022Article
- The Evidence for Sparsentan-Mediated Inhibition ofBiomedicines · 2021Article
- Ranolazine: An Old Drug with Emerging Potential; Lessons from Pre-Clinical and Clinical Investigations for Possible Repositioning.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Block of Voltage-Gated Sodium Channels as a Potential Novel Anti-cancer Mechanism of TIC10.Frontiers in pharmacology · 2021Article
- Tetrodotoxin-Sensitive Neuronal-Type NaJournal of the American Heart Association · 2020Article
- Structural basis for antiarrhythmic drug interactions with the human cardiac sodium channel.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels.Frontiers in pharmacology · 2019Article
- Atrial-ventricular differences in rabbit cardiac voltage-gated NaHeart rhythm · 2017Article
- Pharmacology of the NaProceedings of the National Academy of Sciences of the United States of America · 2017Article
- Ranolazine Therapy Reduces Non-ST-Segment-Elevation Myocardial Infarction and Unstable Angina in Coronary Disease Patients with Angina.The International journal of angiology : official publication of the International College of Angiology, Inc · 2016Article
- Antagonism of Nav channels and α1-adrenergic receptors contributes to vascular smooth muscle effects of ranolazine.Scientific reports · 2015Article
- Late sodium current (INaL) in pancreatic β-cells.Pflugers Archiv : European journal of physiology · 2015Article
- Article
- Comparison of Gating Properties and Use-Dependent Block of Nav1.5 and Nav1.7 Channels by Anti-Arrhythmics Mexiletine and Lidocaine.PloS one · 2015Article
- Treatment and management of neuromuscular channelopathies.Current treatment options in neurology · 2014Article
- Na+ dysregulation coupled with Ca2+ entry through NCX1 promotes muscular dystrophy in mice.Molecular and cellular biology · 2014Article
- Nondystrophic myotonia: challenges and future directions.Experimental neurology · 2014Article
- Anaesthetic tricaine acts preferentially on neural voltage-gated sodium channels and fails to block directly evoked muscle contraction.PloS one · 2014Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
Ranolazine is an antianginal agent that targets a number of ion channels in the heart, including cardiac voltage-gated Na(+) channels. However, ranolazine block of muscle and neuronal Na(+) channel isoforms has not been examined. We compared the state- and use-dependent ranolazine block of Na(+) currents carried by muscle Nav1.4, cardiac Nav1.5, and neuronal Nav1.7 isoforms expressed in human embryonic kidney 293T cells. Resting and inactivated block of Na(+) channels by ranolazine were generally weak, with a 50% inhibitory concentration (IC(50)) >/= 60 microM. Use-dependent block of Na(+) channel isoforms by ranolazine during repetitive pulses (+50 mV/10 ms at 5 Hz) was strong at 100 microM, up to 77% peak current reduction for Nav1.4, 67% for Nav1.5, and 83% for Nav1.7. In addition, we found conspicuous time-dependent block of inactivation-deficient Nav1.4, Nav1.5, and Nav1.7 Na(+) currents by ranolazine with estimated IC(50) values of 2.4, 6.2, and 1.7 microM, respectively. On- and off-rates of ranolazine were 8.2 microM(-1) s(-1) and 22 s(-1), respectively, for Nav1.4 open channels and 7.1 microM(-1) s(-1) and 14 s(-1), respectively, for Nav1.7 counterparts. A F1579K mutation at the local anesthetic receptor of inactivation-deficient Nav1.4 Na(+) channels reduced the potency of ranolazine approximately 17-fold. We conclude that: 1) both muscle and neuronal Na(+) channels are as sensitive to ranolazine block as their cardiac counterparts; 2) at its therapeutic plasma concentrations, ranolazine interacts predominantly with the open but not resting or inactivated Na(+) channels; and 3) ranolazine block of open Na(+) channels is via the conserved local anesthetic receptor albeit with a relatively slow on-rate.
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