State- and Use-Dependent Block of Muscle Nav1.4 and Neuronal Nav1.7 Voltage-Gated Na+ Channel Isoforms by Ranolazine
- 13 December 2007
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET)
- Vol. 73 (3), 940-948
- https://doi.org/10.1124/mol.107.041541
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 (IC50) ≥ 60 μM. Use-dependent block of Na+ channel isoforms by ranolazine during repetitive pulses (+50 mV/10 ms at 5 Hz) was strong at 100 μM, 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 IC50 values of 2.4, 6.2, and 1.7 μM, respectively. On- and off-rates of ranolazine were 8.2 μM-1 s-1 and 22 s-1, respectively, for Nav1.4 open channels and 7.1 μM-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 ∼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.Keywords
This publication has 30 references indexed in Scilit:
- Atrium-Selective Sodium Channel Block as a Strategy for Suppression of Atrial FibrillationCirculation, 2007
- Charge at the lidocaine binding site residue Phe‐1759 affects permeation in human cardiac voltage‐gated sodium channelsThe Journal of Physiology, 2007
- Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazineHeart, 2006
- Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overloadHeart, 2006
- Inherited disorders of voltage-gated sodium channelsJCI Insight, 2005
- Block of Inactivation-deficient Na+ Channels by Local Anesthetics in Stably Transfected Mammalian CellsThe Journal of general physiology, 2004
- Electrophysiologic Properties and Antiarrhythmic Actions of a Novel Antianginal AgentJournal of Cardiovascular Pharmacology and Therapeutics, 2004
- Tryptophan Scanning of D1S6 and D4S6 C-Termini in Voltage-Gated Sodium ChannelsBiophysical Journal, 2003
- Voltage-gated sodium channelsCurrent Opinion in Pharmacology, 2001
- A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agentsThe American Journal of Cardiology, 1999