Original Research ARTICLE
Proton-dependent inhibition of the cardiac sodium channel Nav1.5 by ranolazine
- 1Molecular Cardiac Physiology Group, Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
- 2Department of Biology, Cardiovascular Therapeutic Area, Gilead Sciences, Inc., Fremont, CA, USA
Ranolazine is clinically approved for treatment of angina pectoris and is a potential candidate for antiarrhythmic, antiepileptic, and analgesic applications. These therapeutic effects of ranolazine hinge on its ability to inhibit persistent or late Na+ currents in a variety of voltage-gated sodium channels. Extracellular acidosis, typical of ischemic events, may alter the efficiency of drug/channel interactions. In this study, we examined pH modulation of ranolazine's interaction with the cardiac sodium channel, Nav1.5. We performed whole-cell path clamp experiments at extracellular pH 7.4 and 6.0 on Nav1.5 transiently expressed in HEK293 cell line. Consistent with previous studies, we found that ranolazine induced a stable conformational state in the cardiac sodium channel with onset/recovery kinetics and voltage-dependence resembling intrinsic slow inactivation. This interaction diminished the availability of the channels in a voltage- and use-dependent manner. Low extracellular pH impaired inactivation states leading to an increase in late Na+ currents. Ranolazine interaction with the channel was also slowed 4–5 fold. However, ranolazine restored the voltage-dependent steady-state availability profile, thereby reducing window/persistent currents at pH 6.0 in a manner comparable to pH 7.4. These results suggest that ranolazine is effective at therapeutically relevant concentrations (10 μM), in acidic extracellular pH, where it compensates for impaired native slow inactivation.
Keywords: ranolazine, acidosis, cardiac sodium channel, Nav1.5, electrophysiology
Citation: Sokolov S, Peters CH, Rajamani S and Ruben PC (2013) Proton-dependent inhibition of the cardiac sodium channel Nav1.5 by ranolazine. Front. Pharmacol. 4:78. doi: 10.3389/fphar.2013.00078
Received: 02 May 2013; Accepted: 03 June 2013;
Published online: 21 June 2013.
Edited by:Aurelien Chatelier, Laboratoire Signalisation & Transports Ioniques Membranaires, France
Reviewed by:Wayne R. Giles, The University of Calgary, Canada
Theodore R. Cummins, Indiana University School of Medicine, USA
Copyright © 2013 Sokolov, Peters, Rajamani and Ruben. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: P. C. Ruben, Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6 Canada e-mail: firstname.lastname@example.org