Abstract
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.
Highlights
Ranolazine is a piperazine derivative that was clinically approved by the FDA in 2006 for treatment of angina pectoris
In the present study we examined effects of ranolazine on cardiac sodium channel Nav1.5 transiently expressed in HEK293 cells as well as the effects of extracellular acidification to pH 6.0, typically exhibited during myocardial ischemia
We examined the effects of extracellularly applied ranolazine on Nav1.5, transiently co-expressed in HEK293 cells along with the β1 subunit and eGFP marker
Summary
Ranolazine is a piperazine derivative that was clinically approved by the FDA in 2006 for treatment of angina pectoris. It decreases late sodium currents (INa) through cardiac sodium channel, Nav1.5, and thereby reduces calcium influx through the sodiumcalcium exchanger NCX during reverse mode activity (Sossalla et al, 2008). Ranolazine demonstrated antiarrhythmic properties in both atria and ventricles (Wu et al, 2004; Undrovinas et al, 2006; Burashnikov et al, 2007; Dobrev and Nattel, 2010). Use-dependent inhibition of peak INa as well as IKr is thought to play an important role in treatment of atrial fibrillation, in addition to suppression of late INa (Burashnikov et al, 2007; Sossalla et al, 2010). Ranolazine displayed cardioprotection during ischemia (Hale et al, 2006, 2008; Stone et al, 2010), and effectively diminished late INa in Long QT syndrome type 3 mutations (Fredj et al, 2006; Moss et al, 2008; Kahlig et al, 2010; Huang et al, 2011)
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