Ranolazine Decreases Mechanosensitivity of the Voltage-Gated Sodium Ion Channel NaV1.5: A Novel Mechanism of Drug Action
Background—NaV1.5 is a mechanosensitive voltage gated sodium-selective ion channel responsible for the depolarizing current and maintenance of the action potential plateau in the heart. Ranolazine is a NaV1.5 antagonist with anti-anginal and anti-arrhythmic properties.
Methods and Results—Mechanosensitivity of NaV1.5 was tested in voltage-clamped whole cells and cell-attached patches by bath flow and patch pressure, respectively. In whole cells, bath flow increased peak inward current in both murine ventricular cardiac myocytes (24±8%) and HEK cells heterologously expressing NaV1.5 (18±3%). The flow-induced increases in peak current were blocked by ranolazine. In cell-attached patches from cardiac myocytes and NaV1.5-expressing HEK cells, negative pressure increased NaV peak currents by 27±18% and 18±4% and hyperpolarized voltage dependence of activation by -11 mV and -10 mV, respectively. In HEK cells, negative pressure also increased the window current (250%) and increased late open channel events (250%). Ranolazine decreased pressure-induced shift in the voltage-dependence (IC50 54 μM) and eliminated the pressure-induced increases in window current and late current event numbers. Block of NaV1.5 mechanosensitivity by ranolazine was not due to the known binding site on DIVS6 (F1760). The effect of ranolazine on mechanosensitivity of NaV1.5 was approximated by lidocaine. However, ionized ranolazine and charged lidocaine analog (QX-314) failed to block mechanosensitivity.
Conclusions—Ranolazine effectively inhibits mechanosensitivity of NaV1.5. The block of NaV1.5 mechanosensitivity by ranolazine does not utilize the established binding site, and may require bilayer partitioning. Ranolazine block of NaV1.5 mechanosensitivity may be relevant in disorders of mechano-electric dysfunction.
- Received January 19, 2012.
- Accepted April 10, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited