Ranolazine Decreases Mechanosensitivity of the Voltage-Gated Sodium Ion Channel NaV1.5: A Novel Mechanism of Drug Action

Study Questions:

What is the effect of ranolazine on the mechanical behavior of NaV1.5?

Methods:

Nine- to eleven-week-old BALB/c mice (Harlan Sprague-Dawley, Indianapolis, IN) were used for the isolation of the ventricular cardiac myocytes. Mechanosensitivity of NaV1.5 was tested in voltage-clamped whole cells and cell-attached patches by bath flow and patch pressure, respectively. Whole-cell and macroscopic patch data were analyzed in Pclamp 9, whereas single-channel data were analyzed in QUB.

Results:

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:

The authors concluded that ranolazine effectively inhibits mechanosensitivity of NaV1.5.

Perspective:

This study suggests that ranolazine effectively inhibits mechanosensitivity of NaV1.5. Furthermore, 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 (MEF), and further exploration of these compounds in disorders associated with MEF appears to be indicated. Ranolazine and other inhibitors of NaV1.5 may have a role in heart failure therapy and atrial fibrillation related to stretch of pulmonary veins. Better understanding about the role of ion channels in cardiac physiology may also open new ways to influence these channels with the aim of treating various cardiac arrhythmias.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, EP Basic Science, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism

Keywords: NAV1.5 Voltage-Gated Sodium Channel, Mice, Inbred BALB C, Atrial Fibrillation, Piperazines, Myocytes, Cardiac


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