Ranolazine Decreases Mechanosensitivity of the Voltage-Gated Sodium Ion Channel Na V 1.5

Abstract

Background—: Na _V 1.5 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 Na _V 1.5 antagonist with antianginal and antiarrhythmic properties. Methods and Results—: Mechanosensitivity of Na _V 1.5 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 human embryonic kidney 293 cells heterologously expressing Na _V 1.5 (18±3%). The flow-induced increases in peak current were blocked by ranolazine. In cell-attached patches from cardiac myocytes and Na _V 1.5-expressing human embryonic kidney 293 cells, negative pressure increased Na _V peak currents by 27±18% and 18±4% and hyperpolarized voltage dependence of activation by −11 mV and −10 mV, respectively. In human embryonic kidney 293 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 (IC ₅₀ 54 μmol/L) and eliminated the pressure-induced increases in window current and late current event numbers. Block of Na _V 1.5 mechanosensitivity by ranolazine was not due to the known binding site on DIVS6 (F1760). The effect of ranolazine on mechanosensitivity of Na _V 1.5 was approximated by lidocaine. However, ionized ranolazine and charged lidocaine analog (QX-314) failed to block mechanosensitivity. Conclusions—: Ranolazine effectively inhibits mechanosensitivity of Na _V 1.5. The block of Na _V 1.5 mechanosensitivity by ranolazine does not utilize the established binding site and may require bilayer partitioning. Ranolazine block of Na _V 1.5 mechanosensitivity may be relevant in disorders of mechanoelectric dysfunction.