Ranolazine decreases mechanosensitivity of the voltage-gated sodium ion channel NaV1.5: A novel mechanism of drug action

Abstract

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 antianginal and antiarrhythmic 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 human embryonic kidney 293 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 human embryonic kidney 293 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 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 (IC50 54 μmol/L) 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 mechanoelectric dysfunction. © 2012 American Heart Association, Inc.