Atrial-ventricular differences in rabbit cardiac voltage-gated Na+ currents: Basis for atrial-selective block by ranolazine

作者：Caves Rachel E; Cheng Hongwei; Choisy Stephanie C; Gadeberg Hanne C; Bryant Simon M; Hancox Jules C; James Andrew F^*

来源：Heart Rhythm, 2017, 14(11): 1657-1664.

DOI：10.1016/j.hrthm.2017.06.012

• Antiarrhythmic drug
• Atrial myocytes
• Cardiac regional heterogeneity
• Na+ channel blocker
• Ventricular myocytes

BACKGROUND Class 1 antiarrhythmic drugs are highly effective in restoring and maintaining sinus rhythm in atrial fibrillation patients but carry a risk of ventricular tachyarrhythmia. The antianginal agent ranolazine is a prototypic atrial-selective voltage-gated Na+ channel blocker but the mechanisms underlying its atrial-selective action remain unclear.
OBJECTIVE The present study examined the mechanisms underlying the atrial-selective action of ranolazine.
METHODS Whole-cell voltage-gated Na+ currents (I-Na) were recorded at room temperature (similar to 22 degrees C) from rabbit isolated left atrial and right ventricular myocytes.
RESULTS I-Na conductance density was similar to 1.8-fold greater in atrial than in ventricular cells. Atrial I-Na was activated at command potentials similar to 7 mV more negative and inactivated at conditioning potentials similar to 11 mV more negative than ventricular I-Na. The onset of inactivation of INa was faster in atrial cells than in ventricular myocytes. Ranolazine (30 mu M) inhibited I-Na in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated/inactivated state block. Ranolazine caused a significantly greater negative shift in voltage of half-maximal inactivation in atrial cells than in ventricular cells, the recovery from inactivation of I-Na was slowed by ranolazine to a greater extent in atrial myocytes than in ventricular cells, and ranolazine produced an instantaneous block that showed marked voltage dependence in atrial cells.
CONCLUSION Differences exist between rabbit atrial and ventricular myocytes in the biophysical properties of INa. The more negative voltage dependence of INa activation and inactivation, together with trapping of the drug in the inactivated channel, underlies an atrial-selective action of ranolazine.

• 出版日期2017-11