Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation

Differences in ion channel currents of action potentials from normal atria and ventricles and remodeled atria. A and B, The normal action potential in atria differs from that of the ventricle with respect to ion channel currents that contribute to RMP, phase 1, and phase 3 of the action potential. Resting membrane potential in atria is more depolarized than in the atrial due a smaller I_K1. Phase 1 is more prominent in atria due to the presence of a prominent I_to and I_Kur. Both I_Kur and I_K-ACh are exclusive to atria. Phase 3 of the action potential is much slower to repolarize in atria because of weaker repolarizing currents I_Kr, I_Ks, and I_K1. C, Rapid activation of the atria during AF results in a decrease in I_Ca, I_Kur, and I_to but in an increase in I_K1 and constitutively active I_K-ACh. The abbreviation of action potential duration is due principally to the decrease in I_Ca and the increase in I_K1 and constitutively active I_K-ACh

Ranolazine produces a much greater rate-dependent inhibition of the maximal action potential upstroke velocity (V_max) in atria than in ventricles. Top: V_max and action potentials recordings obtained from coronary-perfused canine right atrium (crista terminalis) before control (C) and after ranolazine (10 μmol/L). Bottom: V_max and action potentials (AP) recordings obtained from coronary-perfused canine left ventricular wedge preparation (M cell) before (C) and after ranolazine (10 μmol/L). Ranolazine prolongs late repolarization in atria but not ventricles and acceleration of rate leads to elimination of the diastolic interval, resulting in a more positive takeoff potential in atrium, which contributes to atrial selectivity of the drug. The diastolic interval remains relatively long in ventricles.