Late Sodium Current Contributes to the Reverse Rate-Dependent Effect of IKr Inhibition on Ventricular Repolarization

Background—The reverse rate dependence (RRD) of actions of IKr-blocking drugs to increase the action potential duration (APD) and beat-to-beat variability of repolarization (BVR) of APD is proarrhythmic. We determined whether inhibition of endogenous, physiological late Na+ current (late INa) attenuates the RRD and proarrhythmic effect of IKr inhibition. Methods and Results—Duration of the monophasic APD (MAPD) was measured from female rabbit hearts paced at cycle lengths from 400 to 2000 milliseconds, and BVR was calculated. In the absence of a drug, duration of monophasic action potential at 90% completion of repolarization (MAPD90) and BVR increased as the cycle length was increased from 400 to 2000 milliseconds (n=36 and 26; P<0.01). Both E-4031 (20 nmol/L) and d-sotalol (10 μmol/L) increased MAPD90 and BVR at all stimulation rates, and the increase was greater at slower than at faster pacing rates (n=19, 11, 12 and 7, respectively; P<0.01). Tetrodotoxin (1 μmol/L) and ranolazine significantly attenua...