Ranolazine Reduces Arrhythmogenic Calcium Waves in Ventricular Cardiomyocytes

Abstract

We have previously shown that reducing Na+ influx by a reduction in peak Na+ current (INa,peak) in isolated cardiac myocytes leads to a decrease in pro-arrhythmic Ca2+ waves. However, INa,peak inhibition can result in reduced conduction velocity and promote wavebreak leading to enhanced arrhythmia in vivo. Here we test if ranolazine, an inhibitor of late Na+ current (INa,late) could also reduce the occurrence of Ca2+ waves without potentially problematic reductions in INa,peak. Cells, loaded with fluo-4AM to monitor intracellular Ca2+, were stimulated at different pacing rates followed by a one-minute rest period for wave detection.10μM ranolazine reduced Ca2+ wave frequency in cells following pacing at 5Hz although less potently than 5μM flecainide (0.13±0.02 waves.s−1 (flecainide) vs 0.16±0.02 waves.s−1 (ranolazine), P<0.01). Comparable effects were achieved when the concentration of ranolazine was increased to 20μM (0.14±0.02 waves.s−1 (flecainide) and 0.18±0.03 waves.s−1 (ranolazine) vs 0.22±0.03 waves.s−1 (control), P<0.001 and 0.05 respectively) although at this concentration there is a significant reduction in INa,peak. Ranolazine's ability to reduce wave occurrence was tested further under two conditions in which enhancement of INa,late, would be expected; in the presence of anemone toxin II and in cells from an established model of chronic heart failure (HF). In both conditions wave frequency was increased (e.g. 0.08±0.01 waves.s−1 (HF) vs 0.06±0.01 waves.s−1 (control), P<0.05) but ranolazine was not effective at reducing frequency (0.19±0.04 waves.s−1 (ranolazine 10μM) vs 0.19±0.04 waves.s−1 (control), P=0.92).Ranolazine decreased Ca2+ wave frequency in isolated cardiomyocytes, particularly at concentrations where INa,peak is reduced. The lack of efficacy in states of enhanced INa,late suggests specific effects of the drug are less important than off-target effects on INa,peak. Thus similar dose-limiting side effects as with conventional INa blockers are expected.