Cardiac pathologies are associated with increased late INa that contributes to the dysregulation of ion homeostasis and causes electrical and contractile dysfunction. This study was designed to test the hypothesis that an increased late
sodium channel current (INa) leads to Ca2+ overload and left ventricular (
LV) dysfunction, and thereby inhibition of late INa (e.g., by
ranolazine) improves Ca2+ homeostasis and reduces
LV dysfunction. Intracellular Ca2+ ([Ca2+]i) and LV function were measured simultaneously in rat isolated perfused hearts. Augmentation of late INa with
sea anemone toxin-II (ATX-II, 12 nM) increased diastolic [Ca2+]i (d[Ca2+]i), and impaired LV mechanical function, but had no effect on [Ca2+]i transient amplitude. Although
ranolazine (4 and 9 microM), an inhibitor of late INa, had no direct effects on d[Ca2+]i or LV function, it significantly reduced the deleterious effects of ATX-II. Global
ischemia increased d[Ca2+]i and inhibited Ca2+ transient amplitude. During reperfusion, Ca2+ transient amplitude recovered fully, but d[Ca2+]i remained elevated and LV function was depressed, indicative of Ca2+ overload.
Ranolazine (9 microM) reduced d[Ca2+]i accumulation during
ischemia as well as reperfusion and improved recovery of LV function. These results show that augmentation of late INa with ATX-II or by
ischemia is associated with diastolic Ca2+ overload and
LV dysfunction. The beneficial effects of
ranolazine in reducing Ca2+ overload and LV mechanical dysfunction during
ischemia/reperfusion is consistent with the inhibition of late INa mechanism of action.