Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts

Cardiac pathologies are associated with increased late I-Na 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 (I-Na) leads to Ca2+ overload and left ventricular (LV) dysfunction, and thereby inhibition of late I-Na (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 I-Na, 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 mu M), an inhibitor of late I-Na 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 mu M) reduced d[Ca2+](i) accumulation during ischemia as well as reperfusion and improved recovery of LV function. These results show that augmentation of late I-Na 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 I-Na mechanism of action. (C) 2006 Elsevier Inc. All rights reserved.