Ranolazine inhibits an oxidative stress-induced increase in myocyte sodium and calcium loading during simulated-demand ischemia

Ranolazine inhibits the late Na+ current and is proposed to reduce angina by decreasing [Na+](i) during ischemia, thereby reducing Ca2+ influx via Na+/Ca2+ exchange (NCX). We sought to test this hypothesis and to determine whether oxidative stress during simulated-demand ischemia activates the late Na+ current. We measured [Ca2+](i) and [Na+](i) in rabbit ventricular myocytes by flow cytometry during metabolic inhibition (MI) with 2 mM cyanide and 0 mM glucose at 37 degrees C plus pacing (P) at 0.5 Hz (P-MI), and in P-MI + 1, 10, or 50 mu M ranolazine. In the clinically relevant concentration range (1-10 mu M), ranolazine decreased Na+ and Ca2+ loading and the development of myocyte contracture. P-MI caused an increase in fluorescence of the oxidative radical probe CM-H(2)DCFDA, which was inhibited by the radical scavenger Tiron 20 mM. The NCX inhibitor KB-R7943 (10 mu M) and Tiron 20 mM reduced the rise in [Ca2+](i) during P-MI and eliminated the effect of 10 mu M ranolazine on [Ca2+](i). These results indicate that oxidative stress increases the late Na+ current during MI. Inhibition of the resulting increase in Na+ and Ca2+ loading and contracture seems to account for the observed antiischemia effects of ranolazine.