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 Nai during ischemia, thereby reducing Ca influx via Na/Ca 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 Cai and Nai 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 microM ranolazine. In the clinically relevant concentration range (1-10 microM), ranolazine decreased Na and Ca loading and the development of myocyte contracture. P-MI caused an increase in fluorescence of the oxidative radical probe CM-H2DCFDA, which was inhibited by the radical scavenger Tiron 20 mM. The NCX inhibitor KB-R7943 (10 microM) and Tiron 20 mM reduced the rise in Cai during P-MI and eliminated the effect of 10 microM ranolazine on Cai. These results indicate that oxidative stress increases the late Na current during MI. Inhibition of the resulting increase in Na and Ca loading and contracture seems to account for the observed antiischemia effects of ranolazine.