Ranolazine, a late sodium current inhibitor, reduces ischemia‐induced superoxide emission and improves functional recovery in guinea pig isolated hearts

Abstract

Ranolazine (RAN) is believed to block a late Na+ (NaL) current that may be activated by reactive oxygen species (ROS) via peroxidation in cardiac cells during ischemia. Na+ loading contributes to cell Ca2+ loading via Na+/Ca2+ exchange (NCE) and cell damage on reperfusion. We tested if RAN treatment during ischemia improves cardiac function on reperfusion and reduces superoxide (O2 ?−) emission. Left ventricular pressure (LVP) and coronary flow (CF) were measured in guinea pig isolated hearts perfused with Krebs‐Ringer's solution; O2 ?− emission was assessed in the LV wall, on‐line, by fluorescence spectrophotometry using DHE. RAN (5 µM), infused for 1 min before 30 min global ischemia, itself decreased heart rate by 20% and LVP by 30% and increased CF by 20%. During late ischemia O2▸− emission increased less with RAN (20% vs. 40% control). At 15 min reperfusion O2▸− emission was reduced 20% by RAN vs. control. At 120 min reperfusion the RAN group (vs. control) exhibited higher LVP (68% vs. 55%) and CF (72% vs. 58%), and reduced incidence of V fibrillation (16% vs. 100%). Ischemia and consequent ROS release are believed to induce a persistent NaL current so blocking this current may reduce Ca2+ loading via NCE. These studies suggest a link between ROS‐induced Na+ loading via NaL and LV function during reperfusion. The decrease in O2▸− emission with RAN during ischemia is likely secondary to improved mitochondrial bioenergetics.