Ranolazine is a clinically approved drug for treating cardiac ventricular dysrhythmias and angina. Its mechanism(s) of protection is not clearly understood but evidence points to blocking the late Na+ current that arises during
ischemia, blocking mitochondrial complex I activity, or modulating mitochondrial metabolism. Here we tested the effect of
ranolazine treatment before
ischemia at the mitochondrial level in intact isolated hearts and in mitochondria isolated from hearts at different times of reperfusion. Left ventricular (LV) pressure (LVP), coronary flow (CF), and O2 metabolism were measured in guinea pig isolated hearts perfused with Krebs-
Ringer's solution; mitochondrial (m)
superoxide (O2·-), Ca2+,
NADH/
FAD (redox state), and cytosolic (c) Ca2+ were assessed on-line in the LV free wall by fluorescence spectrophotometry.
Ranolazine (5 μM), infused for 1 min just before 30 min of global
ischemia, itself did not change O2·-, cCa2+, mCa2+ or redox state. During late
ischemia and reperfusion (IR) O2·- emission and m[Ca2+] increased less in the
ranolazine group vs. the control group.
Ranolazine decreased c[Ca2+] only during
ischemia while
NADH and
FAD were not different during IR in the
ranolazine vs. control groups. Throughout reperfusion LVP and CF were higher, and
ventricular fibrillation was less frequent.
Infarct size was smaller in the
ranolazine group than in the control group. Mitochondria isolated from
ranolazine-treated hearts had mild resistance to permeability transition pore (
mPTP) opening and less
cytochrome c release than control hearts.
Ranolazine may provide functional protection of the heart during IR injury by reducing cCa2+ and mCa2+ loading secondary to its effect to block the late Na+ current. Subsequently it indirectly reduces O2·- emission, preserves bioenergetics, delays
mPTP opening, and restricts loss of
cytochrome c, thereby reducing
necrosis and apoptosis.