Reduction of myocardial ischemic reperfusion injury by sialylated glycosphingolipids, gangliosides.

Gangliosides, sialic acid-containing glycosphigolipids, are localized mostly to the outer leaflet of the lipid bilayer in the plasma membrane, particularly in brain. Gangliosides reduce edema formation, restore glucose metabolism, and increase cerebral blood flow after focal ischemia in the rat brain. We wished to determine whether gangliosides could also reduce myocardial ischemic and reperfusion injury. Isolated rat heart perfused by Langendorff technique was pretreated with gangliosides (1 microM) purified from the rat brain. After 15-min perfusion with gangliosides, hearts were made ischemic for 30 min by termination of coronary flow, followed by 60-min reperfusion. Ganglioside-treated heart exhibited better myocardial preservation, as evidenced by reduction in creatine kinase release and lipid peroxidation product formation enhanced coronary flow and contractile functions [left ventricular developed pressure (LVDP) and maximum first derivative of LVDP, LVdp/dtmax]. In addition, gangliosides reduced the hydroxyl radical formed during reperfusion of ischemic myocardium, as shown by high-performance liquid chromatography (HPLC)-electrochemical detection technique. In vitro studies demonstrated that these gangliosides were direct scavengers of superoxide anions (IC50 0.8 microM), and hydroxyl radicals (IC50 10 microM), as well hypohalite radicals (IC50 0.7 microM). Furthermore, ganglioside pretreatment was accompanied by reduced intracellular calcium overloading during ischemia and reperfusion as compared with untreated controls. The results of this study thus suggest that gangliosides can reduce ischemic reperfusion injury in isolated heart, probably by inhibiting intracellular calcium overloading and/or by directly scavenging the free radicals generated during reperfusion of ischemic myocardium.