Antioxidant activity of U-83836E, a second generation lazaroid, during myocardial ischemia/reperfusion injury

The 21-aminosteroid compounds are potent lipid peroxidation inhibitors belonging to a new class of antioxidants given the collective name of "lazaroids". They protect cells from oxidative damage induced by oxygen-based free radicals in a variety of in vitro and in vivo test systems. U-83836E is one of the second-generation lazaroids that are based on a non steroidal structure characterized by a ring portion of alpha-tocopherol bonded with various amine groups. We investigated the ability of U-83836E to reduce myocardial damage in rats undergoing left coronary artery occlusion for 60 min followed by 6 hours of reperfusion. This ischemia/reperfusion model produced wide heart necrosis, membrane lipid peroxidation, ventricular arrhythmias, tissue neutrophil infiltration and a marked decrease in endogenous antioxidants. Intravenous administration of U-83836E, (7.5, 15 and 30 mg/kg) at onset of reperfusion, reduced myocardial necrosis, expressed as a percentage of either the area at risk or the total left ventricle (p < 0.001), improved haemodynamic conditions by decreasing ventricular arrhythmias (p < 0.005), limited membrane lipid peroxidation (evaluated by assessing conjugated dienes, p < 0.001; and 4-hydroxynonenal, p < 0.001) restored the endogenous antioxidants vitamin E (p < 0.001), and superoxide dismutase (pt < 0.001). Furthermore, the lazaroid inhibited the derimental hydroxyl radical formation (p < 0.001), evaluated indirectly by a trapping agent and reduced heart neutrophil infiltration, measured by testing cardiac tissue elastase (p < 0.001) that is released from the stimulated granulocytes at the site of injury. These data suggest that this compound could be a new useful tool to study the mechanisms of oxidative damage during myocardial infarction.