ANTIOXIDANT ACTIVITY OF U-83836E, A 2ND-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 ox ygen-based free radicals in a variety of in vitro and in vivo test sys tems. U-83836E is one of the second-generation lazaroids that are base d on a non steroidal structure characterized by a ring portion of alph a-tocopherol bonded with various amine groups. We investigated the abi lity of U-83836E to reduce myocardial damage in rats undergoing left c oronary artery occlusion for 60 min followed by 6 hours of reperfusion . This ischemia/reperfusion model produced wide heart necrosis, membra ne lipid peroxidation, ventricular arrhythmias, tissue neutrophil infi ltration and a marked decrease in endogenous antioxidants. Intravenous administration of U-83836E, (7.5, 15 and 30 mg/kg) at onset of reperf usion, reduced myocardial necrosis, expressed as a percentage of eithe r the area at risk or the total left ventricle (p < 0.001), improved h aemodynamic conditions by decreasing ventricular arrhythmias (p < 0.00 5), limited membrane lipid peroxidation (evaluated by assessing conjug ated dienes, p < 0.001; and 4-hydroxy-nonenal, p < 0.001) restored the endogenous antioxidants vitamin E (p < 0.001), and superoxide dismuta se (pt < 0.001). Furthermore, the lazaroid inhibited the derimental hy droxyl radical formation (p < 0.001), evaluated indirectly by a trappi ng agent and reduced heart neutrophil infiltration, measured by testin g cardiac tissue elastase (p < 0.001) that is released from the stimul ated granulocytes at the site of injury. These data suggest that this compound could be a new useful tool to study the mechanisms of oxidati ve damage during myocardial infarction.