REDUCTION OF MYOCARDIAL INFARCT SIZE IN-VIVO BY CARBOHYDRATE-BASED GLYCOMIMETICS

One of the foremost mechanisms involved in the pathogenesis of myocard ial reperfusion injury is the adhesion of neutrophils within the myoca rdium. The initial neutrophil-endothelial cell interactions are mediat ed by the selectin family of adhesion molecules, Blockade of this grou p of adhesion molecules, through the use of synthetic carbohydrate ana logs to the selectin ligand sialyl Lewisx and glycomimetics, has been beneficial in reducing neutrophil influx and infarct size, In the pres ent study, glycyrrhizin (GM1292), a natural structural glycomimetic, w as analyzed for the ability to decrease myocardial infarct size after regional myocardial ischemia/reperfusion. To determine the structural requirements for optimal cardioprotective activity, two additional com pounds related to glycyrrhizin, GM3290 and GM1658 (glycyrrhetinic acid ), were studied. The molecular structures of the latter two compounds differ in the number of glucuronic acid residues in their respective m olecules, Open-chest, anesthetized rabbits were subjected to 30 min oc clusion of the left coronary artery followed by 5 hr of reperfusion. V ehicle or glycomimetic (10 mg/kg/hr) was administered intravenously im mediately before the onset of reperfusion and every hour during the re perfusion period. Myocardial infarct size in rabbits treated with GM12 92 (two glucuronic acid residues) and GM3290 (one glucuronic acid resi due) was reduced significantly when compared with vehicle-treated anim als (P < .05), GM1658, which lacks glucuronic acid residues, did not p rovide a protective effect in vivo. The data suggest that GM1292 and G M3290, which contain carbohydrate moieties, are effective in reducing the degree of myocardial injury after an acute period of ischemia/repe rfusion.