Apelin-13 limits infarct size and improves cardiac post-ischemicmechanical recovery only if given after ischemia.

We studied whether apelin-13 is cardioprotective against ischemia/reperfusion injury if given as either a pre- or postconditioning mimetic, and whether the improved post-ischemic mechanical recovery induced by apelin-13 depends only on the reduced infarct size or also on a recovery of function of the viable myocardium. We also studied whether nitric oxide (NO) is involved in apelin-induced protection and whether the reported ischemia-induced overexpression of the apelin receptor APJ plays a role in cardioprotection. Langendorff perfused rat hearts underwent 30-min of global ischemia and 120 min of reperfusion. Left ventricular pressure was recorded. Infarct size and LDH release were determined to evaluate the severity of myocardial injury. Apelin-13 was infused at 0.5 μM concentration for 20 min either before ischemia or in early reperfusion, without and with nitric oxide-synthase inhibition by L-N(G)-Nitroarginine (L-NNA). In additional experiments, before ischemia also 1 μM apelin-13 was tested. APJ protein level was measured before and after ischemia. While before ischemia apelin-13 (0.5 and 1 μM) was ineffective, after ischemia it reduced infarct size from 54±2% to 26±4% of risk area (p<0.001) and limited the post-ischemic myocardial contracture (p<0.001). L-NNA alone increased post-ischemic myocardial contracture. This increase was attenuated by apelin-13, which however, was unable to reduce infarct size. Ischemia increased APJ protein level after 15-min reperfusion, i.e. after most of reperfusion injury has occurred. Apelin-13 protects the heart only if given after ischemia. In this protection NO plays an important role. Apelin-13 efficiency as postconditioning mimetic cannot be explained by the increased APJ level.