A critical cytoprotective role of endogenous adrenomedullin in acute myocardial infarction

Exogenous administration or transfection of adrenomedullin (AM) affords protection against ischaemia–reperfusion injury. Here we have examined the role of endogenous AM in regulating the development of myocardial infarction. Wild type (WT) and AM+/− mice underwent 30 min regional myocardial ischaemia and 120 min reperfusion. In AM+/− hearts, tetrazolium-determined infarct size was greater than in WT controls (27.9 ± 2.0 vs. 17.7 ± 2.4%, P < 0.01) and mortality rate was increased (35% vs. 14%, P < 0.05). Treatment with exogenous recombinant AM (200 ng/kg) prior to coronary occlusion rescued the ischaemia–reperfusion intolerant phenotype of AM+/− mice and further limited infarct development in WT mice. Administration of recombinant AM was associated with augmented phosphorylation of Akt and eNOS in early reperfusion suggesting a role for AM in regulating this survival pathway. These studies provide the first evidence that expression of AM is a critical factor regulating myocardial tolerance to ischaemia–reperfusion injury.