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.