Adrenomedullin limits reperfusion injury in experimental myocardial infarction

Adrenomedullin (AM) is a vascular-derived polypeptide that exerts numerous actions in cardiovascular homeostasis. Recent studies have demonstrated a cytoprotective action of exogenously applied or genetically over-expressed AM in experimental myocardial infarction. The present studies were undertaken to test the hypothesis that AM exerts its effects through direct augmentation of NO generation in the myocardium during early reperfusion. Rat isolated hearts underwent 35 min left coronary artery occlusion followed by 120 min reperfusion. Infarct size (as percentage of ischaemic riskzone) was determined by Evans' blue and tetrazolium double staining. AM 1 nM administered 5 min prior to and during the first 15 min of ischaemia did not significantly influence infarct size. However, the same concentration of AM given during the last 5 min ischaemia and first 15 min of reperfusion significantly limited infarct size (AM reperfusion 15.9 +/- 3.5% vs control 31.4 +/- 2.1%, P < 0.01). AM at reperfusion improved coronary flow and LV contractility. The protective effects of adrenomedullin were abolished in the presence of the NO synthase inhibitor, L-NAME 100 mu M (infarct size 24.6 +/- 5.7%, P > 0.05 vs control). AM treatment at reperfusion was associated with augmented phosphorylation of the pro-survival kinase, Akt, determined by immunoblotting of tissue sampled 30 min following reperfusion. These studies provide the first evidence that AM exerts its cytoprotective action specifically during early reperfusion through a NO-dependent mechanism.