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The overall aim of this study was to determine if adrenomedullin (AM) protects against myocardial ischaemia (MI)-induced arrhythmias via nitric oxide (NO) and peroxynitrite.In sham-operated rats, the effects of in vivo administration of a bolus dose of AM (1 nmol kg−1) was assessed on arterial blood pressure (BP), ex vivo leukocyte reactive oxygen species generation and nitrotyrosine deposition (a marker for peroxynitrite formation) in the coronary endothelium.In pentobarbitone-anaesthetized rats subjected to ligation of the left main coronary artery for 30 min, the effects of a bolus dose of AM (1 nmol kg−1, i.v.; n=19) or saline (n=18) given 5 min pre-occlusion were assessed on the number and incidence of cardiac arrhythmias. In a further series of experiments, some animals received infusions of the NO synthase inhibitor N(G)-nitro-L-arginine (LNNA) (0.5 mg kg−1 min−1) or the peroxynitrite scavenger N-mercaptopropionyl-glycine (MPG) (20 mg kg−1 h−1) before AM.AM treatment significantly reduced mean arterial blood pressure (MABP) and increased ex vivo chemiluminescence (CL) generation from leukocytes in sham-operated animals. AM also enhanced the staining for nitrotyrosine in the endothelium of coronary arteries.AM significantly reduced the number of total ventricular ectopic beats that occurred during ischaemia (from 1185±101 to 520±74; P<0.05) and the incidences of ventricular fibrillation (from 61 to 26%; P<0.05). AM also induced a significant fall in MABP prior to occlusion. AM-induced cardioprotection was abrogated in animals treated with the NO synthase inhibitor LNNA and the peroxynitrite scavenger MPG.This study has shown that AM exhibits an antiarrhythmic effect through a mechanism that may involve generation of NO and peroxynitrite.British Journal of Pharmacology (2006) 148, 599–609. doi:10.1038/sj.bjp.0706771; published online 22 May 2006 [ABSTRACT FROM AUTHOR]