Adrenomedullin acts via nitric oxide and peroxynitrite to protect against myocardial ischaemia-induced arrhythmias in anaesthetized rats.

1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. This study has shown that AM exhibits an antiarrhythmic effect through a mechanism that may involve generation of NO and peroxynitrite.