The aim of this study is to investigate whether atrial natriuretic peptide can mimic preconditioning to protect ischemia or reperfusion injury in rabbit hearts. New Zealand white rabbits were randomized into 3 groups: (1) Controls. Hearts received a 60 minute-occlusion of the left anterior descending artery, followed by a 180 minute-reperfusion. (2) Preconditioning. Two 5-minute periods of ischemia separated by a 10-minute reperfusion, followed by a 60-minute ischemia and a 180-minute reperfusion. (3) Atrial natriuretic peptide treatment. Bolus injection of exogenous atrial natriuretic peptide (2.5 microg/kg) given intravenously at 15 minutes prior to 60 minute-ischemia followed by a 180-minute reperfusion. Myocardial necrotic area and area at risk of necrosis were determined by triphenyltetrazolium chloride staining. Ratio of necrotic area to area at risk was 49.95% +/- 1.15%, 7.95% +/- 0.33%, and 8.36% +/- 0.61% in the controls, preconditioning group, and atrial natriuretic peptide group, respectively. Both preconditioning and atrial natriuretic peptide significantly reduced the size of infarct caused by ischemia (preconditioning vs controls, P < .05; atrial natriuretic peptide vs controls, P < .05). Atrial natriuretic peptide can mimic ischemic preconditioning to protect rabbit hearts from prolonged ischemia and reperfusion injury. It may be involved in the cardioprotective mechanisms of preconditioning.