Background The aim of this study was to investigate the effects of brief ischemia before prolonged ischemia on cardiac sympathetic neural function. Brief ischemia inhibits the sympathetic neural release of norepinephrine (NE) during subsequent sustained ischemia. However, whether it can attenuate the neural function after sustained ischemia remains unknown. Methods and Results Sympathetic neural function was assessed using ¹²³I-metaiodobenzylguanidine (MIBG) in patients who with (Group I) or without angina (Group II) within 3 days prior to acute myocardial infarction. In the rat experiment, cardiac interstitial NE (iNE) with or without pretreatment of 5-min coronary ligation was determined during a 30-min occlusion. Differences between MIBG and Thallium-201 for the total defect score were significantly greater in Group II than in Group I (6.1±4.0 vs 0.4±4.4). Levels of iNE were less in rats with a 5-min pretreatment (7.3±2.3 vs 18.6±5.9 ×10³ pg/ml, p<0.01) and MIBG uptake of ischemic region was greater (0.061±0.029 vs 0.031±0.011 %kg dose/g, p<0.05) compared with rats without the pretreatment. Conclusion A brief episode of ischemia attenuates the sympathetic neural injury caused by subsequent prolonged ischemia and this protective effect is associated with attenuation of NE release during the prolonged ischemia. (Circ J 2006; 70: 919 - 925)