Sivelestat, a neutrophil elastase inhibitor, has been shown to attenuate pulmonary injury during ischemia and reperfusion by improving microcirculation and may be effective as a cardioprotective agent. Isolated rat hearts were Langendorff-perfused (constant pressure, 75 mmHg) with oxygenated Krebs-Henseleit bicarbonate buffer (KHB). The optimal sivelestat concentration at 19 μmol/l was revealed because left ventricular developed pressure (LVDP) recovery in 19 μmol/l sivelestat was highest among 0.19, 1.9, 19, 190, and 1900 μmol/l sivelestat (26±10, 33±7, 56±5*, 35±2, and 15±5%, respectively
*P&lt
0.01). In order to examine the optimal administration timing, sivelestat was administered at pre- and post-ischemic phases. LVDP recovery and troponin-T were observed in pre-, post-ischemic sivelestat groups and control. After 60 min-reperfusion, LVDP recoveries were 42±10*, 45±19*, and 14±5%, respectively (*P&lt
0.01 compared to control), and troponin-T values were 4±1, 2±1**, and 8±2, respectively (**P&lt
0.05 compared to control). Acetylcholine-induced increase in coronary flow was also investigated to examine the sivelestat's cardioprotective mechanism. Ischemia-reperfusion (I/R) impaired the acetylcholine-induced increase in coronary flow (maximal changes: sham, 125±11%
I/R, 98±3
P&lt
0.01) and this impairment was attenuated by sivelestat-perfusion at reperfusion (maximal change: 112±7%
P&lt
0.05 vs. I/R). Sivelestat attenuates coronary endothelial ischemia-reperfusion injury and improves myocardial protection even when administered at the reperfusion period. This suggests a role for sivelestat in the preservation of coronary endothelial function enhancing myocardial protection. © 2009 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.