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Sivelestat reduces myocardial ischemia and reperfusion injury in rat hearts even when administered after onset of myocardial ischemia

Department of Biological Regulation and Regenerative Surgery, Nippon Medical School Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo, Tokyo, Japan

*Corresponding author. Department of Thoracic and Cardiovascular Surgery, Nippon Medical School Chiba-Hokuso Hospital, 1715, Kamagari, Inba, Chiba 270-1694, Japan. Tel.: +81-476-99-1835; fax: +81-476-99-1921.

E-mail address: shaw{at}nms.ac.jp (M. Kambe).

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<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<0.01 compared to control), and troponin-T values were 4±1, 2±1**, and 8±2, respectively (**P<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<0.01) and this impairment was attenuated by sivelestat-perfusion at reperfusion (maximal change: 112±7%; P<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.

Key Words: Ischemia/reperfusion; Myocardial protection; Endothelium