PROSTACYCLIN ANALOG-SUPPRESSED ISCHEMIA-REPERFUSION INJURY OF THE RAT-LIVER - EVALUATION BY CALPAIN-MU ACTIVATION

Prostaglandin I-2 has a protective effect on hepatic ischemia-reperfus ion injury. However, the exact intracellular mechanisms of this effect have not been elucidated. Calpain mu, a Ca2+-dependent protease, has been found to play a role in the ischemia-reperfusion injury of variou s organs. The hilar area of the left lateral and median lobes of rat l ivers was clamped for 60 min, A prostaglandin I-2 analog (OP2507, C35H 41NO4) was intravenously administered at 0.1, 0.32, or 1.0 mu g/kg/min from 20 min before the ischemia. In addition to biochemical and micro scopic analyses, the activation of calpain mu was investigated using s pecific antibodies against the intermediate (activated) and preactivat ed forms of calpain mu. The degradation of talin was also studied by W estern blotting. When OP2507 was infused at 0.32 and 1.0 mu g/kg/min, bile flow significantly increased after reperfusion compared with the control group, consistent with the decrease in serum transaminase leve ls. Membrane bleb formation and the appearance of the intermediate for m of calpain mu were observed at 60 min of ischemia in the control and OP2507 (0.1 mu g/kg/min) groups and remained present until 120 min af ter reperfusion, OP2507 (1.0 mu g/kg/min) markedly suppressed not only membrane bleb formation but also calpain mu activation and the degrad ation of talin. In conclusion, OP2507 suppresses ischemia-reperfusion injury of the rat liver, and its cytoprotective effect is closely asso ciated with the inhibition of calpain mu activation. (C) 1997 Academic Press.