Prostacyclin analog-suppressed ischemia-reperfusion injury of the rat liver: evaluation by calpain mu activation.
Prostaglandin I2 has a protective effect on hepatic ischemia-reperfusion injury. However, the exact intracellular mechanisms of this effect have not been elucidated. Calpain micro, a Ca2+-dependent protease, has been found to play a role in the ischemia-reperfusion injury of various organs. The hilar area of the left lateral and median lobes of rat livers was clamped for 60 min. A prostaglandin I2 analog (OP2507, C35H41NO4) was intravenously administered at 0.1, 0.32, or 1.0 microg/kg/min from 20 min before the ischemia. In addition to biochemical and microscopic analyses, the activation of calpain mu was investigated using specific antibodies against the intermediate (activated) and preactivated forms of calpain mu. The degradation of talin was also studied by Western blotting. When OP2507 was infused at 0.32 and 1.0 microg/kg/min, bile flow significantly increased after reperfusion compared with the control group, consistent with the decrease in serum transaminase levels. Membrane bleb formation and the appearance of the intermediate form of calpain mu were observed at 60 min of ischemia in the control and OP2507 (0.1 microg/kg/min) groups and remained present until 120 min after reperfusion. OP2507 (1.0 microg/kg/min) markedly suppressed not only membrane bleb formation but also calpain mu activation and the degradation of talin. In conclusion, OP2507 suppresses ischemia-reperfusion injury of the rat liver, and its cytoprotective effect is closely associated with the inhibition of calpain mu activation.
Wang
M
M
Department of Surgery II, Osaka University Medical School, 2-2 Yamadaoka, Osaka, Suita, 565, Japan.
Sakon
M
M
Miyoshi
H
H
Umeshita
K
K
Kishimoto
S
S
Taniguchi
K
K
Gotoh
M
M
Imajoh-Ohmi
S
S
Monden
M
M
D000410:Alanine Transaminase / Q000097:blood; D000595:Amino Acid Sequence; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001646:Bile / Q000187:drug effects / Q000502:physiology; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries*; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000648:ultrastructure; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D013997:Time Factors
C049453:OP 2507; D011464:Epoprostenol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002154:Calpain