Attenuation of ischemic liver injury by prostaglandin E1 analogue, misoprostol, and prostaglandin I2 analogue, OP-41483.
BACKGROUND
Prostaglandin has been reported to have protective effects against liver injury. Use of this agent in clinical settings, however, is limited because of drug-related side effects. This study investigated whether misoprostol, prostaglandin E1 analogue, and OP-41483, prostaglandin I2 analogue, which have fewer adverse effects with a longer half-life, attenuate ischemic liver damage.


METHODS
Thirty beagle dogs underwent 2 hours of hepatic vascular exclusion using venovenous bypass. Misoprostol was administered intravenously for 30 minutes before ischemia and for 3 hours after reperfusion. OP-41483 was administered intraportally for 30 minutes before ischemia (2 microg/kg/min) and for 3 hours after reperfusion (0.5 microg/kg/min). Animals were divided into five groups: untreated control group (n=10); high-dose misoprostol (total 100 microg/kg) group (MP-H, n=5); middle-dose misoprostol (50 microg/kg) group (MP-M, n=5); low-dose misoprostol (25 microg/kg) group (MP-L, n=5); and OP-41483 group (OP, n=5). Animal survival, hepatic tissue blood flow (HTBF), liver function, and histology were analyzed.


RESULTS
Two-week animal survival rates were 30% in control, 60% in MP-H, 100% in MP-M, 80% in MP-L, and 100% in OP. The treatments with prostaglandin analogues improved HTBF, and attenuated liver enzyme release, adenine nucleotrides degradation, and histologic abnormalities. In contrast to the MP-H animals that exhibited unstable cardiovascular systems, the MP-M, MP-L, and OP animals experienced only transient hypotension.


CONCLUSIONS
These results indicate that misoprostol and OP-41483 prevent ischemic liver damage, although careful dose adjustment of misoprostol is required to obtain the best protection with minimal side effects.
Totsuka
E
E
Thomas E Starzl Transplantation Institute, University of Pittsburgh, PA 15213-2582, USA.
Todo
S
S
Zhu
Y
Y
Ishizaki
N
N
Kawashima
Y
Y
Jin
M B
MB
Urakami
A
A
Shimamura
T
T
Starzl
T E
TE
D000704:Analysis of Variance; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D007511:Ischemia / Q000517:prevention & control*; D008099:Liver / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D008111:Liver Function Tests; D016595:Misoprostol / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D011465:Prostaglandins, Synthetic / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D015427:Reperfusion Injury / Q000517:prevention & control
D010975:Platelet Aggregation Inhibitors; D011465:Prostaglandins, Synthetic; D016595:Misoprostol; D011464:Epoprostenol; C035847:ataprost