Attenuation of ischemic liver injury by prostaglandin E1 analogue, misoprostol, and prostaglandin I2 analogue, OP-41483

Abstract

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.

Study design: 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.

Figure 1

Systolic arterial pressure (upper) and heart rate (lower) before, during, and after ischemia (mean ± SEM). Values are expressed as a percentage of the level at 30 min before ischemia. *p < 0.05 versus control value, **p < 0.05 versus control, MP-M, MP-L, and OP values, #p < 0.05 versus MP-M, MP-L, and OP values, ##p < 0.05 versus control, MP-M, and OP values. MP-H, high-dose misoprostal; MP-M, medium-dose misoprostal; MP-L, low-dose misoprostal; OP, prostaglandin I₂ analogue OP-41483.

Figure 2

Survival of dogs after 2 hours of total hepatic vascular exclusion. *p < 0.05 versus control group. MP-M, medium-dose misoprostal; MP-L, low-dose misoprostal; MP-H, high-dose misoprostal.

Figure 3

Tissue blood flow in the liver before, during, and after ischemia (means ± SEM). Values are expressed as a percentage of the level at 30 min before ischemia. *p < 0.005 versus MP-H, MP-M, MP-L, and OP values. MP-H, high-dose misoprostal; MP-M, medium-dose misoprostal; MP-L, low-dose misoprostal; OP, prostaglandin I₂ analogue OP-41483.

Figure 4

Changes in serum aspartate aminotransferase (AST) levels after ischemia (means ± SEM). *p < 0.05 versus control value, #p < 0.05 versus control and MP-H values. MP-H, high-dose misoprostal; MP-M, medium-dose misoprostal; MP-L, low-dose misoprostal; OP, prostaglandin I₂ analogue OP-41483.