ataprost and Reperfusion-Injury

Topics: Animals; Antioxidants; Bilirubin; Epoprostenol; Graft Survival; Hepatectomy; Hypertonic Solutions; Ischemia; Liver Transplantation; Organ Preservation; Organ Preservation Solutions; Platelet Aggregation Inhibitors; Reperfusion Injury; Superoxides; Swine; Thiazoles; Time Factors; Tissue and Organ Harvesting

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.. 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.. 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.. 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.

Topics: Analysis of Variance; Animals; Dogs; Dose-Response Relationship, Drug; Epoprostenol; Female; Ischemia; Liver; Liver Function Tests; Misoprostol; Platelet Aggregation Inhibitors; Prostaglandins, Synthetic; Reperfusion Injury

Prostaglandin I2 (PGI2) analogues have been suggested to protect the liver from ischemia-reperfusion injury, but the exact mechanism remains to be proved.. Primary cultured rat hepatocytes were exposed to superoxide generated by mixing hypoxanthine and xanthine oxidase, and changes in cell viability, cytosolic free calcium concentration ([Ca2+]i), and adenosine 3',5'-cyclic monophosphate (cAMP) concentration were assessed. The PGI2 analogue (OP2507 or OP41483) at 1 to 100 ng/ml was given as treatment.. PGI2 analogues suppressed hepatocyte death in a dose-dependent manner (p < 0.01; OP2507 at 10 and 100 ng/ml, OP41483 at 100 ng/ml). At the end of 1-hour preincubation with OP2507, a significant rise in cAMP concentration was observed. Moreover, addition of dibutyryl cAMP suppressed hepatocyte death. A rise in [Ca2+]i, which preceded cell death, was prevented by PGI2 analogues or dibutyryl cAMP.. The increase in cellular cAMP followed by suppression of [Ca2+]i elevation might be the major cause of the cytoprotective effect of PGI2 analogues in superoxide-induced hepatocyte injury.

Topics: Animals; Calcium; Cells, Cultured; Cyclic AMP; Epoprostenol; L-Lactate Dehydrogenase; Lipid Peroxidation; Liver; Male; Prostaglandins, Synthetic; Rats; Rats, Wistar; Reperfusion Injury; Superoxides

The effect of the stable prostacyclin (PGI2) analogue OP-41483 (OP) on liver preservation was investigated in the rat liver transplant model. In a 1-week survival study, 33 orthotopic liver transplants were performed using Wistar rats. In group A, untreated livers were stored with modified UW (mUW) solution at 4 degrees C. In group B, livers from OP-pretreated donors (2 micrograms/kg, i.v.) were stored with mUW solution containing OP (1 microgram/ml) at 4 degrees C. After 24 h storage, the donor grafts in each group were transplanted to untreated recipients. OP treatment (group B) significantly improved 1-week survival (62.5%, 10/16, P < 0.01 versus group A; 11.8%, 2/17). For the measurement of adenine nucleotides and lipid peroxidation (malondialdehyde, MDA) in liver tissue before preservation, after preservation, and 3 h after transplantation, 20 rat livers in groups A and B were studied. In both groups, the levels of adenosine triphosphate (ATP) declined 6 h after cold preservation, but this degradation of ATP was significantly halted at the level of adenosine monophosphate (AMP) in the OP-treated livers after 24 h of storage. However, OP treatment showed no significant difference in the degree of ATP recovery after transplantation. On the other hand, OP treatment resulted in suppression of the increase in MDA levels and histological amelioration of microcirculatory disturbance 3 h after transplantation. Our data suggested that the combined use of the stable PGI2 analog (OP-41483) and UW solution is beneficial in liver preservation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenine Nucleotides; Animals; Cryopreservation; Energy Metabolism; Epoprostenol; Graft Survival; Lipid Peroxidation; Liver; Liver Transplantation; Male; Malondialdehyde; Organ Preservation; Rats; Rats, Wistar; Reperfusion Injury

To estimate the effects of the prostacyclin analog (OP-41483) on normothermic liver ischemia and reperfusion injury, saline (Group 1, N = 8), heparin (group 2, N = 8, 100 u/kg) or OP-41483 (group 3, N = 8, 400 ng/kg/min) was infused intravenously for 30 min before and after liver ischemia in rats. There were no significant differences in survival, or transaminase at 30 min after reperfusion among the three groups. Hepatic vessel flow and tissue flow were measured for the first 30 min after reperfusion. Hepatic tissue flow increased for the first 30 min after reperfusion in the group 3 rats, but not in the groups 2 and 3 rats. There were significant differences in hepatic tissue flow between the groups 1 and 3 rats at 20 min (p < 0.05), as well as significant differences between the groups 1 and 3 rats (p < 0.01) and the groups 1 and 2 rats (p < 0.05) at 30 min after reperfusion. There were no significant differences in total hepatic inflow among the three groups. Our data suggest that OP-41483 exerts beneficial effects by improving the microcirculation and increasing the effective hepatic blood flow in the ischemically injured liver after reperfusion.

Topics: Animals; Epoprostenol; Female; Ischemia; Liver; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Regional Blood Flow; Reperfusion Injury; Survival Rate

The effects of TCV-309, a specific platelet-activating factor (PAF) antagonist, and OP-41483, a prostaglandin I2 analogue, on warm ischemia/reperfusion injury of the rat liver were studied. Rats were divided into five groups by the duration of warm ischemia and the treatment used. The NS1 group (normal saline pretreatment) had 60 min of warm ischemia, while the NS2 group (normal saline pretreatment), the PGI2 group (OP-41483, 500 ng/kg/min pretreatment), the TCV group (TCV-309, 3 micrograms/kg), and the PGI2+TCV group (both the above dosages) underwent 120 min of warm ischemia. Postoperative survival after 30 days, bile secretion, serum endotoxin levels, and tissue glutathione levels after 60 min of reperfusion were compared between the groups. The survival rates for the NS1, NS2, PGI2, TCV, and PGI2+TCV groups were 80%, 0%, 50%, 80%, and 86.7%, respectively. Bile secretion, which has a strong correlationship with hepatic cellular ATP level, was strongly correlated with survival. The NS2 group had a high serum endotoxin level--however, the PGI2 and PGI2+TCV groups had normal levels. Although there were some discrepancies between survival and the tissue glutathione level, combined treatment with the PGI2 analogue and TCV-309 was most effective in inhibited oxidative stress. In conclusion, TCV-309 increased the survival rate after 120 min of warm hepatic ischemia without endotoxemia by the PGI2 analogue. This finding suggest that warm ischemia/reperfusion injury is related to the generation of PAF. Combined pretreatment with TCV-309 and a PGI2 analogue may be useful in liver transplantation.

Topics: Animals; Bile; Endotoxins; Epoprostenol; Glutathione; Ischemia; Isoquinolines; Liver; Male; Platelet Activating Factor; Pyridinium Compounds; Rats; Rats, Wistar; Reperfusion Injury; Tetrahydroisoquinolines

In living-related transplantation, warm ischemia/reperfusion damage (IRD) of liver grafts is inevitable during harvesting. In this study, we investigated the effects of prostacyclin (PGI2) on IRD of liver grafts in the rat liver transplant model. Donor rats underwent 30-min warm ischemia of part of the liver (right lateral and medial lobes). After 10 min of reflow, the ischemic partial livers were flushed with Ringer's lactate and immediately transplanted into untreated recipients. Donor animals were divided into two groups: group I received vehicle, and group II received PGI2 analog OP-41483 (OP, 500 ng/kg per min, i. v.) during the donor operation. One-week survival was studied and cellular adenine nucleotide levels of donor livers were assayed by high-performance liquid chromatography (HPLC). Donor treatment with PGI2 analog group II significantly improved 1-week survival (86%), in comparison with the controls group I (25%). The levels of total adenine nucleotides (TAN, micromol/g dry wt) of the grafts just before implantation were well maintained by PGI2 treatment (12.22), as compared with the controls (10.36). In summary, PGI2 treatment of the donor maintained high energy metabolism of the liver graft after IRD and improved the survival of recipients after transplantation. Our study suggested that PGI2 treatment of donors improves viability in liver grafts from living donors thus and increases graft availability for transplantation.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Energy Metabolism; Epoprostenol; Hepatocytes; Liver Transplantation; Living Donors; Male; Rats; Rats, Wistar; Reperfusion Injury; Transplantation, Isogeneic