increase in portal pressure and sinusoidal constriction, in The present study was designed to investigate if TAKparallel with a decrease in hepatic arterial and portal blood 044, a novel endothelin (ET) ET A /ET B receptor antagoflow. These pathological changes were reversed after ET-1 nist, inhibits ischemia-reperfusion liver injury. The iniinfusion was completed. tial study showed the presence of both ET A and ET B Several observations were derived from our previous study receptors in canine hepatic membrane fractions using using a partial liver ischemic model. 6 First, the ET levels in the specific binding assay of labeled ET-1 with ET isothe liver tissue and hepatic venous blood of the ischemic lobe mers and TAK-044. The nonselective ET A /ET B receptor increased slightly during ischemia and markedly after reperantagonist TAK-044 inhibited the specific binding of ETfusion, whereas those of the nonischemic lobe showed no sig-1 to the receptors in a concentration-dependent manner.nificant increases. Second, the ET levels in the portal venous In subsequent studies using a canine 70% partial liver blood were significantly higher than the levels in the hepatic ischemic model (60 minutes), we found that an intravevenous blood of the ischemic lobe. Third, the intravenous nous injection of TAK-044 (3 mg/kg) before ischemia sigadministration of ET monoclonal antibody (0.5 mg/kg) before nificantly inhibited the release of serum liver enzymes reperfusion resulted in a significant inhibition of the postre-(aspartate transaminase, alanine transaminase, mitoperfusion release of the liver enzymes and improved the indochondrial glutamic oxaloacetic transaminase, and an incyanine green dye retention rate at 15 minutes. Thus, ET-1 is crease of indocyanine green retention rate after reperfustrongly involved in the pathogenesis of ischemia-reperfusion sion, compared with the control group. Elevation of the injury. portal venous pressure was also suppressed signifiRecently, cyclic pentapeptides, BE-18257B, BQ-123, and cantly during the portal triad occlusion, and a rapid res-BQ-153, 7,8 and a tripeptide, FR139317, 9 have been shown to toration of oxygen pressure in the liver tissue after rebe specific for ET A receptor antagonists, while IRL 1038, 10 perfusion was observed in the TAK-044-treated group. BQ-788, 11 and RES-701-1 12 were specific for ET B receptor anMorphometric analysis revealed that the hepatocyte tagonists. These antagonists are considered to be useful for swelling and sinusoidal contraction 1 hour after reperfustudying ET A -or ET B -mediated responses separately. It resion were significantly less severe in the treated group mains to be clarified if these agents are useful in the protecthan in the control group. The sludging of erythrocytes tion of ET-1-induced liver ischemia-reperfusion injury since in the sinusoidal lumens was also minimal in the treated ET-1 has high affinity for both ET A and ET B receptors, which group. In conclusion, the significant suppression of heare responsible for ET-1-induced vaso...