ET receptor blocker (TAK-044) and NO donor (FK409) were used to improve the hepatic microcirculation following ischemia-reperfusion injury. In the first experiment (60 minutes of ischemia), 15 dogs were divided into three groups: group A (control), saline; group B, TAK 5 mg/kg; and group C, FK 0.4 mg/kg. In the second experiment (90 minutes of ischemia), 38 dogs were divided into six groups that underwent 90 minutes of hepatic ischemia followed by reperfusion: group I (control), saline only; group II, TAK 5 mg/kg and FK 3.2 mg/kg; group III, TAK 5 mg/kg and FK 0.4 mg/kg; group IV, TAK 5 mg/kg; group V, FK 0.4 mg/kg; and group VI, FK3.2 mg/kg. All drugs were administered through the portal vein. Following 60 minutes of ischemia, both FK and TAK produced significant improvement in hepatic microcirculation and enzymatic status when compared with the control group. After 90 minutes of ischemia, low doses of FK and TAK significantly improved hepatic microcirculation and reduced portal pressure following reperfusion in group III compared with group I. Leakage of hepatic enzymes was prevented and tissue injury score was significantly lower in group III. In group VI, early protection was obtained to some extent; however, blood pressure was reduced significantly following reperfusion compared with group I. In contrast, hepatocellular function deteriorated and the tissue injury score was higher in group II animals. TAK pretreatment with low doses of FK provided the best protection for the hepatic microcirculation in ischemiareperfusion injury of the liver. (HEPATOLOGY 1998;28:782-788.)Reperfusion injury is an inevitable consequence of ischemia, produced iatrogenically during liver resection or organ preservation before transplantation surgery or as a disease process, such as after prolonged hypotensive shock. Little is known about the mechanism(s) of the injury, but the microcirculatory disturbance is central. 1,2 Microcirculatory disturbance involves two distinct mechanisms: ''no-reflow'' and ''reflow-paradox.'' The no-reflow phenomenon is the consequence of irreversible damage to the nutritive capillary endothelium following prolonged ischemia, whereas the reflow-paradox occurs after any length of ischemia and is carried out by leukocyte-endothelium interaction and release of toxic products including superoxide radicals from the ischemic tissue. Therefore, the length of ischemia (60 minutes or 90 minutes) might be crucial in determining the extent of microvascular injury in hepatic reperfusion injury.Recently, two major breakthroughs revealed the involvement of endothelin (ET) and nitric oxide (NO) in modulating hepatic blood flow after ethanol-and endotoxin-induced liver injury. 3,4 Ischemia led to release of ET, a potent vasoconstrictor, and also externalized the ET receptors in ischemic organs. [5][6][7] In experimental models, inhibition of the effect of ET during ischemia by anti-ET antibody or ET receptor blocker improved microcirculation and circumvented reperfusion injury of the liver. [8][9][10][11] However, us...