ENDOTHELIN-1 IS INVOLVED IN THE PATHOGENESIS OF ISCHEMIA/REPERFUSION LIVER-INJURY BY HEPATIC MICROCIRCULATORY DISTURBANCES

Hepatic microcirculatory perturbation is observed after ischemia/reperfusion. Endothelin-1, a potent va- soconstrictive peptide, is known to modulate local circulation. This study was designed to examine whether endothelin-1 participates in the mechanism of microcirculatory disturbance and damage of the liver after ischemia/reperfusion. Ischemia in the median and left lateral lobes of the liver was induced for 60 min; it was followed by reperfusion for 24 hr. In some rats, endothelin-1 antiserum or control serum without endothelin-1-blocking activity was administered intravenously just before reperfusion. Rats were divided into three groups: an ischemia/reperfusion group that was injected with control serum, an endothelin-1 antiserum-treated group and a sham-operated group. Endothelin-1 concentrations in blood collected from the suprahepatic vena cava were measured before and after ischemia/reperfusion by use of a sandwich enzyme immunoassay. Index of blood volume in regional hepatic tissue and index of blood oxygenation in regional hepatic tissue were assessed with an organ reflectance spectrophotometry system before and at 5 min and 1, 2, and 24 hr after reperfusion. The endothelin-1 concentration in the ischemia/reperfusion group started to rise immediately at onset of reperfusion from basal values around 1 pg/ml and reached a value of 5 to 6 pg/ml 5 min after reperfusion; it was maintained at significantly high levels during the reperfusion period compared with the sham-operated group. Hepatic microcirculatory disturbance indicated by lowered index of blood volume in regional hepatic tissue and index of blood oxygenation in regional hepatic tissue levels was observed in the early phase of reperfusion in the ischemia/reperfusion group. Endothelin-1 antiserum injection diminished significantly the microcirculatory disturbance in the liver after ischemia/reperfusion. The serum ALT levels in the endothelin-1 antiserum-treated group 2 hr reperfusion were decreased by 40% to 50% compared with the nontreated group. Moreover, liver damage assessed histologically was reduced dramatically in the endothelin-1 antiserum-treated group. In conclusion, endothelin-1 appears to be involved in the microcirculatory disturbance and histological damage in the liver after ischemia/reperfusion. Blockade of endothelin-1 action may prevent liver injury after ischemia/reperfusion.