Dalteparin reduces ischemia/reperfusion-induced liver injury in rats by increasing the hepatic tissue level of prostacyclin

Dalteparin, a low molecular weight heparin, is an anticoagulant that shows less frequency of bleeding than regular heparin. Ischemia/reperfusion (I/R)-induced organ injury is a pathologic condition associated with shock or hepatic transplantation. Since intravascular coagulation is frequently associated with these pathologic conditions, dalteparin is used to treat such disease states. However, whether dalteparin reduces the I/R-induced organ injury is not known. We examined this possibility using a rat model of I/R-induced liver injury. Male Wistar rats were subjected to 60-min ischemia and the subsequent reperfusion. Pretreatment with dalteparin (300 anti-FXa IU/kg) reduced I/R-induced liver injury. The I/R-induced decrease in the hepatic tissue blood flow was inhibited by dalteparin. Hepatic tissue levels of tumor necrosis factor (TNF)-α and neutrophil accumulation were increased after I/R. Dalteparin significantly attenuated these increases. Neither regular heparin nor DX-9065a, a selective inhibitor of FXa, showed any protective effects. Dalteparin inhibited neither monocytic TNF-α production nor neutrophil activation in vitro. Dalteparin increased the hepatic levels of prostacyclin, which reduces the liver injury by inhibiting neutrophil activation. Pretreatment of animals with indomethacin completely abrogated the protective effects of dalteparin. However, dalteparin did not increase the endothelial production of prostacyclin in vitro. The dalteparin-induced increases in hepatic tissue levels of prostacyclin were not observed when animals were pretreated with capsazepine, an inhibitor of vanilloid receptor-1 of the capsaicin-sensitive sensory neurons (CSSN) that increase the tissue level of prostacyclin upon being stimulated. Hepatic tissue levels of calcitonin gene-related peptide (CGRP), which is released from CSSN, were significantly increased by dalteparin. The protective effects induced by dalteparin were not observed in animals pretreated with CGRP 8–37, an antagonist of CGRP, as well as capsazepine. Administration of CGRP produced effects similar to those of dalteparin. These results strongly suggest that dalteparin might reduce the I/R-induced liver injury by increasing the hepatic tissue level of prostacyclin through the stimulation of CSSN. The dalteparin-induced effects could not be explained by its anticoagulant effects.