Atrial natriuretic peptide (ANP) prevents Kupffer cell-induced injury in rat liver

The generation of reactive oxygen species (ROS) by activated Kupffer cells (KC) contributes to liver injury following liver preservation, shock or end otoxemia. Atrial natriuretic peptide (ANP) protects the liver against ische mia-reperfusion injury, suggesting a possible modulation of KC-mediated cyt otoxicity. Therefore, we investigated the mechanism of cytoprotection by AN P during KC activation in perfused rat livers of male Sprague-Dawley rats. Activation of KC by zymosan (150 mu g/ml) resulted in considerable cell dam age as assessed by the sinusoidal release of lactate dehydrogenase. Cell da mage was almost completely prevented by superoxide dismutase (50U/ml)/catal ase (150/ml), indicating ROS-related liver injury. ANP (200nM) reduced the KC induced injury via the guanylyl cyclase-coupled A receptor (GC-A recepto r) and cyclic guanosine monophosphate (cGMP): expression of the GC-A recept or was found in hepatocytes, endothelial cells and Kupffer cells, and the c GMP analogue 8-Br-cGMP (50 mu M) was as potent as ANP in protecting from zy mosan-induced cell damage. Furthermore, ANP and 8-Br-CGMP reduced oxidative cell damage following infusion of H2O2 (500 mu M). In contrast, ANP did no t interfere with O2(-.) formation of isolated KC. In conclusion, ANP protects the liver against KC-related oxidant stress via the GC-A receptor and cGMP without affecting the vital host response funct ion of these cells.