The cytoprotective effect of prostacyclin (PGI2) was examined using hypoxic cat livers perfused with Krebs-Henseleit buffer at constant flow. PGI2 infusion (10 ng . g-1 . min-1) showed no direct vasodilator effect on the hepatic circulation under conditions of normoxia or hypoxia, as studied by changes in perfusion pressure. Hypoxia induced a marked decline in hepatic oxygen consumption, an increase in perfusion pressure, and in perfusate cathepsin D and LDH activity in the hepatic effluent indicating lysosomal and cytoplasmic leakage. Tissue samples, obtained 150 min after hypoxic perfusion, showed higher percent-free cathepsin values (82 +/- 4%, mean +/- SE, 7 livers, P less than 0.025) compared to that of normoxia (58 +/- 4). Phagocytic activity, measured by the clearance rate of colloidal carbon particles, was also depressed by hypoxia. PGI2 infusion significantly inhibited the posthypoxia leakage of liver cathepsin D and LDH into the recirculating perfusate, restored the percent-free cathepsin D to 64 +/- 3%, and preserved the phagocytic activity during hypoxia, indicating preservation of lysosomal and cytoplasmic membrane integrity and Kupffer cell phagocytic function. The preservation of lysosomal integrity by PGI2 was further confirmed by electron microscopy. It is evident that PGI2 has a significant protective effect in hypoxic hepatocytes that may not be related to its vasodilation and inhibition of platelet aggregation.