Arginine is an important substrate in health and disease. It is a commonly held view that arginase-1 release from injured erythrocytes and hepatocytes leads to arginine breakdown. However, the true relationship between plasma arginase-1 concentration and activity has remained unaddressed. Blood was sampled from patients undergoing liver resection, a known cause of hepatocyte injury and arginase-1 release, to determine arginase-1, arginine and ornithine plasma levels. Arginase activity was assessed in vitro by measuring changes in arginine and ornithine plasma levels during incubation of plasma and whole blood samples at 37 degrees C. Arginase-1 plasma levels increased 8 to 10-fold during liver resection, while arginine and ornithine levels remained unchanged. In accordance with these in vivo findings, arginine and ornithine levels remained unchanged in plasma incubated at 37 degrees C irrespective of arginase-1 concentration. In contrast, arginine plasma levels in whole blood decreased significantly during incubation, with ornithine increasing stoichiometrically. These changes were irrespective of arginase-1 plasma levels and were explained by arginase activity, present in intact erythrocytes. Next, plasma samples with 1000-fold normal arginase-1 concentrations were obtained from patients undergoing cadaveric liver transplantation. Here, a significant decrease of arginine plasma levels occurred in vivo and in vitro. In contrast with commonly held views, moderately increased arginase-1 plasma levels do not affect plasma arginine. Very high plasma arginase-1 levels are required to induce potential clinical relevant effects.