Endothelin-1 (ET-1) is known to stimulate glycogenolysis in perfused rat livers and isolated rat hepatocytes. To determine the potential action of endothelin's precursor, big endothelin-1 (big ET-1), isolated rat livers were perfused with big ET-1 in a non-recirculating system. Thereby, big ET-1 (10 nM) induced a maximally three-fold increase (P < 0.01 vs. basal values) in hepatic glucose production at 60 min, which was almost completely abolished by concomitant infusion of 50 microM phosphoramidon, a sensitive inhibitor of the enzymatic cleavage of big ET-1 to ET-1. The corresponding incremental release of glucose by big ET-1 was 20.9-fold higher in the absence of phosphoramidon than in its presence (P < 0.01). In contrast, phosphoramidon did not inhibit hepatic glucose production induced by ET-1 (1 nM), glucagon (1 nM), and phenylephrine (5 microM). Glycogenolytic responses to 1 nM ET-1 (P < 0.01), but not to 1 nM glucagon (n.s.) were blocked by indomethacin (100 microM), indicating that prostaglandin release by non-parenchymal cells is at least in part involved in the hepatic ET-1 action. In conclusion, big ET-1 induces hepatic glucose release, which is suggested to depend on intrahepatic conversion of big ET-1 to ET-1 by a phosphoramidon-sensitive pathway.