ENDOTHELIN-STIMULATED NITRIC-OXIDE PRODUCTION IN THE ISOLATED KUPFFERCELL

Endothelin (ET) is a potent peptide mediator exhibiting a wide variety of effects in both the parenchymal and nonparenchymal hepatic cells. In the Kupffer cell, ET activates several transmembrane signaling path ways to generate numerous second messengers including the phospholipas e C-generated products inositol-1,4,5-trisphosphate and diacylglycerol and the cyclooxygenase product prostaglandin E-2 via specific ETB-typ e receptors. In addition to these findings, we have now demonstrated t hat endothelin stimulates the production of nitric oxide (NO) in the K upffer cell in a time-and concentration-dependent manner. Western blot analysis indicates that ET-stimulated NO production occurs though act ivation of the inducible form of the nitric oxide synthase enzyme. The se findings have important implications as the stimulation of NO produ ction by ET may be part of the physiological response to inflammation or infection, Elevated levels of ET and NO have been found to be assoc iated with numerous hepatic pathophysiological conditions that may con tribute to derangements in the vascular system seen in these condition s. (C) 1997 Academic Press.