NO synthase and have the capacity to produce large amounts Nitric oxide (NO) modulates several metabolic funcof NO in response to lipopolysaccharides and inflammatory tions in hepatocytes, but the role of NO in bile secretion cytokines. [3][4][5][6] NO donors, such as sodium nitroprusside (SNP) has not been clearly defined. In the present study, we and S-nitroso-acetyl-penicillamine (SNAP), spontaneously examined the effects of NO on bile flow and biliary release NO in aqueous solution and have been used widely to HCO 0
3 and glutathione excretion in the isolated perfused study NO effects. [7][8][9][10][11][12][13][14] In liver, NO regulates hepatic vascular rat liver and assessed the role of guanosine 3,5-cyclic tone 15 and modulates various metabolic functions in hepatomonophosphate (cGMP) in mediating these effects. The cytes, such as albumin synthesis, 8 gluconeogenesis, 16 mito-NO donors sodium nitroprusside (SNP) and S-nitrosochondrial respiration, 17,18 and cytochrome P450 activity. 11 In acetyl-penicillamine stimulated bile flow and increased the gastrointestinal tract, NO may be involved in the regulaboth HCO 0 3 and glutathione excretion. Increases in bile tion of pancreatic secretion. 12 However, the effects of NO on flow were linearly related to increases in biliary glutabile secretion are still unclear. thione concentration and output (P õ .0001), which were NO has been shown to affect a number of functions in almost entirely caused by glutathione disulfide, whereas hepatocytes that may be important for bile formation. Exogethe excretion of reduced glutathione remained unnous NO donors inhibit bile canalicular contraction 13 and changed. NO donors increased cGMP concentrations in increase paracellular permeability 19 in isolated rat hepatobile and perfusate, and the membrane-permeant cGMP cyte couplets, effects that would be expected to decrease bile analogue dibutyryl cGMP was also found to stimulate flow. 20 In contrast, membrane-permeant analogues of guanobile flow and HCO 0 3 excretion. However, in contrast to sine 3,5-cyclic monophosphate (cGMP) have been shown to the NO donors, dibutyryl cGMP did not increase glutaincrease bile flow and HCO 0 3 excretion in isolated perfused thione excretion. Furthermore, the NO donors failed to rat livers (IPRL) without affecting bile acid excretion or the stimulate bile flow in mutant TR 0 rats in which the canatranscytotic pathway. 21,22 Because NO stimulates soluble licular transport of glutathione and glutathione conjuguanylate cyclase to produce cGMP in many cells, 1,2 including gates is deficient, although dibutyryl cGMP increased hepatocytes, 19,23 NO might instead be expected to induce a bile flow and HCO 0 3 excretion in the mutant rats as in cGMP-mediated choleresis. Therefore, the aims of the presnormals. These findings indicate that exogenous sources ent study were (1) to investigate the effects of NO on bile of NO increase bile acid-independent bile flow by stimuflow and on biliary HCO 0 3 and glutathione excretion, two malating glutathione disulfide excretion, effects that are jor determinants of bile acid-independent bile flow, 20 and (2) independent of cGMP. (HEPATOLOGY 1997;25:263-269.) to determine whether cGMP mediates these effects of NO on bile secretion. For these investigations, we used SNP or Nitric oxide (NO) is a diffusable mediator produced from SNAP as NO donors 7-14 and dibutyryl cGMP (DBcGMP) as a L-arginine by NO synthase in a range of cells and tissue types membrane-permeant cGMP analogue. We found that exogeand exerts a variety of physiological and pathophysiological nous sources of NO stimulate bile flow by enhancing glutathieffects. 1,2 NO is formed constitutively in low concentrations one disulfide excretion in IPRL and that these effects occur in neurons and endothelial cells. 1,2 Hepatocytes and nonpaindependently of cGMP-induced increases in HCO 0 3 excrerenchymal liver cells (e.g., Kupffer cells) possess an inducible tion. These findings may have important implications for the effects of acute or chronic increases of endogenous NO on bile formation and glutathione metabolism.