7 NO is able to exert dichotomous Tipifarnib effects under physiological and pathological conditions.8 The induction of iNOS in phagocytic cells by a variety of noxious stimuli may lead to high and sustained levels of NO, which may cause cytotoxicity through nitrosative stress.9 At low or physiological concentrations, however, NO has been reported to defend cells from apoptosis10,

11 and to modulate a vast variety of processes, including neurotransmission, relaxation of smooth muscle, and stimulation of different secretions such as bile flow and biliary glutathione secretion,6 intestinal Cl− secretion, and pancreatic HCO secretion.7, 12, 13 NO has a half-life of only 0.05 to 1.8 milliseconds.14 The major immediate breakdown product is nitrite (NO). LDK378 price This substance, like its nitrate derivative NO, is devoid of biological activity at physiological concentrations.15 Recent studies have shown that, once NO is generated, it is not merely degraded

into these products but can be transported by thiol nitrosation of cysteinyl residues of proteins (especially albumin) and low-molecular-weight thiols, of which glutathione is the major NO transport species.16 In the form of nitrosothiols (SNOs), the half-life of NO is prolonged, and it is able to act outside the site of synthesis,15 where it influences cellular signal transduction pathways and behaves as a critical modulator of many physiological processes. Here we show that the infusion of UDCA promotes hepatic synthesis and biliary secretion of S-nitrosoglutathione (GSNO). Biliary transport of this compound is partly mediated by the canalicular carrier ATP–binding cassette C2 (ABCC2)/multidrug resistance–associated protein 2 (Mrp2). GSNO activates protein kinase B (AKT) in cholangiocytes, protects against apoptosis, and enhances UDCA-induced ATP

release to the lumen and thus contributes to stimulation of ductal secretion. These findings illustrate the fact that hepatocytes produce a mediator able to act downstream in the biliary tree and convey NO signals to cholangiocytes to enhance choleresis. ABC, adenosine triphosphate–binding medchemexpress cassette; AE2, anion exchanger 2; AKT, protein kinase B; ATP, adenosine triphosphate; BSO, buthionine sulfoximine; BV, beauvericin; BW, body weight; CA, cholic acid; GSNO, S-nitrosoglutathione; iNOS, inducible nitric oxide synthase; IPRL, isolated and perfused rat liver; isPRL, in situ perfused rat liver; L-NAME, Nω-nitro-L-arginine methyl ester; LMw-SNO, low-molecular-weight nitrosothiol; LY294002, 2-morpholin-4-yl-8-phenylchromen-4-one; Mrp2, multidrug resistance–associated protein 2; MS, mass spectrometry; NO, nitric oxide; NOS, nitric oxide synthase; NRC, normal rat cholangiocyte; PI3K, phosphoinositide 3-kinase; SNO, nitrosothiol; TR−, transport mutant; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid; WT, wild type.