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Nitric oxide blocks bile canalicular contraction by inhibiting inositol trisphosphate-dependent calcium mobilization

Authors
Journal
Gastroenterology
0016-5085
Publisher
Elsevier
Publication Date
Volume
108
Issue
3
Identifiers
DOI: 10.1016/0016-5085(95)90459-x
Keywords
  • Liver
  • Pancreas
  • And Biliary Tract
Disciplines
  • Chemistry
  • Medicine

Abstract

Abstract Background/Aims : The biochemical mechanism of bile canalicular contraction is similar to that of smooth muscle contraction. Contraction follows inositol-1,4,5-trisphosphate (InsP 3)-dependent Ca 2+ release, which activates actin-myosin interactions. Nitric oxide is a myorelaxant through the actions of 5′-cyclic guanosine monophosphate (cGMP) and is produced in hepatocytes exposed to endotoxin and cytokines. The aim of this study was to investigate the effect of nitric oxide on canalicular contraction and to determine the mechanism by which cGMP interferes with the contractile signal. Methods : The canalicular motility in rat hepatocyte doublets was measured by microscopic image analysis, and intracellular Ca 2+ was measured by fluorescence microscopy. cGMP and InsP 3 were determined by radio-immunoassay and high-pressure liquid chromatography. Ca 2+ release from liver homogenate was measured by filtration and superfusion assays. Results : Compounds that release nitric oxide stimulated hepatocellular production of cGMP and prevented agonist-induced contraction by inhibiting the increase in intracellular Ca 2+. The cGMP analogue bromo-cGMP prevented contraction and the increase in Ca 2+. Bromo-cGMP marginally decreased InsP 3 production. cGMP blocked InsP 3-dependent Ca 2+ release from internal stores. Conclusions : These findings suggest that nitric oxide interferes with Ca 2+ signals by cGMP-mediated inhibition of the InsP 3 receptor/Ca 2+ channel and that hepatocellular production of nitric oxide may be cholestatic by impairing canalicular motility.

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