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Am J Physiol Gastrointest Liver Physiol 284: G683-G694, 2003. First published December 27, 2002; doi:10.1152/ajpgi.00302.2002
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Vol. 284, Issue 4, G683-G694, April 2003

Dopaminergic inhibition of secretin-stimulated choleresis by increased PKC-gamma expression and decrease of PKA activity

Shannon Glaser3, Domenico Alvaro6, Tania Roskams8, Jo Lynne Phinizy3, George Stoica7, Heather Francis3, Yoshiyuki Ueno5, Barbara Barbaro2, Marco Marzioni2, Jeremy Mauldin2, Sobia Rashid2, Maria Grazia Mancino6, Gene LeSage1, and Gianfranco Alpini1,2,4

Departments of 1 Internal Medicine and 2 Medical Physiology, 3 Division of Research and Education, Scott & White Hospital, Texas A&M University System Health Sciences Center, College of Medicine, and 4 Central Texas Veterans Health Care System, Temple, Texas 76504; 5 Department of Internal Medicine, Tohoku University School of Medicine, Aobaku, Sendai, Japan 980-8574; 6 Division of Gastroenterology, University of Rome, La Sapienza, Rome, Italy 00100; 7 Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, and 8 Department of Morphology and Molecular Pathology, University of Leuven, 3000 Leuven, Belgium

To determine the role and mechanisms of action by which dopaminergic innervation modulates ductal secretion in bile duct-ligated rats, we determined the expression of D1, D2, and D3 dopaminergic receptors in cholangiocytes. We evaluated whether D1, D2 (quinelorane), or D3 dopaminergic receptor agonists influence basal and secretin-stimulated choleresis and lumen expansion in intrahepatic bile duct units (IBDU) and cAMP levels in cholangiocytes in the absence or presence of BAPTA-AM, chelerythrine, 1-(5-isoquinolinylsulfonyl)-2-methyl piperazine (H7), or rottlerin. We evaluated whether 1) quinelorane effects on ductal secretion were associated with increased expression of Ca2+-dependent PKC isoforms and 2) increased expression of PKC causes inhibition of PKA activity. Quinelorane inhibited secretin-stimulated choleresis in vivo and IBDU lumen space, cAMP levels, and PKA activity in cholangiocytes. The inhibitory effects of quinelorane on secretin-stimulated ductal secretion and PKA activity were blocked by BAPTA-AM, chelerythrine, and H7. Quinelorane effects on ductal secretion were associated with activation of the Ca2+-dependent PKC-gamma but not other PKC isoforms. The dopaminergic nervous system counterregulates secretin-stimulated ductal secretion in experimental cholestasis.

intrahepatic biliary epithelium; bile flow; secretin receptor


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