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Abstract 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 Ca 2+ -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 Ca 2+ -dependent PKC-γ but not other PKC isoforms. The dopaminergic nervous system counterregulates secretin-stimulated ductal secretion in experimental cholestasis. intrahepatic biliary epithelium bile flow secretin receptor Footnotes This work was supported by a Scott & White Hospital grant and the Texas A&M University System (to G. LeSage and G. Alpini), by a Scott & White Hospital grant (to S. Glaser), by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-54208 (to G. LeSage), by a Veterans Affairs Merit Award and National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-58411 (to G. Alpini), and by MURST Grant MM06215421/2 progetto nazionale 2000 (to D. Alvaro). Address for reprint requests and other correspondence: G. Alpini, Associate Professor, Internal Medicine and Medical Physiology, The Texas A&M University System, Health Sciences Center COM and Central Texas Veterans Health Care System, 702 SW H. K. Dodgen Loop, Temple, TX 76504 (E-mail: galpini@tamu.edu ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. First published December 27, 2002;10.1152/ajpgi.00302.2002 Copyright © 2003 the American Physiological Society
AJP - Gastrointestinal and Liver Physiology – The American Physiological Society
Published: Apr 1, 2003
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