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Am J Physiol Cell Physiol 293: C1252-C1262, 2007. First published July 18, 2007; doi:10.1152/ajpcell.00031.2007
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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

The {alpha}2-adrenergic receptor agonist UK 14,304 inhibits secretin-stimulated ductal secretion by downregulation of the cAMP system in bile duct-ligated rats

Heather Francis,4,* Gene LeSage,7,* Sharon DeMorrow,2,4 Domenico Alvaro,5 Yoshiyuki Ueno,8 Julie Venter,2 Shannon Glaser,2,4 Maria Grazia Mancino,5 Luca Marucci,6 Antonio Benedetti,6 and Gianfranco Alpini1,2,3

1Central Texas Veterans Health Care System, 2Department of Medicine, and 3Systems Biology and Translational Medicine, 4Division of Research and Education, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, Texas; 5University of Rome "La Sapienza," Polo Pontino, Latina; 6Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy; 7The University of Texas Houston Medical School, Houston, Texas; and 8Division of Gastroenterology, Tohoku University School of Medicine, Aobaku, Sendai, Japan

Submitted 22 January 2007 ; accepted in final form 16 July 2007

Secretin stimulates ductal secretion by activation of cAMP -> PKA -> CFTR -> Cl–/HCO3– exchanger in cholangiocytes. We evaluated the expression of {alpha}2A-, {alpha}2B-, and {alpha}2C-adrenergic receptors in cholangiocytes and the effects of the selective {alpha}2-adrenergic agonist UK 14,304, on basal and secretin-stimulated ductal secretion. In normal rats, we evaluated the effect of UK 14,304 on bile and bicarbonate secretion. In bile duct-ligated (BDL) rats, we evaluated the effect of UK 14,304 on basal and secretin-stimulated 1) bile and bicarbonate secretion; 2) duct secretion in intrahepatic bile duct units (IBDU) in the absence or presence of 5-(N-ethyl-N-isopropyl)amiloride (EIPA), an inhibitor of the Na+/H+ exchanger isoform NHE3; and 3) cAMP levels, PKA activity, Cl– efflux, and Cl–/HCO3– exchanger activity in purified cholangiocytes. {alpha}2-Adrenergic receptors were expressed by all cholangiocytes in normal and BDL liver sections. UK 14,304 did not change bile and bicarbonate secretion of normal rats. In BDL rats, UK 14,304 inhibited secretin-stimulated 1) bile and bicarbonate secretion, 2) expansion of IBDU luminal spaces, and 3) cAMP levels, PKA activity, Cl– efflux, and Cl–/HCO3– exchanger activity in cholangiocytes. There was decreased lumen size after removal of secretin in IBDU pretreated with UK 14,304. In IBDU pretreated with EIPA, there was no significant decrease in luminal space after removal of secretin in either the absence or presence of UK 14,304. The inhibitory effect of UK 14,304 on ductal secretion is not mediated by the apical cholangiocyte NHE3. {alpha}2-Adrenergic receptors play a role in counterregulating enhanced ductal secretion associated with cholangiocyte proliferation in chronic cholestatic liver diseases.

bicarbonate secretion; chloride efflux; gastrointestinal hormones; intrahepatic biliary epithelium; protein kinase A


Address for reprint requests and other correspondence: G. Alpini, Central Texas Veterans Health Care System, The Texas A & M Univ. System Health Science Center College of Medicine, Medical Research Bldg., 702 SW H.K. Dodgen Loop, Temple, TX 76504 (e-mail: galpini{at}tamu.edu or galpini{at}medicine.tamhsc.edu)






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