Submitted on January 22, 2007
Accepted on July 16, 2007
THE 
-2 ADRENERGIC RECEPTOR AGONIST, UK 14,304, INHIBITS SECRETIN-STIMULATED DUCTAL SECRETION BY DOWNREGULATION OF THE cAMP SYSTEM IN BILE DUCT LIGATED RATS
Heather Francis1, Gene D LeSage2, Sharon DeMorrow3, Domenico Alvaro4, Yoshiyuki Ueno5, Julie Venter6, Shannon Glaser7, Maria Grazia Mancino8, Luca Marucci9, Antonio Benedetti9, and Gianfranco Alpini10*
1 R&E, Scott & White, Temple, Texas, United States
2 Gastroenterology, Medicine, The University of Texas Houston Medical School, Houston, Houston, Texas, United States
3 R&E, Scott & White Hospital, Temple, Texas, United States
4 Medicine, University of Rome "La Sapienza", Polo Pontino, Latina, Italy, Rome, Italy
5 Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
6 Medicine, The Texas A&M University System Health Science Center, College of Medicine, Temple, Texas, United States
7 Medicine and Division of Research and Education, Scott and White Memorial Hospital, Temple, Texas, United States
8 Gastroenterology, University La Sapienza, Rome, Italy
9 Gastroenterology, University of Ancona, Ancona, Marche, Italy
10 Medicine and Systems Biology and Translational Medicine, Central Texas Veterans Health Care System and The Texas A & M University System Health Science Center College of Medicine, Temple, Texas, United States; Internal Medicine and Medical Physiology, Central Texas Veterans Health Care System and The Texas A & M University System Health Science Center College of Medicine, 702 HK Dodgen Loop, Temple, Texas, 76504, United States
* To whom correspondence should be addressed. E-mail: galpini{at}tamu.edu.
Secretin stimulates ductal secretion by activation of cAMP==>PKA==>CFTR==>Cl-/HCO3- exchanger in cholangiocytes. We evaluated the expression of 
-2A, -2B, and -2C adrenergic receptors in cholangiocytes and the effects of the selective -2 adrenergic agonist, UK14,304, on basal and secretin-stimulated ductal secretion. In normal rats, we evaluated the effect of UK14,304 on bile and bicarbonate secretion. In bile duct ligated (BDL) rats, we evaluated the effect of UK14,304 on basal and secretin-stimulated: (i) bile and bicarbonate secretion; (ii) duct secretion in intrahepatic bile duct units (IBDU) in the absence or presence of EIPA, an inhibitor of the sodium/hydrogen exchanger isoform, NHE3; and (iii) cAMP levels, PKA activity, Cl- efflux and Cl-/HCO3- exchanger activity in purified cholangiocytes. -2 adrenergic receptors were expressed by all cholangiocytes in normal and BDL liver sections. UK14,304 did not change bile and bicarbonate secretion of normal rats. In BDL rats, UK14,304 inhibited secretin-stimulated: (i) bile and bicarbonate secretion; (ii) expansion of IBDU luminal spaces; and (iii) 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 UK14,304. In IBDU pretreated with EIPA, there was no significant decrease in luminal space after removal of secretin either in the absence or presence of UK14,304. The inhibitory effect of UK14,304 on ductal secretion is not mediated by the apical cholangiocyte NHE3. -2 adrenergic receptors play a role in counter-regulating enhanced ductal secretion associated with cholangiocyte proliferation in chronic cholestatic liver diseases.
