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Am J Physiol Gastrointest Liver Physiol 290: G813-G826, 2006. First published December 8, 2005; doi:10.1152/ajpgi.00306.2005
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LIVER AND BILIARY TRACT

Adrenergic receptor agonists prevent bile duct injury induced by adrenergic denervation by increased cAMP levels and activation of Akt

Shannon Glaser,1,2 Domenico Alvaro,6 Heather Francis,1 Yoshiyuki Ueno,5 Luca Marucci,7 Antonio Benedetti,7 Sharon De Morrow,1 Marco Marzioni,7 Maria Grazia Mancino,6 Jo Lynne Phinizy,1 Ramona Reichenbach,4 Giammarco Fava,3 Ryun Summers,3 Julie Venter,3 and Gianfranco Alpini2,3,4

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

Submitted 4 July 2005 ; accepted in final form 20 November 2005

Loss of parasympathetic innervation after vagotomy impairs cholangiocyte proliferation, which is associated with depressed cAMP levels, impaired ductal secretion, and enhanced apoptosis. Agonists that elevate cAMP levels prevent cholangiocyte apoptosis and restore cholangiocyte proliferation and ductal secretion. No information exists regarding the role of adrenergic innervation in the regulation of cholangiocyte function. In the present studies, we investigated the role of adrenergic innervation on cholangiocyte proliferative and secretory responses to bile duct ligation (BDL). Adrenergic denervation by treatment with 6-hydroxydopamine (6-OHDA) during BDL decreased cholangiocyte proliferation and secretin-stimulated ductal secretion with concomitant increased apoptosis, which was associated with depressed cholangiocyte cAMP levels. Chronic administration of forskolin (an adenylyl cyclase activator) or beta1- and beta2-adrenergic receptor agonists (clenbuterol or dobutamine) prevented the decrease in cholangiocyte cAMP levels, maintained cholangiocyte secretory and proliferative activities, and decreased cholangiocyte apoptosis resulting from adrenergic denervation. This was associated with enhanced phosphorylation of Akt. The protective effects of clenbuterol, dobutamine, and forskolin on 6-OHDA-induced changes in cholangiocyte apoptosis and proliferation were partially blocked by chronic in vivo administration of wortmannin. In conclusion, we propose that adrenergic innervation plays a role in the regulation of biliary mass and cholangiocyte functions during BDL by modulating intracellular cAMP levels.

apoptosis; bile ducts; growth; nerves; secretin


Address for reprint requests and other correspondence: G. Alpini, Central Texas Veterans Health Care System and The Texas A & M Univ. System Health Science Center College of Medicine, Temple, TX 76504 (e-mail: galpini{at}tamu.edu)




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