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This Article Full Text Full Text (PDF) All Versions of this Article: 290/4/G813    most recent 00306.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Glaser, S. Articles by Alpini, G. Search for Related Content PubMed PubMed Citation Articles by Glaser, S. Articles by Alpini, G.

LIVER AND BILIARY TRACT

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

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 ₁- and ₂-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

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