Adrenergic receptor agonists prevent bile duct injury induced by adrenergic denervation by increased cAMP levels and activation of Akt.
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 beta(1)- and beta(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.
Glaser
Shannon
S
Division of Research and Education, College of Medicine, Scott and White Hospital and The Texas A & M University System Health Science Center, Temple, 76504, USA.
Alvaro
Domenico
D
Francis
Heather
H
Ueno
Yoshiyuki
Y
Marucci
Luca
L
Benedetti
Antonio
A
De Morrow
Sharon
S
Marzioni
Marco
M
Mancino
Maria Grazia
MG
Phinizy
Jo Lynne
JL
Reichenbach
Ramona
R
Fava
Giammarco
G
Summers
Ryun
R
Venter
Julie
J
Alpini
Gianfranco
G
D000322:Adrenergic Agonists / Q000494:pharmacology*; D000818:Animals; D001649:Bile Duct Diseases / Q000503:physiopathology / Q000517:prevention & control*; D001652:Bile Ducts / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D003714:Denervation; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D008297:Male; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D011941:Receptors, Adrenergic / Q000378:metabolism*
D000322:Adrenergic Agonists; D011941:Receptors, Adrenergic; D000242:Cyclic AMP; D051058:Oncogene Protein v-akt