The alpha2-adrenergic receptor agonist UK 14,304 inhibits secretin-stimulated ductal secretion by downregulation of the cAMP system in bile duct-ligated rats.
Secretin stimulates ductal secretion by activation of cAMP --> PKA --> CFTR --> Cl(-)/HCO(3)(-) 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(-)/HCO(3)(-) 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(-)/HCO(3)(-) 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.
Francis
Heather
H
Central Texas Veterans Health Care System, The Texas A & M University System Health Science Center College of Medicine, Medical Research Bldg, Temple, TX 76504, USA.
LeSage
Gene
G
DeMorrow
Sharon
S
Alvaro
Domenico
D
Ueno
Yoshiyuki
Y
Venter
Julie
J
Glaser
Shannon
S
Mancino
Maria Grazia
MG
Marucci
Luca
L
Benedetti
Antonio
A
Alpini
Gianfranco
G
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001639:Bicarbonates / Q000378:metabolism; D001646:Bile / Q000378:metabolism; D001649:Bile Duct Diseases / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery; D000068438:Brimonidine Tartrate; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D012633:Secretin / Q000494:pharmacology*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D015016:Yohimbine / Q000494:pharmacology
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000889:Anti-Arrhythmia Agents; D001639:Bicarbonates; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D012633:Secretin; D015016:Yohimbine; D000068438:Brimonidine Tartrate; D000584:Amiloride; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C039614:ethylisopropylamiloride