THE α-2 ADRENERGIC RECEPTOR AGONIST, UK14,304, 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/HCO3 exchanger in cholangiocytes. We evaluated the expression of α-2A, α-2B, and α-2C adrenergic receptors in cholangiocytes and the effects of the selective α-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. α-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 secretinstimulated: (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. α-2 adrenergic receptors play a role in counter-regulating enhanced ductal secretion associated with cholangiocyte proliferation in chronic cholestatic liver diseases. Page 3 of 50