Possible Regulation of P-Glycoprotein Function by Adrenergic Agonists II: Study with Isolated Rat Jejunal Sheets and...

To clarify the regulation of drug absorption by the enteric nervous system, we investigated how adrenergic agonists (adrenaline (ADR), clonidine (CLO), dobutamine (DOB)) and dibutyryl cAMP (DBcAMP) affected P-glycoprotein (P-gp) function by utilizing isolated rat jejunal sheets and Caco-2 cell monolayers. ADR and CLO significantly decreased the secretory transport (P_app^total) of rhodamine-123 and tended to decrease the transport via P-gp (P_app^P-gp) and passive transport (P_app^passive). In contrast, DBcAMP significantly increased and DOB tended to increase P_app^total and both tended to increase P_app^P-gpand P_app^passive. Changes in P-gp expression on brush border membrane by adrenergic agonists and DBcAMP were significantly correlated with P_app^P-gp, while P-gp expression was not changed in whole cell homogenates, suggesting that the trafficking of P-gp would be responsible for its functional changes. P_app^passive was inversely correlated with transmucosal or transepithelial electrical resistance, indicating that adrenergic agonists affected the paracellular permeability. Adrenergic agonists also changed cAMP levels, which were significantly correlated with P_app^P-gp. Furthermore, protein kinase A (PKA) or PKC inhibitor significantly decreased P_app^P-gp in Caco-2 cell monolayers, suggesting that they would partly contribute to the changes in P-gp activity. In conclusion, adrenergic agonists regulated P-gp function and paracellular permeability, which would be caused via adrenoceptor stimulation.