Possible Regulation of P-Glycoprotein Function by Adrenergic Agonists II: Study with Isolated Rat Jejunal Sheets and Caco-2 Cell monolayers

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.