MODULATION OF INTESTINAL PARACELLULAR PERMEABILITY BY INTRACELLULAR MEDIATORS AND CYTOSKELETON

The influence of cytoskeletal inhibitors (cytochalasin E and colchicin e) and intracellular mediators (cAMP, Ca2+ and protein kinase C) in th e control of paracellular permeability to mannitol has been examined i n rat jejunum in Ussing-type chambers. Cytoskeletal inhibitors, cytoch alasin E (20 mu mol.L-1) or colchicine (0.5 mmol.L-1), when present in mucosal, serosal, or in both mediums, significantly increase unidirec tional mannitol fluxes. Exposure of mucosal and serosal intestinal sur face to 10 mmol.L-1 theophylline or 1 mmol.L-1 cyclic AMP analogue for raising the intracellular cAMP enhances paracellular permeability. In Ca2+-free physiological medium passive permeability strongly increase s. Alterations of cytosolic Ca2+ levels induced by the Ca2+ ionophore A23187 (20 mu mol.L-1) or by 0.3 mmol.L-1 TMB-8, a Ca2+ releasing inhi bitor from the intracellular stores, enhance mannitol flux. Addition o f the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, which activa tes protein kinase C (PKC), also induces a large increase in the intes tinal permeability to mannitol. These results provide evidence that ti ght junctions and consequently epithelial paracellular permeability ca n be physiologically controlled by intracellular mediators (Ca2+, cAMP , and PKC) probably through modulation of the cytoskeleton activity.