In the present study, we clarified how the NaCl gradient across the epithelial cells regulates the paracellular ion conductance. Under isotonic conditions, the absorption-directed NaCl gradient elevated the paracellular conductances of Na+ (G(Na)) and Cl- (G(C1)), while the secretion-directed NaCl gradient diminished the GNa and G(Cl). We further investigated the paracellular ionic conductances of NMDG (G(NMDG)) and gluconate (G(gluconate)) by replacing Na+ with NMDG or Cl- with gluconate. The GNMDG was lower than the GNa and the replacement of Na+ with NMDG decreased the G(Cl). The Ggluconate was lower than the GC1 and the replacement of Cl- with gluconate also decreased the GNa. These observations suggest the interaction of cations and anions on paracellular ionic conductances; i.e., cations affect paracellular anion conductances and anions affect paracellular cation conductances. (C) 2007 Elsevier Inc. All rights reserved.