Probenecid affects chloride secretion in canine tracheal epithelium

The effects of probenecid on the electrophysiology, ion transport properties, and permeability characteristics of the canine tracheal epithelium mounted in Ussing chambers were studied. Mucosal addition of probenecid had 2 effects: at low concentrations (0.1 to 0.5 mM), probenecid increased short-circuit current (Isc) and net Cl secretion, whereas higher concentrations (5 and 10 mM) decreased Isc and net Cl secretion; 1 mM probenecid had no effect. The change in Isc was accounted for entirely by the change in the net Cl secretion. The effects were rapidly reversible and even after prolonged exposure were not associated with any change in the paracellular pathway as evidenced by mannitol fluxes. Submucosal addition of probenecid produced a significant decrease in Isc and net Cl secretion only at 10 mM, and the effect was delayed, suggesting movement of some of the probenecid into the mucosal bath. We conclude from these experiments that probenecid at concentrations greater than 1 mM inhibits Cl secretion in canine tracheal epithelium; the effect is primarily from the mucosal side and is reversible. Because probenecid is structurally related to a group of analogs of benzoic acid that inhibit the Cl conductance at the apical membrane, we suggest that probenecid might also block the electrically conductive Cl exit pathway in the apical cell membrane.