The effects of theophylline and triaminopyrimidine on the passive permeability of Na+ and Cl- across sheets of rabbit ileum treated with 0.1 mM-ouabain were examined by determining the NaCl: mannitol dilution potentials, K+:Na+; choline: Na+ and SO24-:Cl- biionic potentials. The results indicate (a) that triaminopyrimidine reduces paracellular Na+ and K+ permeability without affecting Cl- permeability and (b) that theophylline increases Cl- permeability without affecting Na+ permeability and (c) that neither theophylline nor triaminopyrimidine interfere with each other's action. This is further evidence consistent with separate routes for paracellular Na+ and Cl- movement. 2. Electrical resistance changes across sheets of actively transporting rabbit ileum were measured as a function of time in various conditions. Theophylline has a biphasic effect on resistance. Initially it decreases resistance from 56 omega cm2 (control) to 40 omega cm2. In the ensuing 30 min, resistance rises to 50 omega cm2; whereas it falls to 30 omega cm2 in controls. When theophylline is present, with triaminopyrimidine, or with galactose, no secondary rise in tissue resistance occurs. The initial decrease in resistance is consistent with a theophylline-dependent increase in Cl- conductance and the secondary rise in resistance may be attributed to collapse of the lateral intercellular space following leakage of NaCl and fluid into the mucosal solution. 3. Electron microscopy of glutaraldehyde-fixed tissue confirms the above views, since, with theophylline present, the lateral intercellular spaces are collapsed and with both triaminopyrimidine and theophylline, or both theophylline and 20 mM-galactose present the spaces remain open. 4. It is shown in the Discussion that the theophylline- or choleragen induced increase in passive Cl- permeability of the mucosal border is the only requirement necessary to explain the increase in electrogenic Cl- secretion, the increase in short-circuit current, as well as neutral secretion of NaCl and net fluid secretion.
