Aim: To investigate the effects of a Na⁺ or Cl^- -free luminal milieu on duodenal luminal alkalinization, fluid flux and paracellular permeability. Methods: Experiments were performed in anaesthetized rats in vivo. The duodenum was perfused with different isotonic solutions such as mannitol, choline chloride, sodium sulphate or sodium gluconate and the effects on luminal alkalinization, motility, paracellular solute permeability (⁵¹Cr- EDTA clearance) and net fluid flux were determined. The effects of vasoactive intestinal polypeptide (VIP) and parecoxib (a selective COX-2 inhibitor) on luminal alkalinization in the presence of a Cl^- -free solution in the lumen were also examined. Results: Perfusion of the duodenum with mannitol, sodium sulphate or sodium gluconate markedly reduced while choline chloride had no effect on luminal alkalinization in controls or parecoxib-treated animals. Perfusion with sodium sulphate or sodium gluconate was without effect while mannitol or choline chloride increased duodenal paracellular permeability. All solutions, except sodium gluconate, either decreased net fluid absorption or induced secretion. The parecoxib-induced stimulation of luminal alkalinization, but not that on motility, was greatly attenuated in Cl^- free solution while the response to VIP on alkalinization was essentially the same as in isotonic saline. Conclusions: Low luminal [Cl^-] inhibits while the lack of Na⁺ is without effect on duodenal HCO₃^­ secretion. The parecoxib- induced stimulation of HCO₃^­ secretion is highly dependent on luminal Cl^- while the VIP-induced stimulation appears not. Lack of Na ⁺ in the lumen is a stimulus for increased paracellular permeability, which we believe facilitates the transfer of Na⁺ into the lumen.