In chronic gastric fistula rats provided with a duodenal loop anastomosed to the jejunum (Roux-en-Y), maximal stimulation of acid secretion by continuous intravenous infusion of pentagastrin produced a 15-fold increase of gastric histidine decarboxylase activity. Intraduodenal instillation of 0.20 M HCl or 1200 mOsm X kg-1 solution of polyethylene glycol (PEG) inhibited the maximal acid response to pentagastrin by 61% and hyperosmolal (1200 mOsm X kg-1 of PEG solution) 0.20 M HCl by 79% but did not suppress the pentagastrin-induced increase in enzyme activity. Hence, instillation of HCl and/or hyperosmolal PEG solution in the duodenum depresses the responsiveness of the parietal cells to pentagastrin without interfering with pentagastrin-induced activation of gastric histamine formation.