The isolated perfused rat pancreas was used to examine the influence of the acid-base status of the perfusing solution on the redox states of cytochromes and secretory responses. Lowering the pH in a perfusing solution (pHe) from 7.3 to 6.8 induced simultaneous oxidation of cytochromes aa3, b, and c + c1, and further lowering to 6.0 induced larger oxidation of the cytochromes. Raising the pHe from 7.3 to 8.0 induced reduction of the cytochromes. Continuous stimulation with synthetic C-terminal octapeptide of cholecystokinin (CCK-8) at 100 pM induced the maximum secretory responses (pancreatic juice flow, protein output, and amylase output) during perfusion with the standard solution. The responses were not inhibited at pHe 6.8 but were inhibited significantly at pHe 6.0 or 8.0. The responses induced by stimulation with 20 pM CCK-8 were completely inhibited when pHe was lowered to 6.0 and CaCl2 was removed from the perfusing solution.