To elucidate why arterial pH and carbon dioxide (PaCO2) modify the pancreatic H+/HCO3- secretory response to secretin stimulation, experiments were performed on anaesthetized pigs, recording the effects of arterial pH and PaCO2 on exocrine H+/HCO3- secretion and on morphology of pancreatic duct cells. Duct cells contained numerous cytoplasmic vesicles at secretory rest. Their number more than doubled during elevation of PaCO2 from 5.5 to 11.0 kPa. At arterial pH 7.40, maximal secretin stimulation cleared the cytoplasm of duct cells of more than 90% of the vesicles. At high PaCO2, this was accompanied by doubling the basolateral plasma membrane area and a 30% higher secretion rate than at PaCO2 5.5 kPa. Lowering arterial pH to 7.0 more than halved the secretin-induced vesicle clearance of duct-cell cytoplasm as well as exocrine H+/HCO3- secretion and abolished the secretin-dependent basolateral membrane area changes. Supramaximal secretin stimulation did not reverse the inhibitory effect of severe metabolic acidosis on secretion. It is concluded that PaCO2 and arterial pH may modify the secretory response to secretin through determining the incorporation of cytoplasmic vesicle material into the basolateral plasma membrane of duct cells.