In conscious dogs with chronic pancreatic fistulas, duodenal perfusion with HCl (16 mmol/h) stimulated pancreatic HCO-3 secretion to a similar degree as exogenous secretin (2 U/kg X h), while meat feeding (500 g) and duodenal perfusion with oleate (16 mmol/h) increased this secretion to about 58 and 43% of the highest response to secretin. Plasma secretin increments with duodenal HCl, feeding and duodenal oleate amounted to about 45, 13 and 8% of that achieved with secretin, producing the highest HCO-3 response. Perfusion of the in situ intestine with HCl at gradually increasing rates produced HCO-3 responses similar to those induced by exogenous secretin in graded doses, but the increments in plasma secretin with duodenal HCl were only about half those obtained with exogenous secretin, producing an equal rate of HCO-3 secretion. HCl perfusion of isolated Thiry loops made of the duodenojejunal portion also stimulated the HCO-3 secretion in a dose-dependent way, but raised plasma secretin only to about half that attained with secretin, producing a similar secretory rate. HCl in the proximal duodenal and distal jejunal loop slightly stimulated the HCO-3 secretion without affecting plasma secretin, and that in the ileal loop was without any effect on the pancreatic or plasma secretin. This study provides evidence that (a) endogenous secretin is released by feeding and duodenal perfusion with HCl and oleate, but only HCl appears to release sufficient amounts of secretin to drive the HCO-3 secretion, and (b) the release of secretin is confined mainly to the distal duodenum and proximal jejunum.