Effects of intrapancreatic cholinergic activation by electrical field stimulation (EFS) on secretin-stimulated pancreatic exocrine secretion were investigated in the totally isolated perfused rat pancreas. EFS at 15 V, 2 ms, and 8 Hz for 45 min markedly increased spontaneous pancreatic secretion. This increase was completely inhibited by tetrodotoxin (1 microM) but not by hexamethonium (100 microM). Atropine (2 microM) significantly reduced the EFS-evoked volume flow and amylase output by 52% and 80%, respectively. EFS further increased the secretin (12 pM)-stimulated pancreatic secretion of fluid and amylase. The increases of the two parameters were significantly suppressed by atropine by 28% and 72%, respectively. Interestingly, EFS significantly increased concentrations of somatostatin-like immunoreactivity in portal venous effluents. When pertussis toxin (200 ng/ml) or rabbit antisomatostatin serum (0.1 ml/10 ml; titer of 1:50,000) was intra-arterially administered, EFS further increased the secretin-stimulated pancreatic secretion. In conclusion, the activation of intrapancreatic cholinergic neurons potentiated the secretin action on pancreatic exocrine secretion in the rat. This potentiating effect was significantly reduced by local somatostatin released during EFS that activated intrapancreatic cholinergic tone.