The secretory actions of glucagon on the exocrine pancreas were examined using two kinds of canine preparations. In the isolated and blood-perfused dog pancreas with venous drainage, i.a. injection of glucagon did not inhibit secretin/cholecystokinin-octapeptide (CCK-8)-stimulated pancreatic secretion, but instead dose dependently enhanced both basal and stimulated pancreatic secretion. Glucagon-induced increase of pancreatic secretion was potentiated by 3-isobutyl-1-methylxanthine. In contrast, i.v. bolus injection of glucagon (3 and 10 nmol/kg) first augmented transiently then suppressed secretin/CCK-8-stimulated pancreatic secretion while simultaneously increasing circulating plasma somatostatin immunoreactivity from 14.2 to 214 fmol/ml in anesthetized intact dogs. The inhibition of secretin/CCK-8-stimulated pancreatic secretion and elevation of plasma somatostatin immunoreactivity induced by glucagon were comparable with those due to somatostatin-14. Thus, these results indicate that glucagon stimulates pancreatic secretion directly; the inhibitory action of glucagon is indirect and appears to be related to a rise in the circulating level of somatostatin immunoreactivity.