Infusion of supramaximal doses of the cholecystokinin analog cerulein is well established as an in vivo technique for inducing experimental pancreatitis in small animals. An attempt was made to simulate this model and initiate pancreatitis in the ex vivo isolated perfused canine pancreas. Control preparations gained minimal weight (mean 8.3 +/- 5.1 gm), demonstrated no edema accumulation, and did not develop hyperamylasemia (mean 1342 +/- 790 units) after 4 hours of perfusion. Electron microscopy after 4 hours of perfusion remained normal. Intraarterial cerulein infusion produced significant weight gain (mean 27.6 +/- 12.3 gm; p less than 0.001), edema formation, and marked hyperamylasemia (mean 26,838 +/- 21,341 units; p less than 0.001) after 4 hours of perfusion. During the 4-hour perfusion, electron microscopy of cerulein preparations demonstrated depletion of zymogen granules, condensing vacuole formation, and basolateral exocytosis. Pretreatment of cerulein preparations with the free radical scavengers superoxide dismutase and catalase and the iron chelator deferoxamine did not modify the pancreatitis. Continuous infusion of the nonpeptide cholecystokinin antagonist L364,718 reduced cerulein-induced weight gain (4.3 +/- 3.4 gm; p less than 0.001) and hyperamylasemia (9392 +/- 6718 units; p less than 0.05). We conclude that cerulein pancreatitis in the ex vivo isolated perfused canine pancreatic preparation is identical physiologically, biochemically, and morphologically with that seen in intact animals.