Pancreatic exocrine function was examined in rats during the early stage of acute pancreatitis induced by four subcutaneous injections of 20 micrograms/kg body weight of cerulein at hourly intervals. Basal pancreatic fluid secretion at 6 hr after the first of four cerulein injections was significantly elevated (27.6 +/- 3.7 vs 17.4 +/- 2.1 microliters/30 min in control, P < 0.01) and further increased with time, reaching the peak level at 24 hr (105.1 +/- 4.6 microliters/30 min). Intravenous infusion of loxiglumide (50 mg/kg body wt/hr), atropine (100 micrograms/kg body wt/hr), or anti-secretin serum did not modify the fluid hypersecretion observed at 24 hr after induction of acute pancreatitis. Loxiglumide, when given 30 min before the first cerulein injection, markedly reduced fluid secretion, but could not inhibit the fluid hypersecretion when applied after the last cerulein injection. Leakage of Evans blue dye into pancreatic juice was slightly but significantly increased in postpancreatitic rats compared with that in the control rats (1.30 +/- 0.17 vs 0.75 +/- 0.08 micrograms/ml, P < 0.01), whereas that in the pancreas was not different from the control rats. In vivo labeling with 5-bromo-2'-deoxyuridine showed active proliferation of acinar and ductular cells at 6 hr. In addition, the fluid was rich in chloride (137.1 +/- 2.5 at 24 hr vs 92.4 +/- 3.3 meq/liter in control, P < 0.01) but poor in bicarbonate concentration (39.0 +/- 2.0 at 24 hr vs 46.5 +/- 1.9 mmol/liter in control, P < 0.01), indicating acinar cell secretion. These results indicate that pancreatic fluid secretion during the early stage of acute pancreatitis induced by supramaximal doses of cerulein was markedly increased not by CCK-, secretin-, or cholinergic-dependent mechanisms but probably by acinar cell proliferation.