CCK-, secretin-, and cholinergic-independent pancreatic fluid hypersecretion in protease inhibitor-treated rats

Abstract

Plasma cholecystokinin (CCK) levels in fed rats increased from 2.59 ± 0.13 pmol/l to the peak of 27.6 ± 4.1 pmol/l at 1 h after a single oral administration of synthetic protease inhibitor (PI; ethyl N-allyl- N-{( E)-2-methyl-3-[4-(4-amidino-phenoxycarbonyl)phenyl]propenoyl}amino acetate methansulfonate; 20 mg/kg body wt), but then returned to the preloading value at 12 h after administration. The pancreatic fluid secretion, rich in chloride but poor in bicarbonate, was significantly elevated at 6–12 h postfeeding (100.9 ± 8.2 vs. 27.3 ± 2.3 μl/30 min in control rats, P < 0.01). Loxiglumide (50 mg ⋅ kg body wt−1 ⋅ h−1), atropine (100 μg ⋅ kg body wt−1 ⋅ h−1), or antisecretin serum (100 μl/rat) at 12 h postfeeding did not modify the fluid hypersecretion. Loxiglumide, when given together with PI, completely abolished fluid hypersecretion, but it could not inhibit hypersecretion when applied 3 h after PI treatment. Labeling with 5-bromo-2′-deoxyuridine showed active proliferation of acinar cells at 3 h after PI treatment (3.56 ± 0.29% vs. 0.46 ± 0.08% in control, P < 0.001), but not in rats given loxiglumide together with PI. In rats that fasted from 12 h before to 12 h after PI feeding, neither pancreatic fluid hypersecretion nor active proliferation of acinar cells was observed. These results suggest that pancreatic fluid hypersecretion in fed rats at 6–12 h after PI treatment is caused not by CCK-, secretin-, or cholinergic-dependent mechanisms but probably by acinar cell proliferation.