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.

Differential mechanism and site of action of CCK on the pancreatic secretion and growth in rats

“…3B and 4B). Although the precise mechanism of the hypersecretion remained unclear, we previously observed pancreatic fluid hypersecretion in the proliferative process of acinar cells after oral administration of the protease inhibitor camostat (44). Since the pancreatic growth is stimulated in the capsaicin-treated rats ( Table 1), it is conceivable that acinar cell proliferation might influence pancreatic fluid hypersecretion in capsaicin-treated rats.…”

Water and enzyme secretion are tightly coupled in pancreatic secretion stimulated by food or CCK-58 but not by CCK-8

“…Pancreatic water hypersecretion occurs 6 -12 h after intragastric infusion of trypsin inhibitor and during the recovery phase of caeruleininduced acute pancreatitis (9,10,72). This pancreatic juice was chloride rich (124 meq/l), and the increased secretion was associated with a 7.7-fold increase in the labeling index of acinar cells and a smaller, 2.6-fold increase in the labeling Table 3.…”