CCK-, secretin-, and cholinergic-independent pancreatic fluid hypersecretion in protease inhibitor-treated rats.
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 microliters/30 min in control rats, P < 0.01). Loxiglumide (50 mg.kg body wt-1.h-1), atropine (100 micrograms.kg body wt-1.h-1), or antisecretin serum (100 microliters/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.
Yamamoto
M
M
Third Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Shirohara
H
H
Otsuki
M
M
D000109:Acetylcholine / Q000378:metabolism*; D000501:Allylglycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001550:Benzamidines / Q000494:pharmacology*; D001639:Bicarbonates / Q000378:metabolism; D002455:Cell Division; D002712:Chlorides / Q000378:metabolism; D002766:Cholecystokinin / Q000378:metabolism*; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives*; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012633:Secretin / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
D001550:Benzamidines; D001639:Bicarbonates; D002712:Chlorides; D004952:Esters; D006146:Guanidines; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; C100807:ethyl N-allyl-N-(2-methyl-3-(4-(4-amidinophenoxycarbonyl)phenyl)propenoyl)aminoacetate methanesulfonate; C034532:camostat; D000501:Allylglycine; D012633:Secretin; D016670:Gabexate; D002766:Cholecystokinin; D000109:Acetylcholine