Chronic oral administration of synthetic trypsin inhibitor camostate reduces amylase release from isolated rat pancreatic acini.
In the present study, we examined stimulus-secretion coupling in pancreatic acini prepared from rats given synthetic protease inhibitor camostate at a dose of 200 mg/kg body wt by an orogastric tube once a day for 10 d. Camostate treatment significantly increased pancreatic weight, protein, DNA, and enzyme contents. In acini prepared from the camostate-treated rats, responsiveness to both CCK-8 and carbamylcholine was greatly decreased with no shift in the dose-response curves compared to control acini prepared from saline-treated rats. There were no major changes in the affinity for both high- and low-affinity sites of CCK receptors, but there was a significant reduction in the capacity of low-affinity site based on acinar protein. Responsiveness to secretin in the camostate-treated rat acini was also significantly reduced compared with that in the controls. However, amylase release from the camostate-treated rat acini in response to an increase in intracellular calcium levels induced by the calcium ionophores A23187 or to an increase in intracellular cyclic 3',5'-monophosphate (cyclic AMP) levels caused by 8 bromo cyclic AMP was not significantly different from the control rat acini, suggesting that both Ca(2+)-dependent tyrosine kinase and nucleotide-activated kinases are not impaired. On the other hand, the responsiveness to phorbol ester TPA, which stimulates amylase secretion via a calcium-independent cascade by activating protein kinase C directly, was reduced in the camostate-treated rat acini compared with the controls. These results suggest the possibilities that the reduced amylase secretion in the camostate-treated rats is owing to alterations in both the transmembrane signal transduction and the phosphorylation of regulatory proteins by the Ca(2+)-independent, protein kinase C-dependent mechanisms.
Otsuki
M
M
Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan.
Fujii
M
M
Nakamura
T
T
Tani
S
S
Okabayashi
Y
Y
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000284:Administration, Oral; D000681:Amylases / Q000378:metabolism*; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002766:Cholecystokinin / Q000378:metabolism; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives*; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012633:Secretin / Q000494:pharmacology; D012844:Sincalide / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014361:Trypsin Inhibitors / Q000494:pharmacology*
D004952:Esters; D006146:Guanidines; D014361:Trypsin Inhibitors; C034532:camostat; D012633:Secretin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000001:Calcimycin; D016670:Gabexate; D002217:Carbachol; D002766:Cholecystokinin; D000681:Amylases; D012844:Sincalide; D013755:Tetradecanoylphorbol Acetate