Tu1484 E-Cadherin Is Dispensable for Pancreatic Development of Embryo but Required for Neonatal Pancreatic Growth in Mice

Adaptive exocrine pancreatic growth is mediated primarily by dietary protein and the gastrointestinal hormone cholecystokinin (CCK). Feeding trypsin inhibitors such as camostat (FOY-305) is known to induce CCK release and stimulate pancreatic growth. However, camostat has also been reported to stimulate secretin release and, because secretin often potentiates the action of CCK, it could participate in the growth response. Our aim was to test the role of secretin in pancreatic development and adaptive growth through the use of C57BL/6 mice with genetic deletion of secretin or secretin receptor. The lack of secretin in the intestine or the secretin receptor in the pancreas was confirmed by RT-PCR. Other related components, such as vasoactive intestinal polypeptide (VIP) receptors (VPAC1and VPAC2), were not affected. Secretin increased cAMP levels in acini from wild-type (WT) mice but had no effect on acini from secretin receptor-deleted mice, whereas VIP and forskolin still induced a normal response. Secretin in vivo failed to induce fluid secretion in receptor-deficient mice. The pancreas of secretin or secretin receptor-deficient mice was of normal size and histology, indicating that secretin is not necessary for normal pancreatic differentiation or maintenance. When WT mice were fed 0.1% camostat in powdered chow, the pancreas doubled in size in 1 wk, accompanied by parallel increases in protein and DNA. Camostat-fed littermate secretin and secretin receptor-deficient mice had similar pancreatic mass to WT mice. These results indicate that secretin is not required for normal pancreatic development or adaptive growth mediated by CCK.

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Effects of the CCK receptor antagonist L364,718 on pancreatic growth in adult and developing animals

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1989.257.4.g511 ◽

1989 ◽

Vol 257 (4) ◽

pp. G511-G516 ◽

Cited By ~ 4

Author(s):

K. A. Zucker ◽

T. E. Adrian ◽

A. J. Bilchik ◽

I. M. Modlin

Keyword(s):

Receptor Antagonist ◽

Guinea Pigs ◽

Normal Growth ◽

Dietary Manipulation ◽

Pancreatic Development ◽

Osmotic Pumps ◽

Pancreatic Growth ◽

Old Rats ◽

Cck Receptor Antagonist

Although exogenous administration of cholecystokinin (CCK) or dietary manipulation to increase circulating CCK have previously been shown to promote pancreatic growth, the role of CCK in controlling normal pancreatic development remains unclear. A potent CCK receptor antagonist, L364,718, was administered to rats, guinea pigs, and hamsters to block the effect of endogenous CCK. Animals were given continuous infusions of L364,718 (25 nmol.kg-1.h-1), CCK octapeptide [(CCK-8) 200 pmol.kg-1.h-1], or both CCK-8 and L364,718 for 14 and 28 days. Adult (4-mo-old) and young (4-wk-old) animals were used. CCK-8 and L364,718 were administered via separate, subcutaneously implanted mini-osmotic pumps. Infusions of CCK-8 alone for 28 days resulted in a 21.7% increase in wet pancreatic weight in 4-wk-old rats and a 22.7% increase in 4-wk-old guinea pigs (both P less than 0.001 compared with controls). Similar increases were found in DNA, RNA, and total protein contents. Coadministration of L364,718 totally blocked the trophic effects of exogenously infused CCK-8 in rats and guinea pigs. Administration of L364,718 alone in hamsters, guinea pigs, and rats for 14 and 28 days failed to alter the normal growth of the pancreas gland as measured by these parameters. Although elevated levels of CCK appear to promote a potent trophic response in the growing pancreas, this regulatory peptide does not appear to be an essential trophic factor for the normal growth of the exocrine pancreas in these animals.

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