Effect of a Specific Serine Protease Inhibitor on the Rat Pancreas

Göke, Burkhard; Siegel, E. G.; Stöckmann, F.; Lankisch, P. G.; Creutzfeldt, W.

doi:10.1159/000199189

Cited by 10 publications

(5 citation statements)

References 12 publications

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“…Pancreatic islets were of normal size although decreased in frequency per section as would be expected from distribution in a larger mass of exocrine tissue (data not shown). This selective effect on the exocrine pancreas is consistent with prior reports that total insulin content in the rat pancreas was not changed after camostat administration (16,35).…”

Section: Effect Of Camostat On Pancreatic Growth In Micesupporting

confidence: 92%

Calcineurin mediates pancreatic growth in protease inhibitor-treated mice

Tashiro¹,

Samuelson²,

Liddle³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Calcineurin mediates pancreatic growth in protease inhibitor-treated mice. Am J Physiol Gastrointest Liver Physiol 286: G784-G790, 2004. First published December 18, 2003 10.1152/ ajpgi.00446.2003.-CCK acts on pancreatic acinar cells to increase intracellular Ca 2ϩ leading to secretion of digestive enzymes and, in the long term, pancreatic growth. Calcineurin (CN) is a serine/ threonine-specific protein phosphatase activated by Ca 2ϩ and calmodulin that recently has been shown to participate in the growth regulation of cardiac and skeletal myocytes. We therefore tested the effect of two different CN inhibitors, cyclosporine A (CsA) and FK506, on mouse pancreatic growth induced by oral administration of the synthetic protease inhibitor camostat, a known stimulator of endogenous CCK release. Mice were fed a powdered diet with or without 0.1% camostat. Pancreatic wet weight, protein, and DNA were increased in response to camostat in a time-dependent manner over 10 days in ICR mice but not in CCK-deficient mice. Both CsA (15 mg/kg) and FK506 (3 mg/kg) given twice daily blocked the increase in pancreatic wet weight and protein and DNA content induced by camostat. The increase in plasma CCK induced by camostat was not blocked by CsA or FK506. Camostat feeding also increased the relative amount of CN protein, whereas levels of MAPKs, ERKs, and p38 were not altered. In summary, 1) CCK released by chronic camostat feeding induces pancreatic growth in mice; 2) this growth is blocked by treatment with both CsA and FK506, indicating a role for CN; 3) CCK stimulation also increases CN protein. In conclusion, activation and possibly upregulation of CN may participate in regulation of pancreatic growth by CCK in mice.cholecystokinin; camostat; FK506; cyclosporine A A VARIETY OF GASTROINTESTINAL peptides have been implicated in the regulation of proliferation and differentiation in the mature gastrointestinal tract and the pancreas (30,56). It is well known that feeding initiates pancreatic protein synthesis and secretion and that adaptation to a high-protein diet results in pancreatic growth (17, 18). More detailed studies have shown that among gastrointestinal peptides, CCK is released in response to dietary protein leading to pancreatic growth. Injection of CCK increases pancreatic wet weight and protein and DNA content in vivo over 4-10 days (8,37,40,43). Oral administration of soybean trypsin inhibitor (5, 44) or the synthetic protease inhibitor camostat (10,15,37,52,55), as well as pancreaticobiliary diversion (13, 39), increase the release of endogenous CCK into the blood and induce pancreatic growth. Moreover, CCK-A receptor antagonists that block the action of exogenous and endogenous CCK inhibit pancreatic growth (10, 13, 37, 39, 52). Therefore, most of the studies of pancreatic growth have been focused on CCK as a key regulator.In pancreatic acinar cells, the intracellular mechanisms of enzyme secretion have been well documented. CCK activates the release of intracellular Ca 2ϩ and the influx of Ca 2ϩ and generate...

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Section: Effect Of Camostat On Pancreatic Growth In Micesupporting

confidence: 92%

Calcineurin mediates pancreatic growth in protease inhibitor-treated mice

Tashiro¹,

Samuelson²,

Liddle³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The effect of camostate or CCK treatment on the endocrine pancreas, however, has rarely been investigated, and unfortunately the results are contradictory. Thus it has been reported that insulin content in rat pancreas or isolated pancreatic islets was unchanged (Yamada, Brunstedt & Solomon, 1983;Goke et al 1985;Muller et al 1988) or insignificantly increased (Yamada, Solomon, Petersen, Levin, Lewin & Walsh, 1980). In agreement with a study by Temler and co-workers (Temler, Dormond, Simon & Morel, 1984), we, however, now observed a significant increase in pancreatic insulin content after treatment with both camostate and CCK.…”

Section: Discussionsupporting

confidence: 92%

“…Interestingly, growth of the pancreas was shown to be reversible when treatment with camostate was discontinued (Muller et al 1988). In general, different groups have shown that administration of camostate or CCK increases pancreatic weight and pancreatic concentration or content of RNA and DNA, amylase, trypsin, chymotrypsin and lipase in rats (Solomon, Vanier & Morisset, 1983;Morisset, 1984;Goke, Siegel, Stockmann, Lankisch & Creutzfeldt, 1985;Sarfati, Genik & Morisset, 1985;Goke, Printz, Koop, Rausch, Richter, Arnold & Adler, 1986;Keim & Goke, 1986;Muller et al 1988;Wisner et al 1988;Schmidt et al 1989). Thus our findings on the effect of treatment with camostate or CCK on rat exocrine pancreas are well in agreement with previous studies.…”

Section: Discussionmentioning

confidence: 99%

Rat pancreas after long‐term treatment with the somatostatin analogue octreotide

Schönfeld¹,

Meisse²,

Muller³

1995

Experimental Physiology

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SUMMARYSomatostatin is a potent inhibitor of endocrine and exocrine pancreatic secretion. However, it is not clear whether it also inhibits pancreatic growth. Therefore we treated male Wistar rats with a somatostatin analogue, octreotide ,tg/(kg body wt.day)), over a period of 14 days. In a dose-dependent manner, this potent and long-acting analogue caused a reduction in weight of the pancreas and a reduction in pancreatic content of protein, DNA, trypsin, chymotrypsin, amylase and lipase, as well as pancreatic content of insulin-, glucagon-and somatostatin-like immunoreactivities. When growth of rat pancreas was induced by oral administration of camostate (200 mg/(kg body wt.day) or by subcutaneous administration of cholecystokinin (2 x 10 /tg/(kg body wt.day)) over a period of 14 days, octreotide ,ug/(kg body wt.day)) had the same effects, but these were even more pronounced. We conclude that somatostatin is an important regulator of pancreatic growth.

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“…Chronic administration of camostate to normal rats exerted no effects on the release of insulin (19,20). Our data on diabetic rats are in accordance with these results and put a clear contrast to our previous findings that chronic treatment of normal rats with exogenous CCK or oral cholestyramine, a bile salt sequestrant that stimulates the release of endogenous CCK, enhanced insulin release from the isolated perfused pancreas (9).…”

Section: Discussionsupporting

confidence: 89%

Chronic Effects of Camostate on Growth and Endocrine Function of the Pancreas in Streptozotocin-Induced Diabetic Rats

Kogire

Inoue

et al. 1993

Experimental Biology and Medicine

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Chronic feeding of normal rats with camostate, a synthetic trypsin inhibitor, stimulates the growth of the pancreas chiefly by increasing cholecystokinin release. We examined the effects of camostate on the growth and the endocrine function of the pancreas in streptozotocin-induced diabetic rats. The pancreatic weight of the diabetic rats given camostate (200 mg/kg/day) by oral gavage for 14 days was significantly elevated by 120% over that of diabetic rats not given camostate, and was comparable to that in the nondiabetic rats given camostate. The total pancreatic contents of DNA, RNA, and protein in diabetic rats given camostate were also significantly higher than those in diabetic rats not given camostate, and did not differ from those observed in nondiabetic rats given camostate. The pancreatic growth seen in diabetic rats treated with camostate was associated with moderate hyperplasia and pronounced hypertrophy. By contrast, treatment with camostate did not improve hyperglycemia, hypoinsulinemia, or low pancreatic content of insulin seen in diabetic rats. These findings demonstrate a marked growth of the pancreas in diabetic rats stimulated by camostate, and suggest that camostate-induced pancreatic growth is not affected by the reduced level of the endogenous insulin. The present study also indicates that camostate has no beneficial effects on the function of residual B cells, failing to improve diabetes.

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Effect of a Specific Serine Protease Inhibitor on the Rat Pancreas

Cited by 10 publications

References 12 publications

Calcineurin mediates pancreatic growth in protease inhibitor-treated mice

Calcineurin mediates pancreatic growth in protease inhibitor-treated mice

Rat pancreas after long‐term treatment with the somatostatin analogue octreotide

Chronic Effects of Camostate on Growth and Endocrine Function of the Pancreas in Streptozotocin-Induced Diabetic Rats

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