General and selective inhibition of pancreatic enzyme discharge using a proteinase inhibitor (FOY-305)

Abstract

The guanidino acid esters (FOY, FOY-305) represent a new class of potent proteinase inhibitors and are thought to have a beneficial effect on the course of acute pancreatitis. Because of their structure and low molecular size they might enter cells and interfere with cellular processes. To test this possibility in the case of the exocrine pancreas a series of in vivo and in vitro studies was carried out to analyse intracellular transport and discharge of pancreatic enzymes in the presence of FOY-305. The infusion of FOY-305 to conscious rats led to a transient inhibition of protein and enzyme discharge from the cannulated pancreas accompanied by lower serum enzyme levels and increased enzyme content in the pancreas. An identical inhibition of discharge of newly synthesized proteins was observed in vitro in the presence of 1 microM FOY-305. The analysis of the release of individual enzymes using separation on two-dimensional gels showed a pronounced inhibition of mainly the release of acidic proteins. FOY-305 not only interfered with discharge of serine proteinases (trypsinogen, chymotrypsinogen, proelastase) but also with procarboxypeptidases and lipase. It was concluded that FOY-305 enters the acinar cell and due to an unspecific binding to acidic proteins interferes with the intracellular transport of individual enzyme proteins during their passage through the membrane-bound cellular compartments. This charge-dependent effect is independent of the inhibitory effect on enzymatic activity of serine proteinases.

Effect of a Specific Serine Protease Inhibitor on the Rat Pancreas

“…In addition to these indi rect effects observed also after feeding with soybean trypsin inhibitor or aprotinin. direct effects of camostate on the pancreas could be expected, because this small molecular weight substance may affect intracellular pro cesses [1]. Furthermore, camostate is known to inhibit phospholipase A2 (PLA2) activity in vitro [7,21], and this enzyme has recently been shown to influence insulin secretion [24], The aim of this study was to investigate the short-term and long-term effects of ca mostate on the endocrine pancreas of the rat.…”

Effect of a low-molecular weight serine proteinase inhibitor (camostate) on amylase release from isolated pancreatic acini

“…A similar effect was demonstrated for gabexate mesilate, a closely related compound, on basal and cerulein-stimulated pancreatic protein secretion [5]. However, whereas Adler et al [1] presented evidence for an interference of camostate with the intracellular transport and discharge of newly synthesized enzymes from pancreatic lobules in vitro, St6ckmann et al [11] reported no effect of the proteinase inhibitor on the CCK-stimulated enzyme release from rat pancreatic lobules. In the case of gabexate mesilate, Keim and G6ke [5] were unable to demonstrate an influence of i.v.…”

“…It remains an open question why i.v. infusion of camostate leads to a short lasting but nevertheless pronounced inhibition of protein and enzyme discharge from the cannulated pancreatic duct under both basal and stimulated conditions [1]. Previously, this transient inhibitory effect was ascribed to a possible interference of the proteinase inhibitor with the overal discharge process which involves hormones, membrane receptors, intracellular second messengers, and membrane recogni-tion and fusions events during exocytosis [1].…”

“…Adler et al [1] previously showed that i.v. infusion of camostate to conscious rats leads to a transient inhibition of protein and enzyme discharge from the cannulated pancreas.…”

Towards a Novel Treatment Strategy for Acute Pancreatitis

“…The ability of FOY to enter the acinar cell is a disadvantage in that the drug might sustain the exocytosis blockade [25, 26], and hence the drive to inflammation (fig. 1).…”