Summary
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 µM 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.
Similar content being viewed by others
References
Adler G, Rohr G, Kern HF (1982) Alteration of membrane fusion as a cause of acute pancreatitis in the rat. Dig Dis Sci 27:993–1002
Adler G, Gerhards G, Schick J, Rohr G, Kern HF (1983) Effects of in vivo cholinergic stimulation of rat exocrine pancreas. Am J Physiol 244:G623-G629
Bernfeld P (1955) Amylase α and β. In: Colowick SP, Kaplan NO (ed) Methods in Enzymology. Academic Press, New York, pp 149–158
Bieger W, Martin-Achard A, Bassler M, Kern HF (1976) Studies on intracellular transport of secretory proteins in the rat exocrine pancreas. IV. Stimulation by in vivo infusion of caerulein. Cell Tissue Res 165:435–453
Gardner JD, Jensen RT (1981) Regulation of pancreatic enzyme secretion in vitro. In: Johnson LR (ed) Physiology of the Gastrointestinal Tract. Raven, New York, pp 831–871
Göke B, Stöckmann F, Siegel EG, Otto J, Stumpf A, Lankisch PG, Creutzfeldt W (1983) Effects of gabexate mesylate on pancreatic secretion. Digestion 28:32
Grözinger KH, Schrey A, Wabnitz RW (1982) Proteinasen-Inhibition. Dr C Wolf & Sohn, München
Hummel BC (1959) A modified spectrophotometric determination of chymotrypsin, trypsin and thrombin. Can J Biochem 37:1393–1399
Ito S, Karnovsky MJ (1968) Formaldehyde-glutaraldehyde fixatives containing trinitro compounds. J Cell Biol 39:168a-169a
Kern HF, Bieger W, Völkl A, Rohr G, Adler G (1979) Regulation of intracellular transport of exportable proteins in the rat exocrine pancreas. In: Hopkins CR, Duncan CJ (eds) Secretory mechanisms. University Press, Cambridge, pp 79–99
Kleesiek K, Greiling H (1982) Die Wirkung des Gabexat mesilats und anderer Pharmaka auf den Glykosaminoglykanstoffwechsel kultivierter humaner Synoviafibroblasten. In: Grözinger KH, Schrey A, Wabnitz RW (eds) Proteinasen-Inhibition. Dr C Wolf & Sohn, München, pp 342–357
Lankisch PG, Göke B, Stöckmann F, Otto J, Winckler K, Creutzfeldt W (1983) Protektive Wirkung von Gabexat-Mesilat (FOY) bei akuter Pankreatitis? Z Gastroenterol 21:453
Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275
MRC multicenter trial of glucagon and aprotinin (1977) Death from acute pancreatitis. Lancet II:632–635
Muramatu M, Fujii S (1972) Inhibitory effects of ω-guanidino acid esters on trypsin plasmin, plasma kallikrein and thrombin. Biochim Biophys Acta 268:212–220
Popper HL, Necheles H, Rusell KC (1948) Transition of pancreatic edema into pancreatic necrosis. Surg Gynecol Obstet 87:79–82
Richards GM (1974) Modifications of the diphenylamine reaction giving increased sensitivity and simplicity in the estimation of DNA. Anal Biochem 57:269–276
Saitoh Y (1982) Clinical results with an oral protease inhibitor FOY-305 in chronic pancreatitis. In: Grözinger KH, Schrey A, Wabnitz RW (eds) Proteinasen-Inhibition. Dr Wolf & Sohn, München, pp 156–167
Scheele G (1975a) Two-dimensional gel analysis of soluble proteins: characterization of guinea pig exocrine pancreatic proteins. J Biol Chem 250:5375–5385
Scheele GA, Palade GE (1975b) Studies on the guinea pig pancreas. Parallel discharge of exocrine enzyme activities. J Biol Chem 250:2660–2670
Scheele G, Jacoby R, Carne T (1980) Mechanism of compartmentation of secretory proteins. Transport of exocrine pancreatic proteins across the microsomal membrane. J Cell Biol 87:611–628
Schick HJ, Beil-Moeller H, Kern HF, Scheele GA (1982) Differential rate of synthesis of individual pancreatic enzymes during prolonged in vivo stimulation. In: Robinson JWL, Dowling RH, Riecken EO (eds) Mechanisms of Intestinal Adaptation. MTP, Lancaster, Boston, The Hague, pp 511–514
Stöckmann F, Göke B, Otto J, Lankisch PG (1983) Der Einfluß von Gabexat-Mesilat (Foy) auf die CCK-stimulierte Amylase Sekretion des exokrinen Rattenpankreas in vivo. Z Gastroenterol 21:453
Takasugi S, Yonezawa H, Ikei N, Kanno T (1982) Prevention of acute experimental pancreatitis in rats and dogs by intraduodenal infusion of a synthetic trypsin inhibitor. Digestion 24:35–41
Tartakoff AM, Greene LJ, Jamieson JD, Palade GE (1974) Parallelism in the processing of pancreatic proteins In: Ceccarelli B, Clementi F, Meldolesi J (eds) Advances in Cytopharmacology. Raven Press, New York, pp 177–194
Trapnell JE, Rigby CC, Talbot CH, Duncan EHL (1974) A controlled trial of trasylol in the treatment of acute pancreatitis. Brit J Surg 61:177–182
Wolf H, Seeger W, Neuhof H (1982) Einfluß von Gabexat mesilat (FOY) and Aprotinin auf die Freisetzung der Arachidonsäure in der pulmonalen Strombahn. In: Grözinger KH, Schrey A, Wabnitz RW (eds) Proteinasen-Inhibition. Dr C Wolf & Sohn, München, pp 342–357
Zänker K, Blümel G, Siewert JR (1982) Experimental pharmacology of N,N-dimethyl-carbomylmethyl 4-(4-guanidin-obenzyloxy)phenylacetate methanesulfonate. A proteolytic enzyme inhibitor in tumour cells? J Exp Clin Res 1:105–110
Zoepffel H (1921) Das akute Pankreasödem, eine Vorstufe der akuten Pankreasnekrose. Dtsch Z Chir 175:301–312
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Adler, G., Rausch, U., Weidenbach, F. et al. General and selective inhibition of pancreatic enzyme discharge using a proteinase inhibitor (FOY-305). Klin Wochenschr 62, 406–411 (1984). https://doi.org/10.1007/BF01742297
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01742297