title: Distribution of a synthetic protease inhibitor in rat pancreatic acini after supramaximal secretagogue stimulation.
abstract: Protease inhibitors may have a beneficial effect in acute pancreatitis. The effects of E3123, a new low molecular weight protease inhibitor, on the ultrastructure of isolated pancreatic acini were examined using transmission electron microscopy. Acini supramaximally stimulated with cerulein (10(-8) M) formed large cytoplasmic vacuoles similar to those generated in the cerulein-induced in vivo model of pancreatitis. Pretreatment of isolated acini with E3123 significantly reduced the size and number of vacuoles associated with cerulein treatment. The distribution of 3H-E3123 in acinar cells was examined using a pulse-chase protocol and electron microscopic autoradiography. Cellular levels of 3H-E3123 increased about 30-fold in acinar cells treated with cerulein (10(-8) M) compared to unstimulated controls. In cerulein-treated acini examined after a 5-min chase, 47.4% of the autoradiographic grains were associated with the rough endoplasmic reticulum and 13.2% were associated with zymogen granules. After 30 min of incubation, the grains associated with the endoplasmic reticulum decreased to 18.5% but increased to 26.3% over zymogen granules. Thus, E3123 is taken up by the acinar cell and follows a cellular itinerary similar to that of newly synthesized secretory proteins. One potential conclusion from these studies is that the ability of E3123 to reduce the formation of vacuoles in supra-maximally stimulated acini may be due to its inhibition of proteases within the secretory pathway.
authors.affiliation: First Department of Surgery, University of Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Otani
authors.forename: Y
authors.initials: Y
authors.lastname: Atomi
authors.forename: A
authors.initials: A
authors.lastname: Kuroda
authors.forename: T
authors.initials: T
authors.lastname: Muto
authors.forename: M
authors.initials: M
authors.lastname: Tamura
authors.forename: S
authors.initials: S
authors.lastname: Fukuda
authors.forename: S
authors.initials: S
authors.lastname: Akao
authors.forename: F S
authors.initials: FS
authors.lastname: Gorelick
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D002108:Ceruletide / Q000494:pharmacology*; D018870:Endoplasmic Reticulum, Rough / Q000648:ultrastructure; D006146:Guanidines / Q000032:analysis* / Q000494:pharmacology; D008297:Male; D008854:Microscopy, Electron; D010179:Pancreas / Q000737:chemistry* / Q000187:drug effects* / Q000648:ultrastructure; D011480:Protease Inhibitors / Q000032:analysis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014316:Tritium; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D006146:Guanidines; D011480:Protease Inhibitors; D014316:Tritium; C057059:4-(2-succinimidoethylthio)phenyl 4-guanidinobenzoate; D002108:Ceruletide; D000681:Amylases