title: Early changes in pancreatic acinar cell calcium signaling after pancreatic duct obstruction.
abstract: Intracellular Ca(2+)-changes not only participate in important signaling pathways but have also been implicated in a number of disease states including acute pancreatitis. To investigate the underlying mechanisms in an experimental model mimicking human gallstone-induced pancreatitis, we ligated the pancreatic duct of Sprague-Dawley rats and NMRI mice for up to 6 h and studied intrapancreatic changes including the dynamics of [Ca(2+)](i) in isolated acini. In contrast to bile duct ligation, pancreatic duct obstruction induced intra-pancreatic trypsinogen activation, leukocytosis, hyperamylasemia, and pancreatic edema and increased lung myeloperoxidase activity. Although resting [Ca(2+)](i) in isolated acini rose by 45% to 205 +/- 7 nmol, the acetylcholine- and cholecystokinin (CCK)-stimulated calcium peaks as well as the amylase secretion declined, but neither the [Ca(2+)](i)-signaling pattern nor the amylase output in response to the Ca(2+)-ATPase inhibitor thapsigargin nor the secretin-stimulated amylase release were impaired by pancreatic duct ligation. On the single cell level pancreatic duct ligation reduced the percentage of cells in which submaximal secretagogue stimulation was followed by a physiological response (i.e. Ca(2+) oscillations) and increased the percentage of cells with a pathological response (i.e. peak plateau or absent Ca(2+) signal). Moreover, it reduced the frequency and amplitude of Ca(2+) oscillation as well as the capacitative Ca(2+) influx in response to secretagogue stimulation. Serum pancreatic enzyme elevation as well as trypsinogen activation was significantly reduced by pretreatment of animals with the calcium chelator BAPTA-AM. These experiments suggest that pancreatic duct obstruction rapidly changes the physiological response of the exocrine pancreas to a Ca(2+)-signaling pattern that has been associated with premature digestive enzyme activation and the onset of pancreatitis, both of which can be prevented by administration of an intracellular calcium chelator.
authors.affiliation: Medizinische Klinik B and Institut für Sportmedizin, Westfälische Wilhelms-Universität, 48129 Münster, Germany.
authors.forename: Frank Ch
authors.initials: FCh
authors.lastname: Mooren
authors.forename: Verena
authors.initials: V
authors.lastname: Hlouschek
authors.forename: Till
authors.initials: T
authors.lastname: Finkes
authors.forename: Stefan
authors.initials: S
authors.lastname: Turi
authors.forename: Ina Alexandra
authors.initials: IA
authors.lastname: Weber
authors.forename: Jaipaul
authors.initials: J
authors.lastname: Singh
authors.forename: Wolfram
authors.initials: W
authors.lastname: Domschke
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schnekenburger
authors.forename: Burkhard
authors.initials: B
authors.lastname: Krüger
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000681:Amylases / Q000097:blood; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D002766:Cholecystokinin / Q000378:metabolism; D003251:Constriction, Pathologic; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005434:Flow Cytometry; D008297:Male; D051379:Mice; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism*; D010182:Pancreatic Diseases / Q000473:pathology; D010183:Pancreatic Ducts / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D019284:Thapsigargin / Q000378:metabolism; D013997:Time Factors; D014362:Trypsinogen / Q000378:metabolism
chemical_list: D002614:Chelating Agents; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D019284:Thapsigargin; D014362:Trypsinogen; D002766:Cholecystokinin; D000681:Amylases; D000251:Adenosine Triphosphatases; D002118:Calcium