Early Changes in Pancreatic Acinar Cell Calcium Signaling after Pancreatic Duct Obstruction

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.