Intracellular Ca2؉ -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 [ 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.Alterations in intracellular calcium signaling have previously been reported from an experimental animal model of acute pancreatitis that employs supramaximal secretagogue stimulation for the disease induction (1). Moreover, the spatial and temporal distribution of intracellular calcium signals in response to either physiological or pathological stimuli has been found to be directly related to premature digestive enzyme activation in the pancreas and to acinar cell injury (2-5). Intracellular activation of trypsinogen on the other hand can be completely prevented with agents that interfere with either the uptake of calcium, the maintenance of a calcium gradient across the plasma membrane, or the rapid release of calcium from apical intracellular stores (4, 6). All of these studies indicate clearly that the spatial and temporal distribution of intracellular calcium signals plays a critical role in the early cellular events that precede the onset of pancreatitis. The mechanism, however, that was used to induce acinar cell injury in these studies or in response to which intracellular calcium changes were characterized, supramaximal secretagogue stimulation, is not necessarily an event that is generally involved in the pathogenesis of clinical pancreatitis.In many parts of the world the most common etiological factor associated with acute pancreatitis is gallstone disease. Experimental (7) as well as clinical studies (8, 9) suggest that the onset of gallstone-induced pancreatitis requires migration of the offending stone through the biliary tract and its impaction at the duodenal papilla. Here, at the junction of the common bile duct and the pancreatic duct, the stone can impair the flow of pancreatic secretion or lead to a complete blockage of the pancreatic duct. It is now generally accepted that this impairment of pancreatic secretion (7, 10, 11), rather than a potential reflux of bile into the pancreas (13), represents the critical pathophysiological event for the development gallstoneinduced pancreatitis. To investigate whether this clinically relevant...

Little is known about the pathophysiological factors that determine the clinical severity of acute pancreatitis. Because

Although the role of calcium (Ca2+) in the signal transduction and pathobiology of the exocrine pancreas is firmly established, the role of magnesium (Mg2+) remains unclear. We have characterized the intracellular distribution of Mg2+ in response to hormone stimulation in isolated mouse pancreatic acinar cells and studied the role of Mg2+ in modulating Ca2+ signaling using microspectrofluorometry and digital imaging of Ca2+- or Mg2+-sensitive fluorescent dyes as well as Mg2+-sensitive intracellular microelectrodes. Our results indicate that an increase in intracellular Mg2+ concentrations reduced the cholecystokinin (CCK) -induced Ca2+ oscillations by inhibiting the capacitive Ca2+ influx. An intracellular Ca2+ mobilization, on the other hand, was paralleled by a decrease in [Mg2+]i, which was reversible upon hormone withdrawal independent of the electrochemical gradients for Mg2+, Ca2+, Na+, and K+, and not caused by Mg2+ efflux from acinar cells. In an attempt to characterize possible Mg2+ stores that would explain the reversible, hormone-induced intracellular Mg2+ movements, we ruled out mitochondria or ATP as potential Mg2+ buffers and found that the CCK-induced [Mg2+]i decrease was initiated at the basolateral part of the acinar cells, where most of the endoplasmic reticulum (ER) is located, and progressed from there toward the apical pole of the acinar cells in an antiparallel fashion to Ca2+ waves. These experiments represent the first characterization of intracellular Mg2+ movements in the exocrine pancreas, provide evidence for possible Mg2+ stores in the ER, and indicate that the spatial and temporal distribution of intracellular Mg concentrations profoundly affects acinar cell Ca2+ signaling.

Magnesium supplementation significantly reduces premature protease activation and the severity of pancreatitis, and antagonises pathological [Ca(2+)](i) signals. Nutritional magnesium deficiency increases the susceptibility of the pancreas towards pathological stimuli. These data have prompted two clinical trials on the use of magnesium in patients at risk for pancreatitis.