Effect of magnesium supplementation and depletion on the onset and course of acute experimental pancreatitis.

BACKGROUND AND OBJECTIVE: High calcium concentrations are an established risk factor for pancreatitis. We have investigated whether increasing magnesium concentrations affect pathological calcium signals and premature protease activation in pancreatic acini, and whether dietary or intraperitoneal magnesium administration affects the onset and course of experimental pancreatitis. METHODS: Pancreatic acini were incubated with up to 10 mM magnesium; [Ca(2+)](i) (fura-2AM) and intracellular protease activation (fluorogenic substrates) were determined over 60 min. Wistar rats received chow either supplemented or depleted for magnesium (<300 ppm to 30 000 ppm) over two weeks before pancreatitis induction (intravenous caerulein 10 µg/kg/h/4 h); controls received 1 µg/kg/h caerulein or saline. C57BL6/J mice received four intraperitoneal doses of magnesium (NaCl, Mg(2+) 55 192 or 384 mg/kg bodyweight) over 72 h, then pancreatitis was induced by up to eight hourly supramaximal caerulein applications. Pancreatic enzyme activities, protease activation, morphological changes and the immune response were investigated. RESULTS: Increasing extracellular Mg(2+) concentration significantly reduced [Ca(2+)](i) peaks and frequency of [Ca(2+)](i) oscillations as well as intracellular trypsin and elastase activity. Magnesium administration reduced pancreatic enzyme activities, oedema, tissue necrosis and inflammation and somewhat increased Foxp3-positiv T-cells during experimental pancreatitis. Protease activation was found in animals fed magnesium-deficient chow-even with low caerulein concentrations that normally cause no damage. CONCLUSIONS: 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.

Developmental and metabolic disorders of the pancreas.

The pancreas is an important exocrine and endocrine organ that develops from the dorsal and ventral anlagen during embryogenesis and arises from the endodermal lining of the duodenum within the first month of human embryonic life. A number of developmental disorders can either lead to anatomic abnormalities of the pancreas and its ducts, or can be part of complex disorders that affect multiorgan systems. Other genetic changes can lead to metabolic abnormalities that affect the pancreas exclusively or increase the lifetime risk for developing pancreatitis or pancreatic diabetes. This article reviews some of the developmental and metabolic disorders that can affect the endocrine and exocrine pancreas.

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.