Hypocalcemia and lipid abnormalities commonly occur in acute pancreatitis. Experimentally, increased plasma concentrations of free fatty acids (NEFA) can lower the serum calcium (Ca). We hypothesized that changes in blood-ionized calcium might parallel changes in NEFA concentration in pancreatitis. This hypothesis was tested in a model of severe necrotizing pancreatitis and a model of mild edematous pancreatitis. Adult male Sprague-Dawley rats (300-400 g) were randomized to receive: 100 microL sodium glycodeoxycholic acid (GDOC 34 mmol/L) infused into the pancreatic duct to produce severe necrotizing pancreatitis (Group 1); 100 microL 0.9% NaCl (NS) infused into the pancreatic duct (Group 2); Sham laparotomy (Group 3); A 6 h IV infusion of cerulein (5 mucg/kg/h) to produce mild edematous pancreatitis (Group 4); and a 6 h IV infusion of NS (Group 5). A significant time dependent decrease in blood-ionized Ca concentration, compared to normal rats, was observed in both GDOC-pancreatitis (0.836 +/- .057 vs 1.069 +/- .038 mmol/L p less than 0.001) and cerulein pancreatitis (0.988 +/- .028 vs 1.069 +/- .038 p less than 0.05), which was maximal 24 h after induction of pancreatitis. The degree of hypocalcemia correlated with the severity of pancreatitis (GDOC 0.836 +/- .057 vs cerulein 0.988 +/- .028 p less than .001). Hypocalcemia was not observed in any of the control groups. All experimental and control groups had significantly increased baseline NEFA concentrations compared with normal rats (p less than 0.001); however, no further increase in NEFA concentration occurred in conjunction with the observed time-dependent decline in ionized calcium concentrations. Although the NEFA concentrations observed in these experiments were comparable to those measured in human acute pancreatitis (exclusive of hyperlipemic pancreatitis), the time course of the changes suggests that increases in serum NEFA concentrations in experimental pancreatitis are not the primary factor mediating hypocalcemia.