Hypocalcemia frequently occurs in acute pancreatitis (AP), but its pathogenesis remains unknown. Since AP is often accompanied by acute alteration in the structure and function of cellular membranes, we investigated whether hypocalcemia associated with AP can be explained by acute translocation of Ca from extracellular to intracellular compartments. AP was induced in dogs by injection of autologous bile into the pancreatic duct, and in rats by controlled infusion of artificial bile containing Na-taurochlorate, Keflin, and trypsin into the cannulated bile duct. Plasma Ca, Mg, amylase, and PTH concentrations were determined in the serial samples. Tissue [Ca] and [Mg] were determined in pancreas, liver, kidney, and abdominal wall muscle biopsies obtained immediately before and 24 h after induction of AP in dogs or 2 h following induction of AP in rats to evaluate the temporal correlation between hypocalcemia and excessive intracellular Ca accumulation in soft tissues. Hypocalcemia (p less than 0.001) and hyperamylasemia (p less than 0.01) occurred within 6 h of AP in dogs, and persisted throughout. Plasma [Mg] was lowered and PTH activity was elevated at 6 and 18 h, and returned to a near normal level by 24 h. Concomitant with persisting hypocalcemia and lower ultrafilterable plasma [Ca2+], tissue [Ca] was significantly elevated in pancreas (71%), liver (24%), and abdominal muscle (112%), but was depleted in kidney by 25%. Pancreas biopsy following AP revealed histological signs of fulminant pancreatitis. [Mg] was depleted only in the pancreas (18%) and remained unaltered in other tissues. No significant changes were noted in the sham-operated animals. The observed temporal correlation between profound hypocalcemia and acute excessive intracellular Ca accumulation in soft tissues strongly suggests that hypocalcemia in AP may be precipitated by leaky-plasma-membrane-mediated excessive intracellular Ca accumulation. Similar data together with significantly reduced cellular energy charge (p less than 0.01) obtained from AP rats provided additional support to our hypothesis.