The purpose of this study was to examine the effect of three common divalent cations (Ca2+, Mg2+, and Zn2+) on the release of cholecystokinin (CCK-33), pancreatic polypeptide (PP), and gastrin. Five dogs with pancreatic and gastric fistulas were given 1-h intraduodenal infusions of calcium (5 mmol X kg-1 X h-1), magnesium (4 mmol X kg-1 X h-1), or zinc (1 mmol X kg-1h-1). At another time the same dogs were given an intravenous bolus followed immediately by a 1-h infusion of calcium (0.36 mmol/kg [bolus], 0.36 mmol X kg-1 X h-1), magnesium (0.25 mmol/kg [bolus], 0.25 mmol X kg-1 X h-1), or zinc (0.03 mmol/kg [bolus], 0.03 mmol X kg-1 X h-1). Intraduodenal infusions of calcium, magnesium, and zinc significantly stimulated CCK-33, PP, and gastrin release. Intravenous calcium stimulated CCK-33, PP, and gastrin release to 245, 193, and 155% of basal levels, respectively. Intravenous magnesium increased CCK-33 to 123% of basal levels but did not stimulate PP and gastrin levels. Intravenous zinc stimulated release of CCK-33, PP, and gastrin to 126, 185, and 124%, respectively. This study shows that calcium, magnesium, and zinc can stimulate release of CCK-33, PP, and gastrin in much the same manner. We suggest that these cations may have a nonspecific electrical action that results in an alteration of membrane permeability, which leads to release of gastrointestinal hormones.