Compounds with membrane stabilizing activity were studied as to their ability to affect pancreatic amylase release and the steps in the stimulus-secretion coupling process. Chlorpromazine, propranolol, and thymol were all found to inhibit bethanechol-stimulated amylase release and at slightly higher concentrations to induce release regardless of the presence of the secretagogue. This biphasic effect was similar to that found previously for the local anesthetic tetracaine. Release by high concentrations of propranolol and tetracaine was accompained by ultrastructural evidence of cell damage. Membrane stabilizers at concentrations which inhibited amylase release were shown to block bethanechol-induced depolarization and stimulation of 45Ca++ efflux although the drugs alone partially depolarized pancreatic cells. Release of amylase induced by Ca++ introduced by the ionophore A23187 was also abolished. The findings indicate that membrane stabilizers independently inhibit the steps leading to a rise in intracellular Ca++ and the subsequent Ca++-activated amylase release.