J. Membrane Biol. 33, 185-195 (1977) 9 by Springer-Verlag New York Inc. 1977 Effects of Membrane Stabilizers on Pancreatic Amylase Release John A. Williams, Jorgen Hedemark Poulsen, and Mark Lee Department of Physiology,University of California, San Francisco, California 94143 Received 13 September 1976 Summary. Compounds with membrane stabilizing activity were studied as to their ability to affect pancreatic amylase release and the steps in the stimulus-secretioncoupling process. Chlorpromazine, propranolol, and thymol were all found to inhibit bethanechol- stimulated amylaserelease and at slightlyhigher concentration s to induce release regardless of the presence of the secretagogue.This biphasic effectwas similar to that found previously for the local anesthetic tetracaine. Release by high concentrations of propranolol and tetracaine was accompaniedby ultrastructural evidenceof cell damage. Membrane stabilizers at concentrations which inhibited amylaserelease were shown to block bethanechol-induced depolarization and stimulation of 4SCa++ effiuxalthough the drugs alone partially depolar- ized pancreatic cells. Release of amylase induced by Ca++ introduced by the ionophore A23187 was also abolished. These findingsindicate that membrane stabilizers independently inhibit the steps leading to a rise in intracellular Ca++ and the subsequent Ca ++-activated amylase release. Activation of pancreatic enzyme release by cholinergic agonists and gastrointestinal hormones is believed to involve interaction of the secreta- gogue with a membrane receptor (Galardy & Jamieson, 1975), depolar- ization and release of intracellular Ca + + (Matthews, Petersen & Wil- liams, 1973), with the rise in cytoplasmic Ca + + promoting release of zymogen granule contents by exocytosis (Palade, 1975). A similar mecha- nism applies to other secretory tissues although in many cases Ca + + enters from the outside through membrane channels opened by the secre- tagogue (Douglas, 1968). Local anesthetics block secretion by a number of glands including the exocrine pancreas (Beaudoin, Marois, Dunni- gen & Morisset, 1974; Williams & Lee, 1974), endocrine pancreas (Bress- ler & Brendel, 1971; Ammon, Orci & Steinke, 1973) and the adrenal medulla (Douglas & Kanno, 1967; Jaanus, Miele & Rubin, 1967'). In the case of the adrenal this has been shown to be accompanied by blockage of ACh-activated Ca + + channels (Douglas & Kanno, 1967). By contrast, in the pancreatic acinar cell, tetracaine was shown to block one of the