INHIBITION OF NA/CA EXCHANGE IN PANCREATIC-ISLET CELLS BY 3',4'-DICHLOROBENZAMIL

Na/Ca exchange may play a role in Ca2+ extrusion from the pancreatic B cell. The role played by the exchanger was examined by characterizing the effects of 3'-4'-dichlorobenzamil on ionic fluxes and insulin release in normal rat pancreatic islet cells. 3',4'-Dichlorobenzamil potently inhibited Ca-45 uptake mediated by reverse Na/Ca exchange (IC50: 18-mu-M) in islet cells. The drug failed to decrease intracellular pH but reduced Rb-86 outflow from perifused islets. The effects of glucose and 3',4'-dichlorobenzamil on Rb-86 outflow were not additive. The drug potently blocked Ca-45 uptake through voltage-sensitive Ca2+ channels (IC50: 7.5-mu-M). In the presence of extracellular Ca2+ and 3',4'-dichlorobenzamil, glucose lost part of its ability to reduce Ca-45 outflow. The drug failed to affect the secondary rise in Ca-45 outflow induced by the sugar. In the absence of extracellular Ca2+,3',4'-dichlorobenzamil induced a delayed inhibition of Ca-45 outflow, the effect of the sugar and the drug being not additive. This effect of 3',4'-dichlorobenzamil and its ability to impair the inhibitory effect of glucose were reproduced by the removal of extracellular Na+ and disappeared under the latter experimental condition. 3',4'-Dichlorobenzamil did not affect insulin release in the absence of glucose but significantly increased glucose-induced insulin release when used at a high concentration. It is concluded that 3',4'-dichlorobenzamil is a potent inhibitor of the process of Na/Ca exchange in the pancreatic B cell. Unfortunately, the drug is of poor specificity and blocks, in the same range of concentrations, both K+ channels and voltage-sensitive Ca2+ channels. The data also indicate that glucose inhibits Ca-45 outflow from pancreatic islets to a great extent (at least 75%) by inhibiting Na/Ca exchange. The type of Na/Ca exchange that is inhibited by glucose, remains to be elucidated.