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 45Ca uptake mediated by reverse Na/CA exchange (IC50: 18 microM) in islet cells. The drug failed to decrease intracellular pH but reduced 86Rb outflow from perifused islets. The effects of glucose and 3',4'-dichlorobenzamil on 86Rb outflow were not additive. The drug potently blocked 45Ca uptake through voltage-sensitive Ca2+ channels (IC50: 7.5 microM). In the presence of extracellular Ca2+ and 3',4'-dichlorobenzamil, glucose lost part of its ability to reduce 45Ca outflow. The drug failed to affect the secondary rise in 45Ca outflow induced by the sugar. In the absence of extracellular Ca2+, 3',4'-dichlorobenzamil induced a delayed inhibition of 45Ca 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 45Ca 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.