Opposite effects of tolbutamide and diazoxide on 86Rb+ fluxes and membrane potential in pancreatic B cells

Abstract

The effects of tolbutamide and diazoxide on 86Rb+ fluxes, 45Ca2+ uptake, insulin release and B cell membrane potential have been studied in rat or mouse islets. In the presence of 3 mM glucose, tolbutamide rapidly and reversibly decreased Rb+ efflux from perifused islets and depolarised B cells. The effect on Rb+ efflux was paradoxically more marked with 20 than 100 micrograms/ml tolbutamide, at least in the presence of extracellular calcium. Addition of tolbutamide to a medium containing 6 mM glucose and calcium increased Rb+ efflux transiently with 20 micrograms/ml and permanently with 100 micrograms/ml. The drug also inhibited Rb+ influx in islet cells, but had little effect on Rb+ net uptake. Diazoxide rapidly, steadily and reversibly increased Rb+ efflux in a dose-dependent manner (20-100 micrograms/ml). When 20 micrograms/ml tolbutamide and diazoxide were combined in the presence of 3 mM glucose, only a slight decrease in Rb+ efflux was observed. The depolarisation of B cells normally produced by tolbutamide was markedly reduced and the electrical activity completely suppressed by diazoxide. In the presence of 10mM glucose, diazoxide increased Rb+ efflux from the islets and hyperpolarised B cells. Tolbutamide, tetraethylammonium and quinine reversed the increase in Rb+ efflux the inhibition of Ca2+ uptake and the suppression of insulin release produced by diazoxide. Tolbutamide rapidly reversed the hyperpolarisation and restored electrical activity. It is suggested that the stimulation and inhibition of insulin release by tolbutamide and diazoxide are due to their respective ability to decrease and to increase the K permeability of the B cell membrane. This change in K permeability leads either to depolarisation and stimulation of Ca2+ influx or to hyperpolarisation and inhibition of Ca2+ influx.