The effects of glimepiride and glibenclamide upon 86Rb outflow, 45Ca outflow and insulin release were examined in rat islets perifused at low (zero to 2.8 mM) or close-to-normal (8.3 mM) D-glucose concentrations. At the low hexose concentrations, a marked and not reversible decrease in 86Rb outflow contrasted with a rapid and reversible increase in 45Ca outflow. The latter increase was abolished in the absence of extracellular Ca2+, and was not associated with any pronounced stimulation of insulin release. Inversely, in the presence of 8.3 mM D-glucose, a comparable increase in 45Ca efflux now coincided with an increase in 86Rb efflux and a marked and not reversible stimulation of insulin release. Whether in terms of the time course or glucose dependency of the cationic and secretory responses, a coupled increase in both 40Ca inflow and 45Ca outflow thus coincided with either negative or positive changes in 86Rb outflow and either minimal or marked changes in insulin output. Such dissociated behaviours suggest that the insulinotropic action of hypoglycemic sulfonylureas is not necessarily attributable solely to a primary decrease in K+ conductance.