The influence of extracellular pH upon the ionic and secretory response to gliclazide was examined in perifused rat islets. Gliclazide usually decreased 86Rb outflow from the islets except in the presence of glucose (7.0 mM) and Ca2+ (1.0 mM) and at low (7.0) or normal (7.4) pH, in which cases it caused a rapid increase in 86Rb output. Gliclazide failed to affect 45Ca outflow in the absence of extracellular Ca2+, whatever the extracellular pH. However, in the presence of Ca2+ and glucose (7.0 mM), gliclazide enhanced 45Ca outflow and insulin release. Under the latter experimental conditions, the gliclazide-induced increment in both 45Ca and insulin output was progressively increased as the pH was raised from 7.0 to 7.4 and 7.8, despite the fact that glucose-induced insulin release was progressively decreased over the same pH range. The gliclazide-induced facilitation of Ca2+ inflow into the islet cells and the subsequent stimulation of insulin release, whatever their precise molecular determinants, thus displayed the same dependency towards extracellular pH as that characterizing the ionophoretic action of the drug. The influence of extracellular pH upon the cationic and secretory response to gliclazide is compatible, therefore, with the view that the insulinotropic action of hypoglycemic sulfonylureas is somehow related to their ionophoretic capacity.