The interplay of the ion channels of the pancreatic beta-cell is a crucial step in the regulation of insulin secretion. Though the presence of sodium channels is obvious in the pancreatic beta-cell, their role is not yet understood. Using a specific modulator of sodium channels. BDF 9148, a concentration-dependent reduction of glucose-stimulated insulin release was found. BDF 9148 also reduced tolbutamide- or potassium chloride-induced insulin release. BDF 9148 had no effect on KATP channel function as estimated by 86Rb+ efflux measurement and was also ineffective on 45Ca2+ uptake but augmented 22Na+ uptake. BDF 9148 did not alter the electrical activity of beta-cells significantly. Since BDF 9148 antagonized the stimulatory effect of veratridine on insulin release, sodium channels are likely to be the target of its action. In conclusion, the sodium-channel modulator BDF 9148 inhibits nutrient-induced insulin release by a mechanism which is not involved in the generation of action potentials in the beta-cell.