The phytostilbene resveratrol (RV) improves the metabolic state in animal models by increasing the insulin responsiveness of tissues and there is evidence that RV affects insulin secretion from native beta-cells and insulinoma cells. In whole cell patch clamp experiments on clonal rat INS-1E cells we used high extracellular glucose (20 mM), extracellular hypotonicity (30%) or tolbutamide (100 microM) to elicit membrane depolarizations and electrical activity. Application of RV (50 microM) repolarized the cells, terminated electrical activity and prevented the hypotonicity-induced depolarization. These effects were fully reversible and intermittent application of RV restored tolbutamide-induced electrical activity after desensitization. Glucose-induced depolarization was counteracted by RV in presence of iberiotoxin (50 nM), showing that the RV effect does not depend on BK(Ca) channel activation. RV dose-dependently inhibited K(ATP) currents, L- and T-type Ca(2+) currents and swelling-dependent Cl(-) currents evoked by either hypotonicity or high extracellular glucose--ion conductances crucially involved in regulating the electrical activity of insulin secreting cells. We further show that RV blunts glucose-induced, but not basal insulin release. Our results indicate that RV counteracts/prevents stimulus-induced cell membrane depolarization and electrical activity by blocking voltage-gated Ca(2+)- and swelling-dependent Cl(-) currents despite the inhibition of K(ATP) currents. Copyright 2008 S. Karger AG, Basel.