Disopyramide and its metabolite enhance insulin release from clonal pancreatic beta-cells by blocking K-ATP channels

In an insulin-secreting pancreatic beta -cell line (MIN6), insulin release was caused by disopyramide, an antiarrhythmic drug with Na-channel blocking action, and its main metabolite mono-isopropyl disopyramide (MIP). Insulin secretion, measured as immunoreactive insulin (IRI), was accelerated to 26 5.7% of the control by disopyramide and to 184.4% by MIP, with half-effecti ve concentrations (EC50) of 30.9 +/- 1.5 muM and 92.4 +/- 2.2 muM. We teste d the possibility that these drugs induce insulin release by inhibiting ATP -sensitive K+ (K-ATP) channels of MIN6 cells. In the cell-attached or ATP-f ree inside-out mode with patch membranes on MIN6 cells, K-selective channel s were recorded with unitary conductance of 70.5 +/- 3.5 pS (150 mM externa l K+ ions at room temperature). The channels were concluded to be MIN6-K-AT P channels because they were closed by extracellular high glucose (11.0 mM) or glibenclamide (200 nM) and were reversibly activated by diazoxide (50 m uM). In the inside-out patch mode, they were inhibited by micromolar ATP. I n both cell-attached and insideout mode, disopyramide and MIP inhibited sin gle MIN6-K-ATP channels. In the inside-out mode, they produced a dose-depen dent inhibition of channel activity: the half-blocking concentrations (IC50 ) were 4.8 +/- 0.2 muM for disopyramide and 40.4 +/- 3.1 muM for MIP. It wa s therefore concluded that both agents exert insulinotrphic effect through the inhibition of membrane K-ATP channels in MIN6 cells.