DISOPYRAMIDE BLOCKS PANCREATIC ATP-SENSITIVE K+ CHANNELS AND ENHANCES INSULIN RELEASE

In antiarrhythmic agent, disopyramide, was found to enhance the insulin secretory capacity of Wistar rat pancreatic islets with a half-maximal concentration of 23.3 muM. Employing a patch-clamp technique, disopyramide was found to inhibit ATP-sensitive K+ (K(ATP)) channel activity in rat pancreatic beta-cells in primary culture without altering the unitary conductance. Half-maximal inhibition was achieved by the addition of 3.6 muM disopyramide to the intracellular bathing solution in the inside-out mode, 11.0 muM to the extracellular bathing solution in the outside-out mode, and 87.4 muM in the cell-attached mode. The binding of [H-3]glibenclamide to pancreatic islets was inhibited by unlabeled glibenclamide but not by unlabeled disopyramide. Based on these observations, it is concluded that disopyramide blocks pancreatic K(ATP) channels via binding to a site(s) distinct from the sulfonylurea receptor. This effect may be causatively involved in disopyramide-induced hypoglycemia.