BPDZ 154 activates adenosine 5′-triphosphate-sensitive potassium channels: In vitro studies using rodent insulin-secreting cells and islets isolated from patients with hyperinsulinism

A novel ATP-sensitive potassium channel (KATP) channel agonist, BPDZ 154 (6,7-dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide), was synthesized, and its effects on insulin-secreting cells were evaluated using electrophysiology, 86Rb+ and 45Ca2+ efflux, and RIA determinations of insulin secretion. BPDZ 154, an analog of diazoxide, inhibited both glucose-induced insulin secretion from isolated perifused islets and the secretion of insulin induced by glucose and tolbutamide. These effects were mediated by the activation of ATP-sensitive potassium channels because BPDZ 154 induced a concentration-dependent increase in channel activity that was inhibited by the sulfonylurea tolbutamide and the imidazoline efaroxan. In β-cells isolated from patients with either nontypical hyperinsulinism (preserved KATP channel function) or from the control areas of the pancreas of patients with focal hyperinsulinism, BPDZ 154 activated KATP channels and was found to be more effective and less readily reversible than diazoxide. By contrast, it was not possible to activate KATP channels by either diazoxide or BPDZ 154 in β-cells from patients with hyperinsulinism as a consequence of defects in KATP channel function. In β-cells isolated from a patient with pancreatic insulinoma, KATP channels were readily recorded and modulated by BPDZ 154. These data suggest that BPDZ 154 or BPDZ 154-like compounds may have therapeutic potential in the treatment of certain forms of hyperinsulinism.