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 (K-ATP) channel agonist, BPDZ 154 (6,7-dichloro-3-isopropylamino-4H-1,2,4benzothiadiazine 1,1-dioxide), was synthesized, and its effects on insulin-secreting cells were evaluated using electrophysiology, Rb-86(+) and Ca-45(2+) 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 beta-cells isolated from patients with either nontypical hyperinsulinism (preserved K-ATP channel function) or from the control areas of the pancreas of patients with focal hyperinsulinism, BPDZ 154 activated K-ATP channels and was found to be more effective and less readily reversible than diazoxide. By contrast, it was not possible to activate K-ATP channels by either diazoxide or BPDZ 154 in beta-cells from patients with hyperinsulinism as a consequence of defects in KATP channel function. In beta-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.