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BPDZ 154 Activates Adenosine 5'-Triphosphate-Sensitive Potassium Channels: In Vitro Studies Using Rodent Insulin-Secreting Cells and Islets Isolated from Patients with Hyperinsulinism

Institute of Molecular Physiology and Department of Biomedical Science (K.E.C., A.T.L., P.D.B., M.J.D.), University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom; Laboratory of Pharmacology (M.-H.A., P.L.), Faculty of Medicine, Université Libre de Bruxelles, Bruxelles 1070, Belgium; Department of Medicinal Chemistry (P.d.T., B.P.), Université de Liège, Liège 4000, Belgium; Manchester Children’s Hospital (P.C.), Manchester M27 4MA, United Kingdom; Department of Surgery (R.M.), Department of Medicine, Manchester Royal Infirmary, Manchester M13 9WL, United Kingdom; Department of Pediatrics, Hôpital Necker-Enfants Malades (P.D.L., C.N.-F., J.-J.R., J.-M.S.), 75743 Paris, France; Université Catholique de Louvain (J.R.), Bruxelles, Belgium; and Institute of Child Health (K.J.L., K.H., A.A.-G.), Great Ormond Street Hospital, London WC1N 1EH, United Kingdom

Address all correspondence and requests for reprints to: Prof. M. J. Dunne, Institute of Molecular Physiology and Department of Biomedical Science, The University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom. E-mail: m.j.dunne{at}sheffield.ac.uk.

Abstract

A novel ATP-sensitive potassium channel (K_ATP) 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 ß-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 ß-cells from patients with hyperinsulinism as a consequence of defects in K_ATP channel function. In ß-cells isolated from a patient with pancreatic insulinoma, K_ATP 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.

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