title: BPDZ 154 activates adenosine 5'-triphosphate-sensitive potassium channels: in vitro studies using rodent insulin-secreting cells and islets isolated from patients with hyperinsulinism.
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, (86)Rb(+) and (45)Ca(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 K(ATP) channel function. In beta-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.
authors.affiliation: Department of Biomedical Science, Institute of Molecular Physiology, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Cosgrove
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Antoine
authors.forename: Anne T
authors.initials: AT
authors.lastname: Lee
authors.forename: Philippa D
authors.initials: PD
authors.lastname: Barnes
authors.forename: Pascale
authors.initials: P
authors.lastname: de Tullio
authors.forename: Peter
authors.initials: P
authors.lastname: Clayton
authors.forename: Rory
authors.initials: R
authors.lastname: McCloy
authors.forename: Pascal
authors.initials: P
authors.lastname: De Lonlay
authors.forename: Claire
authors.initials: C
authors.lastname: Nihoul-Fékété
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Robert
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saudubray
authors.forename: Jacques
authors.initials: J
authors.lastname: Rahier
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Lindley
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
authors.forename: Al
authors.initials: A
authors.lastname: Aynsley-Green
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.forename: Philippe
authors.initials: P
authors.lastname: Lebrun
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dunne
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000293:Adolescent; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D001581:Benzothiadiazines / Q000494:pharmacology*; D002132:Calcium Radioisotopes / Q000378:metabolism; D002460:Cell Line; D002675:Child, Preschool; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006946:Hyperinsulinism / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007223:Infant; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000503:physiopathology; D007515:Islets of Langerhans / Q000503:physiopathology*; D008297:Male; D010190:Pancreatic Neoplasms / Q000503:physiopathology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012414:Rubidium Radioisotopes / Q000378:metabolism; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; C468751:BPDZ 154; D001572:Benzofurans; D001581:Benzothiadiazines; D002132:Calcium Radioisotopes; D003499:Cyclic S-Oxides; D007004:Hypoglycemic Agents; D007093:Imidazoles; D007328:Insulin; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; D000255:Adenosine Triphosphate; D014044:Tolbutamide; C062597:efaroxan; D005947:Glucose