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-1,2,4-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.
Cosgrove
Karen E
KE
Department of Biomedical Science, Institute of Molecular Physiology, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
Antoine
Marie-Hélène
MH
Lee
Anne T
AT
Barnes
Philippa D
PD
de Tullio
Pascale
P
Clayton
Peter
P
McCloy
Rory
R
De Lonlay
Pascal
P
Nihoul-Fékété
Claire
C
Robert
Jean-Jacques
JJ
Saudubray
Jean-Marie
JM
Rahier
Jacques
J
Lindley
Keith J
KJ
Hussain
Khalid
K
Aynsley-Green
Al
A
Pirotte
Bernard
B
Lebrun
Philippe
P
Dunne
Mark J
MJ
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
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