A pyridothiadiazine (BPDZ 44) as a new and potent activator of ATP-sensitive K+ channels.
The present study was undertaken to characterize the effects of [3-(1',2'-dimethyl-propyl)amino-4H-pyrido[4,3-e][1,2,4]thiadiazine 1,1-dioxide] (BPDZ 44), a new pyridothiadiazine derivative, on ionic and secretory events in rat pancreatic islets. The drug increased the rate of 86Rb outflow regardless of the extracellular glucose concentration. The effects of BPDZ 44 on 86Rb outflow persisted in the absence of extracellular Ca2+ but were abolished by glibenclamide. BPDZ 44 markedly decreased 45Ca outflow and insulin output from islets perifused in the presence of 16.7 mM glucose and extracellular Ca2+. The drug did not affect the increase in 45Ca outflow mediated by K+ depolarization. Lastly, in single B-cells, BPDZ 44 inhibited the glucose but not the KCl-induced rise in cytosolic Ca2+ concentration ([Ca2+]i). These data suggest that BPDZ 44 inhibits the insulin releasing process by activating ATP-sensitive K+ channels. This K+ channel activation will lead to a decrease in Ca2+ influx and reduction in [Ca2+]i.
Pirotte
B
B
Laboratory of Pharmacology, Free University of Brussels, Belgium.
Antoine
M H
MH
de Tullio
P
P
Hermann
M
M
Herchuelz
A
A
Delarge
J
J
Lebrun
P
P
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002132:Calcium Radioisotopes / Q000378:metabolism; D002478:Cells, Cultured; D016257:Fura-2; D005947:Glucose / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D012414:Rubidium Radioisotopes / Q000378:metabolism; D013829:Thiadiazines / Q000494:pharmacology*
D002132:Calcium Radioisotopes; D015221:Potassium Channels; D011725:Pyridines; D012414:Rubidium Radioisotopes; D013829:Thiadiazines; C087201:BPDZ 44; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium; D016257:Fura-2