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'-dimethylpropyl)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 Rb-86 outflow regardless of the extracellular glucose concentration. The effects of BPDZ 44 on Rb-86 outflow persisted in the absence of extracellular Ca2+ but were abolished by glibenclamide. BPDZ 44 markedly decreased Ca-45 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 Ca-45 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).