A potent diazoxide analogue activating ATP-sensitive K+ channels and inhibiting insulin release

Aims/hypothesis. To characterise the effects of BPDZ 73 (7-chloro-3-isoprop ylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide), a newly synthesised diazoxi de analogue, on insulin secretory cells. Methods. Measurements of Rb-86, Ca-45 outflow, membrane potential, [Ca2+](i ), insulin release in secretory cells as well as measurements of smooth mus cle contractile activity and glycaemia were carried out. Results. The analogue BPDZ 73 induced a dose-dependent decrease in insulin output. The IC50 value averaged 0.73 +/- 0.05 mu mol/l. The drug increased the rate of Rb-86 (K-42 substitute) outflow from perifused rat pancreatic i slets. This effect was inhibited by glibenclamide, a K-ATP channel blocker. Measurements of DiBAC(4)(3) fluorescence further indicated that BPDZ 73 hy perpolarised the insulin secreting cells. It also decreased Ca-45 outflow f rom pancreatic islets perifused throughout in the presence of 16.7 mmol/l g lucose and extracellular Ca2+. By contrast, the drug did not affect the inc rease in Ca-45 outflow mediated by K+ depolarisation. In single beta cells, BPDZ 73 inhibited the glucose-induced but not the K+-induced rise in [Ca2](i). Moreover, in Wistar rats, i.p. injection of BPDZ 73 provoked a consid erable increase in blood glucose concentration whereas diazoxide induced a modest rise in glycaemia. Lastly, the vasorelaxant properties of BPDZ 73 we re slightly less pronounced than those of diazoxide. Conclusion/interpretation. The inhibitory effect of BPDZ 73 on the insulin- releasing process results from the activation of K-ATP channels with subseq uent decrease in Ca2+ inflow and [Ca2+](i). The drug seems to be a K-ATP ch annel opener, more potent and more selective than diazoxide for insulin sec reting cells.