caa a22 4500 475771192 CHVBK 20180406123617.0 cr unu---uuuuu 170329e20000601xx s 000 0 eng 10.1007/s001250051370 doi (NATIONALLICENCE)springer-10.1007/s001250051370 A potent diazoxide analogue activating ATP-sensitive K+ channels and inhibiting insulin release [Elektronische Daten] [P. Lebrun, P. Arkhammar, M. -H. Antoine, Q. -A. Nguyen, J. Bondo Hansen, B. Pirotte] Aims/hypothesis. To characterise the effects of BPDZ 73 (7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide), a newly synthesised diazoxide analogue, on insulin secretory cells.¶Methods. Measurements of 86Rb, 45Ca outflow, membrane potential, [Ca2+]i, insulin release in secretory cells as well as measurements of smooth muscle 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 μmol/l. The drug increased the rate of 86Rb (42K substitute) outflow from perifused rat pancreatic islets. This effect was inhibited by glibenclamide, a KATP channel blocker. Measurements of DiBAC4(3) fluorescence further indicated that BPDZ 73 hyperpolarised the insulin secreting cells. It also decreased 45Ca outflow from pancreatic islets perifused throughout in the presence of 16.7 mmol/l glucose and extracellular Ca2+. By contrast, the drug did not affect the increase in 45Ca 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 considerable increase in blood glucose concentration whereas diazoxide induced a modest rise in glycaemia. Lastly, the vasorelaxant properties of BPDZ 73 were 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 KATP channels with subsequent decrease in Ca2+ inflow and [Ca2+]i. The drug seems to be a KATP channel opener, more potent and more selective than diazoxide for insulin secreting cells. [Diabetologia (2000) 43: 723-732] Springer-Verlag Berlin Heidelberg, 2000 Keywords Diazoxide, ATP sensitive K+ channel, rat pancreatic islets, insulin release nationallicence Lebrun P. Laboratory of Pharmacology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium, BE aut Arkhammar P. Bioimage Novo Nordisk, Soborg, Denmark, DK aut Antoine M. -H Laboratory of Pharmacology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium, BE aut Nguyen Q. -A Laboratory of Pharmacology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium, BE aut Bondo Hansen J. Health Care Discovery, Novo Nordisk, Malov, Denmark, DK aut Pirotte B. Department of Medicinal Chemistry, Institute of Pharmacy, University of Liège, Liège, Belgium, BE aut https://doi.org/10.1007/s001250051370 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s001250051370 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lebrun P. Laboratory of Pharmacology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium, BE aut NATIONALLICENCE 700 1- Arkhammar P. Bioimage Novo Nordisk, Soborg, Denmark, DK aut NATIONALLICENCE 700 1- Antoine M. -H Laboratory of Pharmacology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium, BE aut NATIONALLICENCE 700 1- Nguyen Q. -A Laboratory of Pharmacology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium, BE aut NATIONALLICENCE 700 1- Bondo Hansen J. Health Care Discovery, Novo Nordisk, Malov, Denmark, DK aut NATIONALLICENCE 700 1- Pirotte B. Department of Medicinal Chemistry, Institute of Pharmacy, University of Liège, Liège, Belgium, BE aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer