Synthesis and characterization of a quinolinonic compound activating ATP-sensitive K+ channels in endocrine smooth muscle tissues

Original quinolinone derivatives structurally related to diazoxide were syn thesized and their effects on insulin secretion from rat pancreatic islets and the contractile activity of rat aortic rings determined. 2 A concentration-dependent decrease of insulin release was induced by 6-ch loro-2-methylquinolin-4(1H)-one (HEI 713). The average IC50 values were 16. 9 +/- 0.8 mum for HEI 713 and 18.4 +/- 2.2 mum for diazoxide. 3 HEI 713 increased the rate of Rb-86 outflow from perifused pancreatic isl ets. This effect persisted in the absence of external Ca2+ but was inhibite d by glibenclamide, a K-ATP channel blocker. Inside-out patch-clamp experim ents revealed that HEI 713 increased K-ATP channel openings. 4 HEI 713 decreased Ca-45 outflow, insulin output and cytosolic free Ca2+ c oncentration in pancreatic islets and islet cells incubated in the presence of 16.7 or 20 mM glucose and extracellular Ca2+. The drug did not affect t he K+ (50 mM)-induced increase in Ca-45 outflow. 5 In aortic rings, the vasorelaxant effects of HEI 713, less potent than di azoxide, were sensitive to glibenclamide and to the extracellular K+ concen tration. 6 The drug elicited a glibenclamide-sensitive increase in Rb-86 outflow fro m perifused rat aortic rings. 7 Our data describe an original compound which inhibits insulin release wit h a similar potency to diazoxide but which has fewer vasorelaxant effects. 8 Our results suggest that, in both aortic rings and islet tissue, the biol ogical effects of HEI 713 mainly result from activation of KATP channels ul timately leading to a decrease in Ca2+ inflow.