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 synthesized 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-chloro-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 islets. This effect persisted in the absence of external Ca2+ but was inhibited by glibenclamide, a K-ATP channel blocker. Inside-out patch-clamp experiments revealed that HEI 713 increased K-ATP channel openings. 4 HEI 713 decreased Ca-45 outflow, insulin output and cytosolic free Ca2+ concentration 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 the K+ (50 mM)-induced increase in Ca-45 outflow. 5 In aortic rings, the vasorelaxant effects of HEI 713, less potent than diazoxide, were sensitive to glibenclamide and to the extracellular K+ concentration. 6 The drug elicited a glibenclamide-sensitive increase in Rb-86 outflow from perifused rat aortic rings. 7 Our data describe an original compound which inhibits insulin release with a similar potency to diazoxide but which has fewer vasorelaxant effects. 8 Our results suggest that, in both aortic rings and islet tissue, the biological effects of HEI 713 mainly result from activation of KATP channels ultimately leading to a decrease in Ca2+ inflow.