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

1. 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-methylquinolin4(1H)-one (HEI 713). The average IC 50 values were 16.9±0.8 μM for HEI 713 and 18.4±2.2μM for diazoxide. 3. HEI 713 increased the rate of 86Rb outflow from perifused pancreatic islets. This effect persisted in the absence of external Ca 2+ 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 45Ca outflow, insulin output and cytosolic free Ca 2+ concentration in pancreatic islets and islet cells incubated in the presence of 16.7 or 20 mM glucose and extracellular Ca 2+. The drug did not affect the K +(50 mM)-induced increase in 45Ca 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 86Rb 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 K ATP channels ultimately leading to a decrease in Ca 2+ inflow.