The antimalarial agent mefloquine inhibits ATP-sensitive K-channels

1 The aim of this study was to determine whether antimalarial agents inhibi t ATP-sensitive potassium (K-ATP) channels and thereby contribute to the ob served side-effects of these drugs. 2 Mefloquine (10-100 muM), but not artenusate (100 muM), stimulated insulin release from pancreatic islets in vitvo. 3 Macroscopic K-ATP currents were studied in inside-out patches excised fro m Xenopus oocytes expressing cloned K-ATP channels. 4 Mefloquine (IC50 similar to3 muM), quinine (IC50 similar to3 muM), and ch loroquine inhibited the pancreatic beta -cell type of KATP channel Kir6.2/S UR1. Artenusate (100 muM) was without effect. 5 Mefloquine and quinine also blocked a truncated form of Kir6.2 (Kir6.2 De lta C36) when expressed in the absence of SUR1. The extent of block was sim ilar to that observed for Kir6.2/SUR1 currents. 6 Our results suggest that inhibition of the beta -cell K-ATP channel accou nts for the ability of quinoline-based antimalarial drugs to stimulate insu lin secretion, and thereby produce hypoglycaemia. 7 The results also indicate that quinoline-based antimalarial agents inhibi t K-ATP channels by interaction with the Kir6.2 subunit. This subunit is co mmon to beta -cell, neuronal, cardiac, skeletal muscle, and some smooth mus cle K-ATP channels suggesting that K-ATP channel inhibition may contribute to the other side effects of these drugs, which include cardiac conduction abnormalities and neuropsychiatric disturbances.