The antimalarial agent mefloquine inhibits ATP‐sensitive K‐channels

The aim of this study was to determine whether antimalarial agents inhibit ATP‐sensitive potassium (K ATP ) channels and thereby contribute to the observed side‐effects of these drugs. Mefloquine (10–100 μ M ), but not artenusate (100 μ M ), stimulated insulin release from pancreatic islets in vitro . Macroscopic K ATP currents were studied in inside‐out patches excised from Xenopus oocytes expressing cloned K ATP channels. Mefloquine (IC 50 ∼3 μ M ), quinine (IC 50 ∼3 μ M ), and chloroquine inhibited the pancreatic β‐cell type of K ATP channel Kir6.2/SUR1. Artenusate (100 μ M ) was without effect. Mefloquine and quinine also blocked a truncated form of Kir6.2 (Kir6.2ΔC36) when expressed in the absence of SUR1. The extent of block was similar to that observed for Kir6.2/SUR1 currents. Our results suggest that inhibition of the β‐cell K ATP channel accounts for the ability of quinoline‐based antimalarial drugs to stimulate insulin secretion, and thereby produce hypoglycaemia. The results also indicate that quinoline‐based antimalarial agents inhibit K ATP channels by interaction with the Kir6.2 subunit. This subunit is common to β‐cell, neuronal, cardiac, skeletal muscle, and some smooth muscle 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.British Journal of Pharmacology (2000) 131 , 756–760; doi: 10.1038/sj.bjp.0703638