Vol. 295, Issue 1, 29-36, October 2000

Inhibition of Volume-Regulated and Calcium-Activated Chloride Channels by the Antimalarial Mefloquine¹

Chantal Maertens, Lin Wei, Guy Droogmans and Bernd Nilius

KU Leuven, Laboratorium voor Fysiologie, Campus Gasthuisberg, Leuven, Belgium

We have used the whole-cell patch-clamp technique to study the effect of mefloquine (Lariam), a commonly used antimalarial drug, on the volume-regulated anion channel (VRAC) in cultured bovine pulmonary artery endothelial cells. We also examined its effects on other Cl channels, i.e., the Ca²⁺-activated Cl channel and the cystic fibrosis transmembrane conductance regulator, to assess the specificity of this compound for VRAC. At pH 7.4 mefloquine induced a fast and reversible block of the volume-sensitive chloride current (I_Cl,swell), with an IC₅₀ value of 1.19 ± 0.07 µM. The blocking efficiency increased with increasing extracellular pH (IC₅₀ value for pH 8.8 was 0.15 ± 0.01 µM), indicating that this effect is mediated by the uncharged form of mefloquine. Ca²⁺-activated Cl currents, I_Cl,Ca, activated by loading T84 cells via the patch pipette with 1 µM free Ca²⁺ also were inhibited by mefloquine (IC₅₀ value 3.01 ± 0.17 µM at pH 7.4). The cystic fibrosis transmembrane conductance regulator channel, transiently transfected in cultured bovine pulmonary artery endothelial cells, was not affected by 10 µM of the drug. This study describes for the first time effects of mefloquine on anion channels. Our data reveal a potent block of VRAC and Ca²⁺-activated Cl channel at therapeutic concentrations. These results may contribute to a better understanding of the actions and side effects of this widely used antimalarial drug.