Inhibition of heterologously expressed cystic fibrosis transmembrane conductance regulator Cl− channels by non‐sulphonylurea hypoglycaemic agents

Hypoglycaemia‐inducing sulphonylureas, such as glibenclamide, inhibit cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channels. In search of modulators of CFTR, we investigated the effects of the non‐sulphonylurea hypoglycaemic agents meglitinide, repaglinide, and mitiglinide (KAD‐1229) on CFTR Cl− channels in excised inside‐out membrane patches from C127 cells expressing wild‐type human CFTR. When added to the intracellular solution, meglitinide and mitiglinide inhibited CFTR Cl− currents with half‐maximal concentrations of 164±19 μM and 148±36 μM, respectively. However, repaglinide only weakly inhibited CFTR Cl− currents. To understand better how non‐sulphonylurea hypoglycaemic agents inhibit CFTR, we studied single channels. Channel blockade by both meglitinide and mitiglinide was characterized by flickery closures and a significant decrease in open probability (Po). In contrast, repaglinide was without effect on either channel gating or Po, but caused a small decrease in single‐channel current amplitude. Analysis of the dwell time distributions of single channels indicated that both meglitinide and mitiglinide greatly decreased the open time of CFTR. Mitiglinide‐induced channel closures were about 3‐fold longer than those of meglitinide. Inhibition of CFTR by meglitinide and mitiglinide was voltage‐dependent: at positive voltages channel blockade was relieved. The data demonstrate that non‐sulphonylurea hypoglycaemic agents inhibit CFTR. This indicates that these agents have a wider specificity of action than previously recognized. Like glibenclamide, non‐sulphonylurea hypoglycaemic agents may inhibit CFTR by occluding the channel pore and preventing Cl− permeation.