Gliclazide produces high-affinity block of KATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells

Aims/hypothesis. Sulphonylureas stimulate insulin secretion by closing ATP-sensitive potassium (K-ATP) channels in the pancreatic beta-cell membrane. K-ATP channels are also found in other tissues, including heart and smooth muscle, where they link cellular metabolism to electrical activity. The sulphonylurea gliclazide blocks recombinant beta-cell K-ATP channels (Kir6.2/SUR1) but not heart (Kir6.2/SUR2A) or smooth muscle (Kir6.2/SUR2B) K-ATP channels with high potency. In this study, we examined the specificity of gliclazide for the native (as opposed to recombinant) K-ATP channels in beta cells, heart and smooth muscle. Methods. The action of the drug was studied by whole-cell current recordings of native K-ATP channels in isolated pancreatic beta-cells and myocytes from heart and smooth muscle. Results. Gliclazide blocked whole-cell beta-cell K-ATP currents with an IC50 of 184 +/- 30 nmol/l (n = 6-10) but was much less effective in cardiac and smooth muscle (IC(50)s of 19.5 +/- 5.4 mu mol/l (n = 6-12) and 37.9 +/- 1.0 mu mol/l (n = 5-10), respectively). In all three tissues, the action of the drug on whole-cell K-ATP currents was rapidly reversible. In inside-out patches on beta-cells, gliclazide (1 mu mol/1) produced a maximum of 66 +/- 13% inhibition (n = 5), compared with more than 98% block in the whole-cell configuration. Conclusion/interpretation. Gliclazide is a high-potency sulphonylurea which shows specificity for the pancreatic beta-cell K-ATP channel over heart and smooth muscle. In this respect, it differs from glibenclamide. The difference in the maximal block observed in the excised patch and whole-cell recordings from beta-cells, may be due to the absence of intracellular Mg-nucleotides in the excised patch experiments.