Gliclazide produces high-affinity block of K-ATP 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 sul phonylurea gliclazide blocks recombinant beta-cell K-ATP channels (Kir6.2/S UR1) but not heart (Kir6.2/SUR2A) or smooth muscle (Kir6.2/SUR2B) K-ATP cha nnels with high potency. In this study, we examined the specificity of glic lazide for the native (as opposed to recombinant) K-ATP channels in beta ce lls, heart and smooth muscle. Methods. The action of the drug was studied by whole-cell current recording s of native K-ATP channels in isolated pancreatic beta-cells and myocytes f rom heart and smooth muscle. Results. Gliclazide blocked whole-cell beta-cell K-ATP currents with an IC5 0 of 184 +/- 30 nmol/l (n = 6-10) but was much less effective in cardiac an d 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-ce ll configuration. Conclusion/interpretation. Gliclazide is a high-potency sulphonylurea which shows specificity for the pancreatic beta-cell K-ATP channel over heart an d smooth muscle. In this respect, it differs from glibenclamide. The differ ence in the maximal block observed in the excised patch and whole-cell reco rdings from beta-cells, may be due to the absence of intracellular Mg-nucle otides in the excised patch experiments.