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 IC ₅₀ of 184 ± 30 nmol/l (n = 6–10) but was much less effective in cardiac and smooth muscle (IC ₅₀s of 19.5 ± 5.4 μmol/l (n = 6–12) and 37.9 ± 1.0 μmol/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 μmol/l) 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. Diabetologia (2001) 44: 1019–1025] Received: 21 March 2001 and in revised form: 30 April 2001