title: Gliclazide produces high-affinity block of KATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells.
abstract: OBJECTIVE
  Sulphonylureas stimulate insulin secretion by closing ATP-sensitive potassium (KATP) channels in the pancreatic beta-cell membrane. KATP 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 KATP channels (Kir6.2/SUR1) but not heart (Kir6.2/SUR2A) or smooth muscle (Kir6.2/SUR2B) KATP channels with high potency. In this study, we examined the specificity of gliclazide for the native (as opposed to recombinant) KATP channels in beta cells, heart and smooth muscle.
  
  
  METHODS
  The action of the drug was studied by whole-cell current recordings of native KATP channels in isolated pancreatic beta-cells and myocytes from heart and smooth muscle.
  
  
  RESULTS
  Gliclazide blocked whole-cell beta-cell KATP currents with an IC50 of 184 +/- 30 nmol/l (n = 6-10) but was much less effective in cardiac and smooth muscle (IC50s of 19.5 +/- 5.4 micromol/l (n = 6-12) and 37.9 +/- 1.0 micromol/l (n = 5-10), respectively). In all three tissues, the action of the drug on whole-cell KATP currents was rapidly reversible. In inside-out patches on beta-cells, gliclazide (1 micromol/l) produced a maximum of 66 +/- 13 % inhibition (n = 5), compared with more than 98 % block in the whole-cell configuration.
  
  
  CONCLUSIONS
  Gliclazide is a high-potency sulphonylurea which shows specificity for the pancreatic beta-cell KATP 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.
authors.affiliation: Ion Channel Group, Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, UK.
authors.forename: C L
authors.initials: CL
authors.lastname: Lawrence
authors.forename: P
authors.initials: P
authors.lastname: Proks
authors.forename: G C
authors.initials: GC
authors.lastname: Rodrigo
authors.forename: P
authors.initials: P
authors.lastname: Jones
authors.forename: Y
authors.initials: Y
authors.lastname: Hayabuchi
authors.forename: N B
authors.initials: NB
authors.lastname: Standen
authors.forename: F M
authors.initials: FM
authors.lastname: Ashcroft
mesh_terms: D000818:Animals; D004553:Electric Conductivity; D005907:Gliclazide / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017208:Rats, Wistar
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D005907:Gliclazide