title: Myocardial protection from either ischaemic preconditioning or nicorandil is not blocked by gliclazide.
abstract: OBJECTIVE
  We compared the effects of two sulphonylureas, glibenclamide and gliclazide, on ischaemic preconditioning (IPC) and nicorandil-induced protection in the in-vivo rat. We also studied the effects of these agents on the membrane potential of isolated rat mitochondria.
  
  
  METHODS
  Anaesthetised male Sprague-Dawley rats were used in an open chest model of myocardial infarction. Animals were randomly assigned to receive one of the following drugs: (1) saline control, (2) glibenclamide, 0.3 mg/kg, or (3) gliclazide, 1 mg/kg i.v. bolus. Each was then further randomised to one of the following treatments: (a) control, (b) IPC (consisting of 2 x 5 mins of regional ischaemia and 5 minutes reperfusion) or (c) nicorandil (50 ug/kg/min i.v). infusion. Each group then underwent 25 mins regional ischaemia and 2 hrs reperfusion. Infarct to risk zone ratio (%) was calculated by computerised planimetry of tetrazolium stained heart slices. The membrane potential of mitochondria isolated from rat ventricles was measured using flow cytometry. Comparisons were made between groups in control medium, nicorandil alone, and nicorandil with either glibenclamide or gliclazide.
  
  
  RESULTS
  Infarct size was significantly reduced with IPC (15.0 +/- 1.1%,) and nicorandil (25.5 +/- 4.2%), versus control (44.1 +/- 3.2%), p < 0.005. Glibenclamide abolished IPC (40.8 +/- 4.6%) and nicorandil-induced protection completely (39.5 +/- 5.1%). Gliclazide had no adverse effect on IPC (20.4 +/- 1.9%) or nicorandil-induced protection (23.6 +/- 2.2%), p < 0.005. Nicorandil caused a partial depolarisation of the mitochondrial membrane potential (-14.92 +/- 2.34%), which was abolished by glibenclamide (+2.03 +/- 0.53%), but not gliclazide (-16.47 +/- 3.36%), p < 0.01.
  
  
  CONCLUSIONS
  Both IPC and nicorandil-induced protection are abolished by glibenclamide but not gliclazide in-vivo. These results may have important clinical implications in type II diabetic patients at risk of acute coronary syndromes.
authors.affiliation: Hatter Institute for Cardiovascular Studies, Centre for Cardiology, University College London Hospitals and Medical School, Grafton Way, London WC1E 6DB, UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Maddock
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Siedlecka
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D005907:Gliclazide / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects*; D009203:Myocardial Infarction / Q000517:prevention & control*; D020108:Nicorandil / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000889:Anti-Arrhythmia Agents; D007004:Hypoglycemic Agents; D020108:Nicorandil; D005907:Gliclazide; D005905:Glyburide