title: Glimepiride treatment facilitates ischemic preconditioning in the diabetic heart.
abstract: OBJECTIVE
  The diabetic heart is resistant to the myocardial infarct-limiting effects of ischemic preconditioning (IPC). This may be in part due to the downregulation of the phosphatidylinositol 3'-kinase-Akt pathway, an essential component of IPC protection. We hypothesized that treating the diabetic heart with the sulfonylurea, glimepiride, which has been reported to activate Akt, may lower the threshold required to protect the diabetic heart by IPC.
  
  
  METHODS
  Goto-Kakizaki rats (a type II lean model of diabetes) received glimepiride (20 mg/kg per d, by oral gavage) or vehicle for (a) 3 months (chronic treatment) or (b) 24 hours (subacute treatment). In the third group, glimepiride (10 μmol/L) was administered only to the isolated hearts on the Langendorff apparatus (acute treatment). All hearts were subjected to 35 minutes ischemia and 120 minutes reperfusion ex vivo, at the end of which infarct size was determined by tetrazolium staining. Preconditioning treatment comprised 1 (IPC-1) or 3 (IPC-3) cycles of 5 minutes global ischemia and 10 minutes reperfusion.
  
  
  RESULTS
  The diabetic heart was found to be resistant to IPC such that 3-IPC cycles, instead of the usual 1-IPC cycle, were required for cardioprotection. However, pretreatment with glimepiride lowered the threshold for IPC such that both 1 and 3 cycles of IPC elicited cardioprotection: chronic glimepiride treatment (IPC-1 31.9% ± 3.8% and IPC-3 33.5% ± 2.4% vs 43.9% ± 1.4% control, P < .05; N > 6 per group); subacute glimepiride treatment (IPC-1 31.1% ± 3.0% and IPC-3 29.3% ± 3.3% vs 42.2% ± 2.3% control, P < .05 N > 6 per group); and acute glimepiride treatment (IPC-1 28.2% ± 3.7% and IPC-3 24.6% ± 5.4% vs 41.9% ± 5.4% control, P < .05; N > 6 per group). This effect of glimepiride was independent of changes in blood glucose.
  
  
  CONCLUSIONS
  We report for the first time that glimepiride treatment facilitates the cardioprotective effect elicited by IPC in the diabetic heart.
authors.affiliation: The Hatter Cardiovascular Institute, University College London Hospital and Medical School, London, UK. d.hausenloy@ucl.ac.uk
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Hausenloy
authors.forename: Abigail M
authors.initials: AM
authors.lastname: Wynne
authors.forename: Mihaela M
authors.initials: MM
authors.lastname: Mocanu
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D020536:Enzyme Activators / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000032:analysis; D006321:Heart / Q000187:drug effects; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010477:Perfusion; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002316:Cardiotonic Agents; D020536:Enzyme Activators; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D051057:Proto-Oncogene Proteins c-akt; D013453:Sulfonylurea Compounds; C057619:glimepiride