title: Combined vildagliptin and metformin exert better cardioprotection than monotherapy against ischemia-reperfusion injury in obese-insulin resistant rats.
abstract: BACKGROUND
  Obese-insulin resistance caused by long-term high-fat diet (HFD) consumption is associated with left ventricular (LV) dysfunction and increased risk of myocardial infarction. Metformin and vildagliptin have been shown to exert cardioprotective effects. However, the effect of these drugs on the hearts under obese-insulin resistance with ischemia-reperfusion (I/R) injury is unclear. We hypothesized that combined vildagliptin and metformin provide better protective effects against I/R injury than monotherapy in obese-insulin resistant rats.
  
  
  METHODS
  Male Wistar rats were fed either HFD or normal diet. Rats in each diet group were divided into 4 subgroups to receive vildagliptin, metformin, combined vildagliptin and metformin, or saline for 21 days. Ischemia due to left anterior descending artery ligation was allowed for 30-min, followed by 120-min reperfusion. Metabolic parameters, heart rate variability (HRV), LV function, infarct size, mitochondrial function, calcium transient, Bax and Bcl-2, and Connexin 43 (Cx43) were determined. Rats developed insulin resistance after 12 weeks of HFD consumption. Vildagliptin, metformin, and combined drugs improved metabolic parameters, HRV, and LV function. During I/R, all treatments improved LV function, reduced infarct size and Bax, increased Bcl-2, and improved mitochondrial function in HFD rats. However, only combined drugs delayed the time to the first VT/VF onset, reduced arrhythmia score and mortality rate, and increased p-Cx43 in HFD rats.
  
  
  CONCLUSIONS
  Although both vildagliptin and metformin improved insulin resistance and attenuate myocardial injury caused by I/R, combined drugs provided better outcomes than single therapy by reducing arrhythmia score and mortality rate.
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Nattayaporn
authors.initials: N
authors.lastname: Apaijai
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Kroekkiat
authors.initials: K
authors.lastname: Chinda
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; School of Medicine, Mae FahLuang University, Chiang Rai, Thailand.
authors.forename: Siripong
authors.initials: S
authors.lastname: Palee
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Siriporn
authors.initials: S
authors.lastname: Chattipakorn
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Biomedical Engineering Center, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000188:drug therapy; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004347:Drug Interactions; D006339:Heart Rate / Q000187:drug effects; D007333:Insulin Resistance; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D017202:Myocardial Ischemia / Q000150:complications*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D009765:Obesity / Q000150:complications*; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy; D000077597:Vildagliptin
chemical_list: D002316:Cardiotonic Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D008687:Metformin; D000077597:Vildagliptin; D000218:Adamantane; D002118:Calcium