title: Metformin induces cardioprotection against ischaemia/reperfusion injury in the rat heart 24 hours after administration.
abstract: The UK Prospective Diabetes Study demonstrated that the hypoglycaemic drug metformin is associated with a reduction in cardiovascular events in a group of obese type 2 diabetes patients. The energy sensing enzyme AMP-activated protein kinase (AMPK) has been indicated to play an important protective role in the ischaemic heart and is activated by metformin. The aim of this study was to determine whether a single dose of metformin protects the myocardium against experimentally induced ischaemia 24 hr after the administration, and furthermore to determine whether a single dose of metformin results in an acute increase in myocardial AMPK activity. Wistar rats were given either a single oral dose of metformin (250 mg/kg body weight), or a single oral dose of saline. After 24 hr, the hearts were Langendorff-perfused and subjected to 45 min. of coronary artery occlusion. Infarct size was determined by staining with triphenyltetrazoliumchloride (TTC) and Evans Blue and expressed as a percentage of the risk zone (IS/AAR %). Isoform specific AMPK activity was measured 2 hr after administration of metformin or saline. Infarct size was significantly reduced in the metformin treated (I/R: 19.9 +/- 3.9%versus 36.7 +/- 3.6%, P < 0.01, n = 8-14) compared to the control group. A single oral dose of metformin resulted in an approximately ~2-fold increase in AMPK-alpha2 activity 2 hr after administration (P < 0.015, n = 10). In conclusion, a single dose of metformin results in an acute increase in myocardial AMPK activity measured 2 hr after administration and induces a significant reduction in myocardial infarct size 24 hr after metformin administration. Increased AMPK activity may be an important signal mediator involved in the mechanisms behind the cardioprotective effects afforded by metformin.
authors.affiliation: Institute of Pharmacology, University of Aarhus, Aarhus C, Denmark. lsj@farm.au.dk
authors.forename: Lasse
authors.initials: L
authors.lastname: Solskov
authors.forename: Bo
authors.initials: B
authors.lastname: Løfgren
authors.forename: Steen B
authors.initials: SB
authors.lastname: Kristiansen
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
authors.forename: Rasmus
authors.initials: R
authors.lastname: Pold
authors.forename: Torsten T
authors.initials: TT
authors.lastname: Nielsen
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Bøtker
authors.forename: Ole
authors.initials: O
authors.lastname: Schmitz
authors.forename: Sten
authors.initials: S
authors.lastname: Lund
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism; D009203:Myocardial Infarction / Q000201:enzymology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*
chemical_list: D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases