title: Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies.
abstract: BACKGROUND
  Glucagon-like peptide-1 (7-36) amide (GLP-1) protects against stunning and cumulative left ventricular dysfunction in humans. The mechanism remains uncertain but GLP-1 may act by opening mitochondrial K-ATP channels in a similar fashion to ischemic conditioning. We investigated whether blockade of K-ATP channels with glibenclamide abrogated the protective effect of GLP-1 in humans.
  
  
  METHODS
  Thirty-two non-diabetic patients awaiting stenting of the left anterior descending artery (LAD) were allocated into 4 groups (control, glibenclamide, GLP-1, and GLP-1 + glibenclamide). Glibenclamide was given orally prior to the procedure. A left ventricular conductance catheter recorded pressure-volume loops during a 1-min low-pressure balloon occlusion (BO1) of the LAD. GLP-1 or saline was then infused for 30-min followed by a further 1-min balloon occlusion (BO2). In a non-invasive study, 10 non-diabetic patients were randomized to receive two dobutamine stress echocardiograms (DSE) during GLP-1 infusion with or without oral glibenclamide pretreatment.
  
  
  RESULTS
  GLP-1 prevented stunning even with glibenclamide pretreatment; the Δ % dP/dtmax 30-min post-BO1 normalized to baseline after GLP-1: 0.3 ± 6.8 % (p = 0.02) and GLP-1 + glibenclamide: -0.8 ± 9.0 % (p = 0.04) compared to control: -11.5 ± 10.0 %. GLP-1 also reduced cumulative stunning after BO2: -12.8 ± 10.5 % (p = 0.02) as did GLP-1 + glibenclamide: -14.9 ± 9.2 % (p = 0.02) compared to control: -25.7 ± 9.6 %. Glibenclamide alone was no different to control. Glibenclamide pretreatment did not affect global or regional systolic function after GLP-1 at peak DSE stress (EF 74.6 ± 6.4 vs. 74.0 ± 8.0, p = 0.76) or recovery (EF 61.9 ± 5.7 vs. 61.4 ± 5.6, p = 0.74).
  
  
  CONCLUSIONS
  Glibenclamide pretreatment does not abrogate the protective effect of GLP-1 in human models of non-lethal myocardial ischemia. Trial registration Clinicaltrials.gov Unique Identifier: NCT02128022.
authors.affiliation: Department of Interventional Cardiology, Papworth Hospital, Papworth Everard, Cambridge, CB23 3RE, UK.|Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Joel P
authors.initials: JP
authors.lastname: Giblett
authors.affiliation: Department of Clinical Engineering, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Axell
authors.affiliation: Department of Clinical Engineering, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: White
authors.affiliation: Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Clarke
authors.affiliation: Department of Interventional Cardiology, Papworth Hospital, Papworth Everard, Cambridge, CB23 3RE, UK.
authors.forename: Liam
authors.initials: L
authors.lastname: McCormick
authors.affiliation: Department of Interventional Cardiology, Papworth Hospital, Papworth Everard, Cambridge, CB23 3RE, UK.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Read
authors.affiliation: Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Johannes
authors.initials: J
authors.lastname: Reinhold
authors.affiliation: Department of Interventional Cardiology, Papworth Hospital, Papworth Everard, Cambridge, CB23 3RE, UK.|Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Brown
authors.affiliation: Department of Interventional Cardiology, Papworth Hospital, Papworth Everard, Cambridge, CB23 3RE, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: O'Sullivan
authors.affiliation: Department of Interventional Cardiology, Papworth Hospital, Papworth Everard, Cambridge, CB23 3RE, UK.
authors.forename: Nick E J
authors.initials: NE
authors.lastname: West
authors.affiliation: Department of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Dutka
authors.affiliation: Department of Interventional Cardiology, Papworth Hospital, Papworth Everard, Cambridge, CB23 3RE, UK. s.hoole@nhs.net.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hoole
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D025401:Echocardiography, Stress / Q000379:methods; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000627:therapeutic use*; D005905:Glyburide / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015221:Potassium Channels / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D052216:Glucagon-Like Peptide 1; D005905:Glyburide
keywords: Cardioprotection; Glucagon-like peptide-1; Ischemia–reperfusion injury; KATP