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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2016

Open Access 01-12-2016 | Original investigation

Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies

Authors: Joel P. Giblett, Richard G. Axell, Paul A. White, Sophie J. Clarke, Liam McCormick, Philip A. Read, Johannes Reinhold, Adam J. Brown, Michael O’Sullivan, Nick E. J. West, David P. Dutka, Stephen P. Hoole

Published in: Cardiovascular Diabetology | Issue 1/2016

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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
Appendix
Available only for authorised users
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Metadata
Title
Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies
Authors
Joel P. Giblett
Richard G. Axell
Paul A. White
Sophie J. Clarke
Liam McCormick
Philip A. Read
Johannes Reinhold
Adam J. Brown
Michael O’Sullivan
Nick E. J. West
David P. Dutka
Stephen P. Hoole
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2016
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-016-0416-3

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