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

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

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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.
Original languageEnglish
Article number99
Number of pages12
JournalCardiovascular Diabetology
Volume15
DOIs
Publication statusPublished - 19 Jul 2016
Externally publishedYes

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