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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 Electronic supplementary material The online version of this article (doi:10.1186/s12933-016-0416-3) contains supplementary material, which is available to authorized users.

Introduction Glucagon-like Peptide-1 (GLP-1) protects against left ventricular (LV) stunning but the mechanism is unclear. Two protocols (P1 and P2) investigated whether blockade of mitochondrial K-ATP channels (responsible for ischaemic conditioning) with glibenclamide abrogates GLP-1 cardioprotection in humans. Methods P1. Patients attending for elective PCI to their LAD were assigned to 4 groups (Figure 1). Pressure-volume loops, allowing systolic/diastolic assessment, were recorded at baseline (BL1) and after 1-minute LAD balloon occlusion (BO1). GLP-1 or saline infusion was started after BO1, with loops repeated (BL2 and BO2) at 30mins. P2. Patients awaiting PCI underwent serial dobutamine stress echos (DSE) with tissue Doppler, to assess impact of GLP-1 and glibenclamide on global and regional systolic function. Results P1. BO1 reduced LV function in all groups. Recovery from stunning (BL2) and cumulative dysfunction (BO2) improved with GLP-1 alone, and when glibenclamide was added. P2. At peak stress and recovery there was additional improvement in systolic function with GLP-1 versus control. However, systolic function was unchanged, with and without glibenclamide. Conclusion Glibenclamide did not abrogate GLP-1-mediated cardioprotection, suggesting GLP-1 acts through a non-KATP-dependent pathway in humans.