Nitroglycerin protects the endothelium from ischaemia and reperfusion: human mechanistic insight
Bibliographic record
Abstract
What is already known about this subject • The production of oxygen free radicals upon administration of nitroglycerin (GTN) and other organic nitrates has been advocated as one of the causes of nitrate‐induce tolerance and endothelial dysfunction. • It has been shown that nitrates also cause a protective phenomenon that is similar to ischaemic preconditioning, but the mechanisms of this effect have never been investigated in humans. What this study adds • We show, in vivo in humans, that GTN causes endothelial protection against ischaemic damage. • Furthermore, we show that this effect is mediated by release of oxygen free radicals and by opening of the mitochondrial permeability transition pore. Aims Nitroglycerin (GTN) modulates tissue damage induced by ischaemia and reperfusion (IR) in a mechanism that is similar to ischaemic preconditioning. We set out to study, using a human model of endothelial IR injury, whether GTN‐induced endothelial preconditioning is mediated by reactive oxygen species (ROS) formation and/or opening of mitochondrial permeability transition pores (mPTP). Methods In two double‐blind, randomized, parallel studies, a total of 66 volunteers underwent measurement of radial artery endothelium‐dependent, flow‐mediated dilation (FMD) before and after local IR. Subjects were treated, 24 h before IR, with different drugs in order to test the mechanism of GTN‐induced endothelial protection. Results Transdermal GTN (0.6 mg h −1 for 2 h, administered 24 h before IR) significantly reduced the impairment of FMD caused by IR (placebo group: FMD after IR, 1.3 ± 0.8%; GTN group: FMD after IR, 5.3 ± 0.9%, P < 0.01 compared with placebo). This protective effect was lost when vitamin C (2 g i.v. at the time of GTN administration) or ciclosporin (an inhibitor of mPTP, 100 mg 2 h prior to GTN administration) were coadministered (FMD after IR: vit C + GTN group, 2.1 ± 1.0%; ciclosporin + GTN group, 1.7 ± 0.8%; both P < 0.05 compared with GTN alone). Conclusions We demonstrate that GTN protects the endothelium against IR‐induced endothelial dysfunction, in an effect similar to delayed ischaemic preconditioning. Using a human model, we provide evidence supporting the concept that this protective effect is mediated by ROS release and mPTP opening upon GTN administration.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".