Nitroglycerin protects the endothelium from ischaemia and reperfusion: human mechanistic insight.
OBJECTIVE
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.
Gori
Tommaso
T
Department of Internal, Cardiovascular and Geriatric Medicine, University of Siena, Siena, Italy.
Di Stolfo
Giuseppe
G
Sicuro
Silvia
S
Dragoni
Saverio
S
Lisi
Monica
M
Forconi
Sandro
S
Parker
John D
JD
D000328:Adult; D004311:Double-Blind Method; D004730:Endothelium, Vascular; D006801:Humans; D008297:Male; D008875:Middle Aged; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D005996:Nitroglycerin / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use*
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D005996:Nitroglycerin