Nitroglycerin protects the endothelium from ischaemia and reperfusion: human mechanistic insight

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. 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). MethodsIn 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. ResultsTransdermal 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 Ϯ 0.8%; GTN group: FMD after IR, 5.3 Ϯ 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 Ϯ 1.0%; ciclosporin + GTN group, 1.7 Ϯ 0.8%; both P < 0.05 compared with GTN alone). ConclusionsWe 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.

Loss of the preconditioning effect of rosuvastatin during sustained therapy: a human in vivo study

“…Radial artery diameter and radial artery blood flow returned to baseline values 15 min after local IR ( (10,12,14,15). Reproducing previous findings from our laboratory, rosuvastatin administration prevented the impairment in FMD associated with IR ( Fig.…”

“…The methods for assessment of FMD and blood flow in our laboratory (12,14,15,25), as well as the repeatability of FMD measurements, have been previously described in detail. Briefly, end-diastolic, ECG-gated, longitudinal, B-mode images of the artery 10 -15 cm below the antecubital fossa were digitally acquired and stored for offline analysis.…”

Nitroglycerine causes mitochondrial reactive oxygen species production: In vitro mechanistic insights

“…Conversely, we recently demonstrated (14) that GTN-triggered ROS production is responsible for GTN-induced preconditioning, in a paradoxically protective effect of ROS. We also demonstrated that mPTP opening is crucial for this latter property of GTN (4). Because mPTP and K-ATP channel opening can theoretically be up-and downstream of GTN-induced ROS (10), the present study tested whether inhibition of these channels or of GTN biotransformation prevents GTN-induced ROS production.…”

“…Of importance, we recently documented that exposure to GTN causes a rapid increase in mitochondrial reactive oxygen species (ROS) production (2), and it has been shown that this may depend on the uncoupling of the mitochondrial respiratory chain (3). Furthermore, we recently demonstrated that this GTN-triggered ROS production is responsible for GTN-induced ischemic preconditioning (a short-term beneficial effect of GTN-induced ROS) (4) and GTN tolerance occurring in concert with the development of endothelial dysfunction (a long-term toxic effect of GTN-derived ROS) (5). It has also been demonstrated that opening of the mitochondrial permeability transition pore (mPTP) is critical in GTN-induced preconditioning (4).…”

“…Furthermore, we recently demonstrated that this GTN-triggered ROS production is responsible for GTN-induced ischemic preconditioning (a short-term beneficial effect of GTN-induced ROS) (4) and GTN tolerance occurring in concert with the development of endothelial dysfunction (a long-term toxic effect of GTN-derived ROS) (5). It has also been demonstrated that opening of the mitochondrial permeability transition pore (mPTP) is critical in GTN-induced preconditioning (4). Because mPTP opening causes depolarization of the mitochondrial inner membrane (6), a direct effect of GTN on the mPTP may represent a mechanism for GTN-induced ROS production.…”