Abstract 461: Nitroglycerin Protects the Endothelium from Ischemia and Reperfusion: in vitro and Human in vivo Mechanistic Insight
Objective: Nitroglycerin (GTN) modulates tissue damage induced by ischemia and reperfusion (IR) in a mechanism that is similar to ischemic preconditioning. We set out to study 1) 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); 2) in vitro, whether GTN-induced ROS production depends on opening of mitochondrial potassium ATP-dependent channels (K-ATP), mPTP opening and/or GTN biotransformation.
Methods and Results: 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. Transdermal GTN (0.6mh/hour/2 hours, administered 24 hours before IR) significantly reduced the impairment of FMD caused by IR. This protective effect was lost when vitamin C (2 grams i.v. at the time of GTN administration) or cyclosporine (an inhibitor of mPTP, 100 mg 2 hours prior to GTN administration) were co-administered. In vitro, vitamin C prevented GTN-induced mitochondrial ROS production, while inhibitors of
GTN biotransformation or of
mPTP opening did not modify it.
Conclusions: We show, for the first time in humans, that ROS release, as well as mPTP opening, mediate GTN protection against IR-induced endothelial dysfunction.