Nitroglycerin tolerance: Different mechanisms in vascular segments with or without intact endothelial function

In vivo tolerance to nitroglycerin seems to be induced by an increase in vascular superoxide anion levels. In rabbits with normal endothelial function, in vivo induced tolerance is functionally reversed by ex vivo removal of the endothelium, probably due to a reduction in superoxide anion levels. However, the impact of in vivo endothelial dysfunction on tolerance development has not been examined. This study investigated how in vivo endothelium denudation affects the development of in vivo nitroglycerin tolerance. The effect of in vivo endothelium denudation was examined ex vivo (myograph experiments) after prolonged continuous nitroglycerin infusion in a conscious rat model. The vascular reactivity to nitroglycerin was studied in vivo in endothelium-denuded and corresponding endothelium-intact arteries. The results show that in vivo endothelium denudation does not affect the degree of tolerance development but significantly alters the effect of interventions targeted to inhibit tolerance development. In endothelium-intact vessels, superoxide dismutase and the angiotensin II receptor blocker losartan significantly inhibited tolerance-inducing properties of the prolonged nitroglycerin infusion (E-max,E- nitroglycerin response in % of normal controls: nitroglycerin tolerant 70%, superoxide dismutase 93%, losartan 99%). This effect was absent in in vivo endothelium-denuded segments (nitroglycerin tolerant 57%, superoxide dismutase 72%, losartan 60%). These findings suggest that interventions against in vivo tolerance development, within the same animal, may elicit different results depending on the presence or absence of an in vivo dysfunctional endothelium.