Multitarget Antioxidant NO-Donor Organic Nitrates: A Novel Approach to Overcome Nitrates Tolerance, an Ex Vivo Study

Abstract

Chronic use of glyceryl trinitrate (GTN) is limited by serious side effects, such as tolerance and endothelial dysfunction of coronary and resistance arteries. Although GTN is used as a drug since more than 130 years, the mechanisms of the vasodilatory effects and of tolerance development to organic nitrates are still incompletely elucidated. New synthesized organic nitrates with and without antioxidant properties were characterized for their ex vivo tolerance profile, in order to investigate the oxidative stress hypothesis of nitrate tolerance. The organic nitrates studied showed different vasodilation and tolerance profiles, probably due to the ability or inability of the compounds to interact with the aldehyde dehydrogenase-2 enzyme (ALDH-2) involved in bioactivation. Furthermore, nitrooxy derivatives endowed with antioxidant properties did not determine the onset of tolerance, even if bioactivated by ALDH-2. The results of this study could be further evidence of the involvement of ALDH-2 in the development of nitrate tolerance. Moreover, the behavior of organic nitrates with antioxidant properties supports the hypothesis of the involvement of ROS in inactivating ALDH-2.

Protective role of nitric oxide donors on endothelium in ischemia-reperfusion injury: a meta-analysis of randomized controlled trials

“…This may be due to the development of tolerance after prolonged use of NO donors. After repeated administration, oxidative modifications in ALDH-2 may lead to loss of function of the enzyme, resulting in reduced GTN biotransformation and inhibition of the final effects of pharmacological pretreatment [ 35 , 36 ]. However, not all nitrates are tolerated, and there is experimental evidence that long-term continuous application of PETN [ 37 ] does not lead to the development of tolerance, in part due to the ability of PETN to induce HO-1.…”

The Generation of Nitric Oxide from Aldehyde Dehydrogenase-2: The Role of Dietary Nitrates and Their Implication in Cardiovascular Disease Management

“…In addition, ROS has been shown to be responsible for disrupting cross-talk to the cytoplasm and mitochondria [ 80 ]. Interestingly, nitrates are responsible for inhibiting ALDH2, which is responsible for decreasing or canceling the protective mechanism against oxidative stress [ 81 ]. GTN can potently and rapidly inactivate ALDH2, which is an even earlier effect of nitrate tolerance.…”

“…Another important result was that of relating the nitrooxy derivatives to possessing antioxidant properties. In fact, despite the fact that they were bioactivated by ALDH2, they did not inactivate the enzyme, thus demonstrating the involvement of ROS in deactivating ALDH2 [ 81 ]. Another way to prevent and modify GTN tolerance, as well as its subsequent endothelial dysfunction, could be a change in ALDH2 expression.…”

Preclinical study for the ameliorating effect of l-ascorbic acid for the oxidative stress of chronic administration of organic nitrates on myocardial tissue in high sucrose/fat rat model

“…GTNs block xanthine oxidase (XO), a rate-limiting enzyme for the metabolic bioactivation of GTNs into NO. l -ascorbic acid prevented XO blockage which results in an increased NO production from GTN ( Axton et al, 2018 , Marini et al, 2022 ). Nitrate tolerance is handled by generating a 12-h nitrate-free interval.…”

“…Nitrate tolerance has been considered to be a limitation of nitrate therapy. The effectiveness and benignity of nitrate therapy could be dramatically improved (two to three times) upon concomitant administration of antioxidants which prevents the need for nitrate-free intervals ( Marini et al, 2022 , Knuuti et al, 2020 ).…”