Toxicology Center “Alessandro Bertinaria”, Regione Gonzole 10/1, I-10043 Orbassano, Italy; [email protected] Division of Chemistry, University of Turin, via Pietro Giuria five, I-10125 Torino, Italy; [email protected] Correspondence: [email protected] These authors contributed equally to this work.Citation: Marini, E.; Giorgis, M.; Leporati, M.; Rolando, B.; Chegaev, K.; Lazzarato, L.; Bertinaria, M.; Vincenti, M.; Di Stilo, A. Multitarget Antioxidant NO-Donor Organic Nitrates: A Novel Strategy to Overcome Nitrates Tolerance, an Ex Vivo Study. Bax Activator site antioxidants 2022, 11, 166. doi.org/10.3390/ antiox11010166 Academic Editor: Stanley Omaye Received: 5 November 2021 Accepted: 14 January 2022 Published: 16 January 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Abstract: Chronic use of glyceryl trinitrate (GTN) is limited by critical unwanted side effects, including tolerance and endothelial dysfunction of coronary and resistance arteries. Even though GTN is applied as a drug considering that more than 130 years, the mechanisms with the vasodilatory effects and of tolerance improvement to organic nitrates are still incompletely elucidated. New synthesized organic nitrates with and without the need of antioxidant properties were characterized for their ex vivo tolerance profile, in an effort to investigate the oxidative anxiety hypothesis of nitrate tolerance. The organic nitrates studied showed distinctive vasodilation and tolerance profiles, probably because of the capacity or inability from the compounds to interact together with the aldehyde dehydrogenase-2 enzyme (ALDH-2) involved in bioactivation. Furthermore, nitrooxy derivatives endowed with antioxidant properties didn’t identify the onset of tolerance, even if bioactivated by ALDH-2. The results of this study might be additional proof with the involvement of ALDH-2 inside the improvement of nitrate tolerance. In addition, the behavior of organic nitrates with antioxidant properties supports the hypothesis in the involvement of ROS in inactivating ALDH-2. Keywords and phrases: multitarget drugs; tolerance; antioxidants; organic nitrates; aldehyde dehydrogenase1. Introduction Organic nitrates such as glyceryl trinitrate (GTN) would be the most typically adopted vasodilators in coronary artery illnesses. The mechanism by which organic nitrates dilate blood vessels continues to be not completely understood. It truly is generally accepted that they’re prodrugs that require CDK2 Inhibitor drug bioactivation to yield NO or an `NO’-like species resulting in relaxation of your vascular smooth muscle [1]. Distinctive enzymes happen to be implicated in the bioconversion of organic nitrates, in unique glutathione S-transferases, the cytochrome P450 program, xanthine oxidoreductase, and glyceraldehyde-3-phosphate dehydrogenase, while recent proof suggests a central part for mitochondrial lipoic acid-dependent aldehyde dehydrogenase (ALDH)-2 [4]. The truth is, it has been reported that the GTN bioactivation catalyzed by ALDH-2 entails the oxidation of two vicinal cysteine residues, major to the formation of a disulfide; this mechanism implicates the requirement of a decreasing agent (for instance lipoic acid) for sustained catalysis [7]. Though organic nitrates are nevertheless among essentially the most commonly prescribed drugs for the remedy of angina pectoris and myocardial infarction, any hypothesis regarding the mechanism of action of those drugs will have to take into account the phenomenon of tolerance. In reality, the chronic efficacy of nitrat
