{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T06:42:36Z","timestamp":1764225756043,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,16]],"date-time":"2022-01-16T00:00:00Z","timestamp":1642291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/antiox11010166","type":"journal-article","created":{"date-parts":[[2022,1,16]],"date-time":"2022-01-16T20:44:00Z","timestamp":1642365840000},"page":"166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Multitarget Antioxidant NO-Donor Organic Nitrates: A Novel Approach to Overcome Nitrates Tolerance, an Ex Vivo Study"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3638-5219","authenticated-orcid":false,"given":"Elisabetta","family":"Marini","sequence":"first","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, I-10125 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3282-1220","authenticated-orcid":false,"given":"Marta","family":"Giorgis","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, I-10125 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Leporati","sequence":"additional","affiliation":[{"name":"Regional Antidoping & Toxicology Center \u201cAlessandro Bertinaria\u201d, Regione Gonzole 10\/1, I-10043 Orbassano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Rolando","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, I-10125 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9962-1218","authenticated-orcid":false,"given":"Konstantin","family":"Chegaev","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, I-10125 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7100-8593","authenticated-orcid":false,"given":"Loretta","family":"Lazzarato","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, I-10125 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2533-5830","authenticated-orcid":false,"given":"Massimo","family":"Bertinaria","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, I-10125 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6275-7194","authenticated-orcid":false,"given":"Marco","family":"Vincenti","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Turin, via Pietro Giuria 5, I-10125 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Di Stilo","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, I-10125 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1146\/annurev.pharmtox.44.101802.121646","article-title":"Biochemical mechanism of nitroglycerin action and tolerance: Is this old mistery solved?","volume":"44","author":"Fung","year":"2004","journal-title":"Annu. 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