title: Quercetin mitochondriotropic derivatives antagonize nitrate tolerance and endothelial dysfunction of isolated rat aorta rings.
abstract: Chronic use of glyceryl trinitrate is limited by serious side effects, inter alia tolerance and endothelial dysfunction of coronary and resistance arteries. The natural flavonoid quercetin has been shown to counteract the development of glyceryl trinitrate tolerance in vitro. Two mitochondriotropic, 4-O-triphenylphosphoniumbutyl derivatives of quercetin (QTA-3BTPI and Q-3BTPI) were compared to quercetin for protection against glyceryl trinitrate-induced tolerance and endothelial dysfunction of isolated rat aorta rings. Both QTA-3BTPI and Q-3BTPI significantly counteracted the reduced vascular responsiveness to both glyceryl trinitrate and acetylcholine caused by prolonged exposure of the vessel to glyceryl trinitrate itself, their potency being much greater than that of quercetin. QTA-3BTPI, however, turned out to cause endothelial dysfunction per se. Since Q-3BTPI antagonized in vitro nitrate tolerance and endothelial dysfunction of vessels, this encourages assessing whether this effect is displayed also in vivo during long-term glyceryl trinitrate treatment.
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Siena, Siena, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Durante
authors.forename: Giampietro
authors.initials: G
authors.lastname: Sgaragli
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.forename: Fabio
authors.initials: F
authors.lastname: Fusi
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D005996:Nitroglycerin / Q000633:toxicity*; D018384:Oxidative Stress; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats
chemical_list: C584168:3',4',5,7-tetra-acetyl-3-(4-O-triphenylphosphoniumbutyl)quercetin iodide; C584167:3-(4-O-triphenylphosphoniumbutyl)quercetin iodide; D011794:Quercetin; D005996:Nitroglycerin; D000109:Acetylcholine