title: Cardioprotective effects of inorganic nitrate/nitrite in chronic anthracycline cardiotoxicity: Comparison with dexrazoxane.
abstract: Dexrazoxane (DEX) is a clinically available cardioprotectant that reduces the toxicity induced by anthracycline (ANT) anticancer drugs; however, DEX is seldom used and its action is poorly understood. Inorganic nitrate/nitrite has shown promising results in myocardial ischemia-reperfusion injury and recently in acute high-dose ANT cardiotoxicity. However, the utility of this approach for overcoming clinically more relevant chronic forms of cardiotoxicity remains elusive. Hence, in this study, the protective potential of inorganic nitrate and nitrite against chronic ANT cardiotoxicity was investigated, and the results were compared to those using DEX. Chronic cardiotoxicity was induced in rabbits with daunorubicin (DAU). Sodium nitrate (1g/L) was administered daily in drinking water, while sodium nitrite (0.15 or 5mg/kg) or DEX (60mg/kg) was administered parenterally before each DAU dose. Although oral nitrate induced a marked increase in plasma NOx, it showed no improvement in DAU-induced mortality, myocardial damage or heart failure. Instead, the higher nitrite dose reduced the incidence of end-stage cardiotoxicity, prevented related premature deaths and significantly ameliorated several molecular and cellular perturbations induced by DAU, particularly those concerning mitochondria. The latter result was also confirmed in vitro. Nevertheless, inorganic nitrite failed to prevent DAU-induced cardiac dysfunction and molecular remodeling in vivo and failed to overcome the cytotoxicity of DAU to cardiomyocytes in vitro. In contrast, DEX completely prevented all of the investigated molecular, cellular and functional perturbations that were induced by DAU. Our data suggest that the difference in cardioprotective efficacy between DEX and inorganic nitrite may be related to their different abilities to address a recently proposed upstream target for ANT in the heart - topoisomerase IIβ.
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: lencovao@lfhk.cuni.cz.
authors.forename: Olga
authors.initials: O
authors.lastname: Lenčová-Popelová
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: jirkovskye@lfhk.cuni.cz.
authors.forename: Eduard
authors.initials: E
authors.lastname: Jirkovský
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: jansovah@faf.cuni.cz.
authors.forename: Hana
authors.initials: H
authors.lastname: Jansová
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: jirkovan@faf.cuni.cz.
authors.forename: Anna
authors.initials: A
authors.lastname: Jirkovská-Vávrová
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: lucie.tichotova@gmail.com.
authors.forename: Lucie
authors.initials: L
authors.lastname: Vostatková-Tichotová
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: mazurova@lfhk.cuni.cz.
authors.forename: Yvona
authors.initials: Y
authors.lastname: Mazurová
authors.affiliation: Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: adamcova@lfhk.cuni.cz.
authors.forename: Michaela
authors.initials: M
authors.lastname: Adamcová
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: chladekj@lfhk.cuni.cz.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Chládek
authors.affiliation: Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: hrochm@lfhk.cuni.cz.
authors.forename: Miloš
authors.initials: M
authors.lastname: Hroch
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: pokornzu@lfhk.cuni.cz.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Pokorná
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: gersl@lfhk.cuni.cz.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Geršl
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: tomas.simunek@faf.cuni.cz.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Šimůnek
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: sterbam@lfhk.cuni.cz.
authors.forename: Martin
authors.initials: M
authors.lastname: Štěrba
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D066126:Cardiotoxicity / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D003630:Daunorubicin / Q000009:adverse effects; D064730:Dexrazoxane / Q000494:pharmacology*; D004334:Drug Administration Schedule; D007262:Infusions, Intravenous; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000494:pharmacology*; D011817:Rabbits; D012977:Sodium Nitrite / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D004268:DNA-Binding Proteins; D009566:Nitrates; D064730:Dexrazoxane; C031618:sodium nitrate; D004250:DNA Topoisomerases, Type II; D012977:Sodium Nitrite; D003630:Daunorubicin
keywords: Anthracyclines; Cardioprotection; Cardiotoxicity; Dexrazoxane; Inorganic nitrate and nitrite