Nitrate tolerance does not increase production of peroxynitrite in the heart.
Clinical studies have suggested that long-term nitrate treatment does not improve and may even worsen cardiovascular mortality, and the possible role of nitrate tolerance has been suspected. Nitrate tolerance has been recently shown to increase vascular superoxide and peroxynitrite production leading to vascular dysfunction. Nevertheless, nitrates exert direct cardiac effects independent from their vascular actions. Therefore, we investigated whether in vivo nitroglycerin treatment leading to vascular nitrate tolerance increases cardiac formation of nitric oxide (NO), reactive oxygen species, and peroxynitrite, thereby leading to cardiac dysfunction. Nitrate tolerance increased bioavailability of NO in the heart without increasing formation of reactive oxygen species. Despite elevated myocardial NO, neither cardiac markers of peroxynitrite formation nor cardiac mechanical function were affected by nitroglycerin treatment. However, serum free nitrotyrosine, a marker for systemic peroxynitrite formation, was significantly elevated in nitroglycerin-treated animals. This is the first demonstration that, although the systemic effects of nitroglycerin may be deleterious due to enhancement of extracardiac peroxynitrite formation, nitroglycerin does not result in oxidative damage in the heart.
Csont
Tamás
T
Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, H-6720, Hungary.
CsonkA
Csaba
C
Onody
Annamária
A
Görbe
Anikó
A
Dux
László
L
Schulz
Richard
R
Baxter
Gary F
GF
Ferdinandy
Péter
P
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000032:analysis; D004361:Drug Tolerance; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D017665:Hydroxyl Radical / Q000032:analysis / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D013995:Time; D014968:Xanthine Dehydrogenase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D015415:Biomarkers; D017382:Reactive Oxygen Species; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D019001:Nitric Oxide Synthase; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D005996:Nitroglycerin