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Urinary Nitrotyrosine Content as a Marker of Peroxynitrite-induced Tolerance to Organic NitratesInstitute of Applied Physiology, University Freiburg, Freiburg, Germany
Institute of Chemical Physics, Moscow, Russia
Institute of Chemical Physics, Moscow, Russia
Institute of Applied Physiology, University Freiburg, Freiburg, Germany
Institute of Applied Physiology, University Freiburg, Freiburg, Germany Background: Anti-ischemic therapy with nitrovasodilators as NO-donors is complicated by the induction of tolerance. When nitrovasodilators are metabolized to release NO there is a considerable coproduction of oxygen-derived radicals leading to a diminished cyclic GMP production and to impaired vasomotory responses. We analyzed in vivo the glyceroltrinitrate- induced generation of strong oxidative/nitrating compounds contributing to development of tolerance. Methods and Results: In 16 patients we studied the urinary nitrotyrosine excretion during either (1) placebo control conditions, (2) 2-day nonintermittent transdermal nitroglycerin administration (0.4 mg/h), (3) 2-day nonintermittent glyceroltrinitrate administration (0.4 mg/h) along with a continuous infusion of vitamin C (55 µg/kg/min) as an antioxidant, or (4) with vitamin C but without glyceroltrinitrate (diminished urinary nitrotyrosine content of 34 ± 18 µg/day observed). Glyceroltrinitrate administration augmented urinary nitrotyrosine from 56 ± 24 (basal) to 186 ± 32 µg/day (glyceroltrinitrate tolerance). Coadministration of vitamin C caused complete elimination of tolerance and a decrease in urinary nitrotyrosine to 130 ± 28 µg/day. Glyceroltrinitrate-induced formation of oxidants was confirmed in vitro comparing glyceroltrinitrate-induced and peroxynitrite-induced tachyphylaxis in isolated perfused rabbit hearts and analyzing tolerance-induced inactivation of soluble guanylyl cyclase in cultured aortic smooth muscle cells. Conclusions: Augmented urinary nitrotyrosine excretion during glyceroltrinitrate adminis tration reflects enhanced formation of peroxynitrite and of nitrotyrosine. Glyceroltrinitrate- induced tolerance is the result of oxidative stress and can be suppressed by additional antiox idant therapy aimed to prevent glyceroltrinitrate-induced formation and/or actions of peroxynitrite.
Key Words: oxidative stress • nitrovasodilators • vascular dysfunction • oxygen-derived radicals.
Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 2, No. 2,
85-96 (1997) This article has been cited by other articles:
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