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  • Title: Role for peroxynitrite in the inhibition of prostacyclin synthase in nitrate tolerance.
    Author: Hink U, Oelze M, Kolb P, Bachschmid M, Zou MH, Daiber A, Mollnau H, August M, Baldus S, Tsilimingas N, Walter U, Ullrich V, Münzel T.
    Journal: J Am Coll Cardiol; 2003 Nov 19; 42(10):1826-34. PubMed ID: 14642695.
    Abstract:
    OBJECTIVES: We tested whether in vivo nitroglycerin (NTG) treatment causes tyrosine nitration of prostacyclin synthase (PGI(2)-S), one of the nitration targets of peroxynitrite, and whether this may contribute to nitrate tolerance. BACKGROUND: Long-term NTG therapy causes tolerance secondary to increased vasoconstrictor sensitivity and increased vascular formation of reactive oxygen species. Because NTG releases nitric oxide (NO), NTG-induced stimulation of superoxide production should increase vascular nitrotyrosine levels, compatible with increased formation of peroxynitrite, the reaction product from NO and superoxide. METHODS: New Zealand White rabbits and Wistar rats were treated with NTG (0.4 mg/h for 3 days). Tolerance was assessed with isometric tension studies. Vascular peroxynitrite levels were quantified with luminol-derived chemiluminescence (LDCL) and peroxynitrite scavengers, such as uric acid and ebselen. As a surrogate parameter for the assessment of the activity of cyclic guanosine monophosphate-dependent kinase-I (cGK-I; the final signaling pathway for NO), the phosphorylation of the vasodilator-stimulated phosphoprotein (P-VASP) at serine 239 was analyzed. RESULTS: Nitroglycerin treatment increased LDCL, and the inhibitory effect of uric acid and ebselen on LDCL was augmented in tolerant rings. Immunoprecipitation of 3-nitrotyrosine-containing proteins and immunohistochemistry analysis identified PGI(2)-S as a tyrosine-nitrated protein. Accordingly, conversion of ((14)C)-PGH(2) into 6-keto-PGF(1 alpha) (=PGI(2)-S activity) was strongly inhibited. In vitro incubation of tolerant rings with ebselen and uric acid markedly increased the depressed P-VASP levels and improved NTG sensitivity of the tolerant vasculature. CONCLUSIONS: Nitroglycerin-induced vascular peroxynitrite formation inhibits the activity of PGI(2)-S as well as NO, cGMP, and cGK-I signaling, which may contribute to vascular dysfunction in the setting of tolerance.
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