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BASIC RESEARCH

Role for peroxynitrite in the inhibition of prostacyclin synthase in nitrate tolerance

Ulrich Hink, MD^*, Matthias Oelze, PhD^*, Philip Kolb, MD^*, Markus Bachschmid, PhD, Ming-Hui Zou, PhD, Andreas Daiber, PhD^*, Hanke Mollnau, MD^*, Michael August, PhD^*, Stefan Baldus, MD^*, Nikos Tsilimingas, MD^*, Ulrich Walter, MD, Volker Ullrich, PhD and Thomas Münzel, MD^*,*

^* University Hospital Eppendorf, Division of Cardiology, Hamburg, Germany
Department of Clinical Biochemistry, Würzburg, Germany
Department of Biology, University Konstanz, Konstanz, Germany

Manuscript received January 17, 2003; revised manuscript received May 13, 2003, accepted July 1, 2003.

^* Reprint request and correspondence: Dr. Thomas Münzel, Abteilung für Kardiologie, Universitäts-Krankenhaus Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
muenzel{at}uke.uni-hamburg.de

OBJECTIVES: We tested whether in vivo nitroglycerin (NTG) treatment causes tyrosine nitration of prostacyclin synthase (PGI₂-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 PGI₂-S as a tyrosine-nitrated protein. Accordingly, conversion of (¹⁴C)-PGH₂ into 6-keto-PGF₁ (=PGI₂-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 PGI₂-S as well as NO, cGMP, and cGK-I signaling, which may contribute to vascular dysfunction in the setting of tolerance.

Abbreviations and Acronyms   COX = cyclooxygenase   cGK-I = cyclic guanosine monophosphate-dependent kinase-I   cGMP = cyclic guanosine monophosphate   LDCL = luminol-derived chemiluminescence   NO = nitric oxide   NOSIII = endothelial nitric oxide synthase   NTG = nitroglycerin   PGI2(-S) = prostacyclin (synthase)   P-VASP = phosphorylated vasodilator-stimulated phosphoprotein   sGC = soluble guanylyl cyclase   TXA2 = thromboxane A2

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