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Bioactivation of Nitroglycerin by Ascorbate

Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria (A.K., M.B., A.C.F.G., K.S., B.M.); and Department of Pharmacology and Toxicology, Ruhr-Universität Bochum, Bochum, Germany (M.R., D.K.)

Bioactivation of nitroglycerin (GTN) into an activator of soluble guanylate cyclase (sGC) is essential for the vasorelaxant effect of the drug. Besides several enzymes that catalyze GTN bioactivation, the reaction with cysteine is the sole nonenzymatic mechanism known so far. Here we show that a reaction with ascorbate results in GTN bioactivation. In the absence of ascorbate, GTN did not affect the activity of purified sGC. However, the enzyme was activated to 20% of maximal NO-stimulated activity by GTN in the presence of 10 mM ascorbate with an EC₅₀ value of 27.3 ± 4.9 µM GTN. The EC₅₀ value of ascorbate was 0.11 ± 0.011 mM. Activation of sGC was sensitive to oxyhemoglobin, superoxide, and a heme-site enzyme inhibitor. GTN had no effect when ascorbate was replaced by 1000 U of superoxide dismutase per milliliter. Ascorbate is known to reduce inorganic nitrite to NO. In the presence of 10 mM ascorbate, 30 µM nitrite caused the same increase in sGC activity as 0.3 mM GTN. Determination of ascorbate-driven 1,2- and 1,3-glycerol dinitrate formation indicated that a 140 nM concentration of products was generated from 0.3 mM GTN within 10 min, excluding nitrite as a relevant intermediate. Our results suggest that a reaction between GTN and ascorbate or an ascorbate-derived species yields an activator of sGC with NO-like chemical properties. This reaction may contribute to GTN bioactivation in blood vessels under conditions of GTN tolerance and ascorbate supplementation.

Address correspondence to: Dr. Bernd Mayer, Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria. E-mail: mayer{at}uni-graz.at

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