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Received for publication March 2, 2007.
Revised April 19, 2007.
Accepted for publication April 19, 2007.
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 non-enzymatic 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 of 27.3±4.9 µM GTN. The EC50 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 1,000 U of SOD per ml. Ascorbate is known to reduce inorganic nitrite to NO. In the presence 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 140 nM of products were generated from 0.3 mM GTN within 10 min, excluding nitrite as 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.
Key words:
Guanylyl cyclase, Nitric oxide, cGMP
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