Nitric Oxide Inhibits Vascular Bioactivation of Glyceryl Trinitrate: A Novel Mechanism to Explain Preferential Venodilation of Organic Nitrates

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Abstract
Organic nitrates undergo enzymatic metabolization in the vasculature to release the active compound nitric oxide (NO). The resulting preferential venodilation has been suggested to be related to the vascular bioactivation process of organic nitrates because sodium nitroprusside, which is bioactivated differently, is not venoselective. We sought to determine whether NO has an influence on vascular bioconversion of organic nitrates because endogenous endothelial production of NO is smaller in veins than in arteries. Rings of porcine coronary arteries were subjected to radioactive glyceryl trinitrate (GTN) after preincubation with defined amounts of NO. The vascular content of GTN and the dinitrates (GDNs) 1,2-GDN and 1,3-GDN then was quantified. NO (3 μm, 30 min) significantly impaired bioactivation of GTN as indicated by a 30–50% reduction in the accumulation of 1,2-GDN and 1,3-GDN, whereas unchanged GTN was increased. Incubation with NO also reduced the stimulated specific activity of soluble guanylate cyclase isolated from human platelets. Its specific activity was reduced from 2.6 ± 0.2 to 2.1 ± 0.13 nmol of cGMP/mg/min. Relaxation studies with rings of porcine coronary arteries showed that NO-induced inhibition of vascular GTN metabolism and cGMP accumulation decreased the vasodilator potency of GTN by 10-fold. Further experiments showed that the duration of NO treatment is more important for this effect than the concentration of NO. We suggest that NO can inhibit vascular bioactivation of organic nitrates and might slightly desensitize soluble guanylate cyclase. The preferential venodilation induced by organic nitrates might be the result of the comparably low production of endogenous NO in veins.