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Vol. 53, Issue 3, 547-554, March 1998
Institut für Pharmakologie, Medizinische Einrichtungen,
Heinrich-Heine-Universität, 40225 Düsseldorf, Germany
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.
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