Published online before print October 9, 2003, doi: 10.1161/01.RES.0000100067.62876.50
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© 2003 American Heart Association, Inc.
UltraRapid Communications |
Does Nitric Oxide Mediate the Vasodilator Activity of Nitroglycerin?
From the Division of Cardiology (A.L.K., M.O., A.D., Y.H., H.M., E.S., K.S., T.M.), University Hospital Hamburg-Eppendorf, Hamburg, Germany; and the Institute of Cardiovascular Physiology (B.F., A.M.), Johann Wolfgang Goethe University Hospital, Frankfurt, Germany.
Correspondence to Andrei L. Kleschyov, Division of Cardiology, University Hospital Hamburg-Eppendorf, Martinistr 52, Hamburg 20246, Germany. E-mail kleschyo{at}uke.uni-hamburg.de
Nitroglycerin (glyceryl trinitrate, GTN) relaxes blood vessels primarily via activation of the soluble guanylyl cyclase (sGC)/cGMP/cGMP-dependent protein kinase (cGK-I) pathway. Although the precise mechanism of sGC activation by GTN in the vascular wall is unknown, the mediatory role of nitric oxide (NO) has been postulated. We tested the GTN/NO hypothesis in different types of isolated rat and rabbit blood vessels using two novel approaches: (1) EPR spin trapping using colloid Fe(DETC)2 and (2) analysis of cGK-I–dependent phosphorylation of the vasodilator-stimulated phosphoprotein at Ser239 (P-VASP). For comparison, another organic nitrate, isosorbide dinitrate (ISDN), and endothelium-dependent vasodilator, calcium ionophore A23187, were tested. We found a marked discrepancy between GTN’s strong vasoactivity (vasodilation and augmentation of P-VASP) and its poor NO donor properties. In aortas precontracted with phenylephrine, GTN, ISDN, and A23187 induced nearly full relaxations (>80%) and doubling of vascular P-VASP content at concentrations of 100 nmol/L, 100 µmol/L, and 1 µmol/L, respectively. GTN applied in vasorelaxant concentrations (10 to 1000 nmol/L) did not significantly increase the basal vascular NO production, in contrast to ISDN and A23187. The absence of GTN-derived NO was confirmed in rabbit vena cava and renal artery. A significant increase in vascular NO formation was observed only at suprapharmacological GTN concentrations (>10 µmol/L). The concentration dependency of NO formation from GTN was comparable to that of ISDN, although the latter exhibits 100-folds lower vasorelaxant potency. We conclude that GTN activates the sGC/cGMP/cGK-I pathway and induces vasorelaxation without intermediacy of the free radical NO. The full text of this article is available online at http://www.circresaha.org.
Key Words: nitroglycerin • nitric oxide • cGMP • vasodilation • spin trapping
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