Does Nitric Oxide Mediate the Vasodilator Activity of Nitroglycerin?

• Published in: Circulation research Vol. 93; no. 9; pp. e104 - e112
• Main Authors: Kleschyov, Andrei L, Oelze, Matthias, Daiber, Andreas, Huang, Yale, Mollnau, Hanke, Schulz, Eberhard, Sydow, Karsten, Fichtlscherer, Birgit, Mülsch, Alexander, Münzel, Thomas
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 31.10.2003; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiology; Benomyl - pharmacology; Calcimycin - pharmacology; Cell Adhesion Molecules - drug effects; Cell Adhesion Molecules - metabolism; Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; Enzyme Inhibitors - pharmacology; Guanylate Cyclase; In Vitro Techniques; Ionophores - pharmacology; Isosorbide Dinitrate - pharmacology; Male; Microfilament Proteins; Nitric Oxide - metabolism; Nitroglycerin - pharmacology; Phosphoproteins - drug effects; Phosphoproteins - metabolism; Phosphorylation - drug effects; Rabbits; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear - metabolism; Renal Artery - drug effects; Renal Artery - physiology; Soluble Guanylyl Cyclase; Spin Trapping; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects; Vasodilation - physiology; Vasodilator Agents - pharmacology; Venae Cavae - drug effects; Venae Cavae - physiology
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000100067.62876.50

ABSTRACT—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.