Published online before print October 9, 2003, doi: 10.1161/01.RES.0000100067.62876.50
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on July 25, 2003
Revised on September 9, 2003
Accepted on September 26, 2003
Does Nitric Oxide Mediate the Vasodilator Activity of Nitroglycerin?
Andrei L. Kleschyov *;
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.
* To whom correspondence should be addressed. 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
This article has been cited by other articles:
 |
|
 |
|
  R. Parent, N. Leblanc, and M. Lavallee Nitroglycerin reduces myocardial oxygen consumption during exercise despite vascular tolerance Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1226 - H1234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Neishi, S. Mochizuki, T. Miyasaka, T. Kawamoto, T. Kume, R. Sukmawan, M. Tsukiji, Y. Ogasawara, F. Kajiya, T. Akasaka, et al. Evaluation of bioavailability of nitric oxide in coronary circulation by direct measurement of plasma nitric oxide concentration PNAS, August 9, 2005; 102(32): 11456 - 11461. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Li, H. Cui, X. Liu, and J. L. Zweier Xanthine Oxidase Catalyzes Anaerobic Transformation of Organic Nitrates to Nitric Oxide and Nitrosothiols: CHARACTERIZATION OF THIS MECHANISM AND THE LINK BETWEEN ORGANIC NITRATE AND GUANYLYL CYCLASE ACTIVATION J. Biol. Chem., April 29, 2005; 280(17): 16594 - 16600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Daiber, M. Oelze, M. Coldewey, M. Bachschmid, P. Wenzel, K. Sydow, M. Wendt, A. L. Kleschyov, D. Stalleicken, V. Ullrich, et al. Oxidative Stress and Mitochondrial Aldehyde Dehydrogenase Activity: A Comparison of Pentaerythritol Tetranitrate with Other Organic Nitrates Mol. Pharmacol., December 1, 2004; 66(6): 1372 - 1382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ramasethu Pharmacology Review: Prevention and Management of Extravasation Injuries in Neonates NeoReviews, November 1, 2004; 5(11): e491 - e497. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhang, Z. Chen, F. R. Cobb, and J. S. Stamler Role of Mitochondrial Aldehyde Dehydrogenase in Nitroglycerin-Induced Vasodilation of Coronary and Systemic Vessels: An Intact Canine Model Circulation, August 10, 2004; 110(6): 750 - 755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Gori and J. D. Parker Long-term therapy with organic nitrates: The pros and cons of nitric oxide replacement therapy J. Am. Coll. Cardiol., August 4, 2004; 44(3): 632 - 634. [Full Text] [PDF]
|
|