Advertisement

Click here for more guidelines.

 
 




CME Topic Collections Past Issues Search Current Issue Home
     

J Am Coll Cardiol, 2007; 49:1289-1295, doi:10.1016/j.jacc.2006.10.074 (Published online 9 March 2007).
© 2007 by the American College of Cardiology Foundation
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
j.jacc.2006.10.074v1
49/12/1289    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Thomas, G. R.
Right arrow Articles by Parker, J. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Thomas, G. R.
Right arrow Articles by Parker, J. D.
Related Collections
Right arrowRelated Article

CLINICAL RESEARCH: CORONARY ARTERY DISEASE

Once Daily Therapy With Isosorbide-5-Mononitrate Causes Endothelial Dysfunction in Humans

Evidence of a Free-Radical–Mediated Mechanism

George R. Thomas, PhD*, Jonathan M. DiFabio, MSc*, Tommaso Gori, MD, PhD{dagger} and John D. Parker, MD, FACC*,*

* Division of Cardiology, Department of Medicine, University Health Network and Mount Sinai Hospitals and the Department of Pharmacology, University of Toronto, Toronto, Canada
{dagger} Department of Internal, Cardiovascular and Geriatric Medicine, University of Siena, Siena, Italy. Supported by a research donation from the Henry White Kinnear Foundation. Dr. Parker holds a Career Investigator Award from the Heart and Stroke Foundation of Ontario, Canada. Dr. Gori is the recipient of a grant from the Italian Ministry of Research

Manuscript received May 19, 2006; revised manuscript received September 13, 2006, accepted October 12, 2006.

* Reprint requests and correspondence: Dr. John D. Parker, Mount Sinai Hospital, 600 University Avenue, Room 1609, Toronto, Ontario, Canada, M5G 1X5. (Email: jdp{at}ca.inter.net).

Objectives: The aim of the study was to determine if isosorbide-5-mononitrate (IS-5-MN) 120 mg, taken once daily for 7 days, is associated with evidence of endothelial dysfunction and whether this effect is determined by increased free radical production.

Background: Tolerance to nitroglycerin is associated with increased free radical production and abnormal endothelial function. To date, no data is available concerning the effect of IS-5-MN, administered in clinically employed dosages, on endothelial function in humans.

Methods: A total of 19 healthy volunteers were randomized in a double-blind fashion to therapy with IS-5-MN (120 mg once daily) or placebo. After 7 days of treatment, forearm blood flow responses to acetylcholine (Ach; 7.5, 15, and 30 µg/min) and N-monomethyl-L-arginine (L-NMMA; 1, 2, and 4 µmol/min) were measured. In a separate study, after 7 days of therapy with IS-5-MN 120 mg once daily, the responses to Ach were assessed during intra-arterial coinfusion of vitamin C (24 mg/min) or saline.

Results: As compared with placebo, IS-5-MN caused significant blunting of the responses to both Ach (peak responses: placebo 127 ± 31%; IS-5-MN 52 ± 24%) and L-NMMA (peak responses: placebo 41 ± 5%; IS-5-MN 22 ± 8%). Vitamin C completely restored the forearm blood flow responses to Ach (peak responses: vitamin C 180 ± 33%; saline 107 ± 17%).

Conclusions: We document for the first time that IS-5-MN impairs endothelial function in humans in vivo. Suggesting a role of oxygen free radicals, nitrate-induced abnormalities in endothelium-dependent vasomotor responses were reversed by the antioxidant vitamin C.

Abbreviations and Acronyms
  Ach = acetylcholine
  FBF = forearm blood flow
  GTN = nitroglycerin
  IS-5-MN = isosorbide-5-mononitrate
  L-NMMA = N-monomethyl-L-arginine
  PETN = pentaerithrityl tetranitrate
  ROS = reactive oxygen species


Related Article

Do We Still Need Organic Nitrates?
Thomas Münzel, Philip Wenzel, and Andreas Daiber
J. Am. Coll. Cardiol. 2007 49: 1296-1298. [Full Text] [PDF]



This article has been cited by other articles:


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
M. Knorr, M. Hausding, S. Kroller-Schuhmacher, S. Steven, M. Oelze, T. Heeren, A. Scholz, T. Gori, P. Wenzel, E. Schulz, et al.
Nitroglycerin-Induced Endothelial Dysfunction and Tolerance Involve Adverse Phosphorylation and S-Glutathionylation of Endothelial Nitric Oxide Synthase: Beneficial Effects of Therapy With the AT1 Receptor Blocker Telmisartan
Arterioscler Thromb Vasc Biol, October 1, 2011; 31(10): 2223 - 2231.
[Abstract] [Full Text] [PDF]


Home page
DiabetesHome page
S. Schuhmacher, M. Oelze, F. Bollmann, H. Kleinert, C. Otto, T. Heeren, S. Steven, M. Hausding, M. Knorr, A. Pautz, et al.
Vascular Dysfunction in Experimental Diabetes Is Improved by Pentaerithrityl Tetranitrate but Not Isosorbide-5-Mononitrate Therapy
Diabetes, October 1, 2011; 60(10): 2608 - 2616.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
T. Munzel, A. Daiber, and T. Gori
Nitrate Therapy: New Aspects Concerning Molecular Action and Tolerance
Circulation, May 17, 2011; 123(19): 2132 - 2144.
[Full Text] [PDF]


Home page
J Am Coll CardiolHome page
A. Liuni, M. C. Luca, G. Di Stolfo, A. Uxa, J. A. Mariani, T. Gori, and J. D. Parker
Coadministration of Atorvastatin Prevents Nitroglycerin-Induced Endothelial Dysfunction and Nitrate Tolerance in Healthy Humans
J. Am. Coll. Cardiol., January 4, 2011; 57(1): 93 - 98.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
S. Schuhmacher, P. Wenzel, E. Schulz, M. Oelze, C. Mang, J. Kamuf, T. Gori, T. Jansen, M. Knorr, S. Karbach, et al.
Pentaerythritol Tetranitrate Improves Angiotensin II-Induced Vascular Dysfunction via Induction of Heme Oxygenase-1
Hypertension, April 1, 2010; 55(4): 897 - 904.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
T. Gori, S. Dragoni, G. Di Stolfo, S. Sicuro, A. Liuni, M. C. Luca, G. Thomas, M. Oelze, A. Daiber, and J. D. Parker
Tolerance to nitroglycerin-induced preconditioning of the endothelium: a human in vivo study
Am J Physiol Heart Circ Physiol, February 1, 2010; 298(2): H340 - H345.
[Abstract] [Full Text] [PDF]


Home page
J. Pharmacol. Exp. Ther.Home page
P. Wenzel, E. Schulz, T. Gori, M. A. Ostad, F. Mathner, S. Schildknecht, S. Gobel, M. Oelze, D. Stalleicken, A. Warnholtz, et al.
Monitoring White Blood Cell Mitochondrial Aldehyde Dehydrogenase Activity: Implications for Nitrate Therapy in Humans
J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 63 - 71.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
T. Gori and J. D. Parker
Nitrate-Induced Toxicity and Preconditioning: A Rationale for Reconsidering the Use of These Drugs
J. Am. Coll. Cardiol., July 22, 2008; 52(4): 251 - 254.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
A. L. Moens, C. J. Vrints, M. J. Claeys, J.-P. Timmermans, H. C. Champion, and D. A. Kass
Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease
Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H1971 - H1977.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
S. Dragoni, T. Gori, M. Lisi, G. Di Stolfo, A. Pautz, H. Kleinert, and J. D. Parker
Pentaerythrityl Tetranitrate and Nitroglycerin, but not Isosorbide Mononitrate, Prevent Endothelial Dysfunction Induced by Ischemia and Reperfusion
Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1955 - 1959.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
T. Munzel, P. Wenzel, and A. Daiber
Do We Still Need Organic Nitrates?
J. Am. Coll. Cardiol., March 27, 2007; 49(12): 1296 - 1298.
[Full Text] [PDF]



 
  CME Topic Collections Past Issues Search Current Issue Home

Advertisement