This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gori, T. Articles by Parker, J. D. Search for Related Content PubMed PubMed Citation Articles by Gori, T. Articles by Parker, J. D. Related Collections Cardiovascular Pharmacology Endothelium/vascular type/nitric oxide

(Circulation. 2002;106:2404.)
© 2002 American Heart Association, Inc.

Mini-Review

The Puzzle of Nitrate Tolerance

Pieces Smaller Than We Thought?

Tommaso Gori, MD; John D. Parker, MD

From the Division of Cardiology, Department of Medicine, Mount Sinai and University Health Network Hospitals, the University of Toronto, Toronto, Canada.

Correspondence to John D. Parker, MD, FRCP(C), Division of Cardiology, Department of Medicine, Mount Sinai Hospital, 600 University Ave, Suite 1609, Toronto, Ontario, Canada. E-mail jdp@inforamp.net

Key Words: acetylcholine • nitroglycerin • endothelium • nitric oxide synthase • blood flow

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Nitroglycerin (GTN) and other organic nitrates are important drugs commonly used in cardiovascular medicine, and, more recently, in obstetrics as tocolytic agents.¹ The development of tolerance, ie, the reduction in effect or the requirement for higher doses that appears after continuous use,² is a major factor limiting the efficacy of these drugs. Despite their clinical importance in the therapy of ischemic heart disease and heart failure, many aspects of the pharmacology of organic nitrates, including the mechanism(s) of tolerance, remain unclear.

In the past decade, studies have demonstrated that organic nitrate therapy leads to complex interactions between the vasculature, neurohormones, and free oxygen radicals. In particular, the concept that GTN treatment causes increased vascular superoxide anion (·O₂^-) production, the mechanisms leading to this production, and the consequences of this phenomenon on endothelial function, have all been investigated. In the first part of this 2-part review, these recent findings, as well as the potential role of neurohormonal and autonomic abnormalities, will be described. In the second part, which will appear in the next issue of Circulation, we will propose a new, integrated view on the pathophysiology of nitrate tolerance.

The Vascular Free Radical Hypothesis of Nitrate Tolerance

There is evidence from both animal and human studies that nitrate tolerance, especially when induced in vivo,³ is associated with an increased bioavailability of ·O₂^-, and that this process is responsible for the development of tolerance.⁴ Superoxide anion is normally scavenged by multiple intra- and extracellular mechanisms, including the enzyme superoxide dismutase (SOD). However, in higher concentrations, it can . . . [Full Text of this Article]

This article has been cited by other articles:

				S. Kamaruzzaman, H. Watt, C. Carson, and S. Ebrahim The association between orthostatic hypotension and medication use in the British Women's Heart and Health Study Age Ageing, November 6, 2009; (2009) afp192v1. [Abstract] [Full Text] [PDF]

				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]

				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]

				A. Fukatsu, T. Hayashi, A. Miyazaki-Akita, H. Matsui-Hirai, Y. Furutate, A. Ishitsuka, Y. Hattori, and A. Iguchi Possible usefulness of apocynin, an NADPH oxidase inhibitor, for nitrate tolerance: prevention of NO donor-induced endothelial cell abnormalities Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H790 - H797. [Abstract] [Full Text] [PDF]

				J. C. Irvine, J. L. Favaloro, R. E. Widdop, and B. K. Kemp-Harper Nitroxyl Anion Donor, Angeli's Salt, Does Not Develop Tolerance in Rat Isolated Aortae Hypertension, April 1, 2007; 49(4): 885 - 892. [Abstract] [Full Text] [PDF]

				G. R. Thomas, J. M. DiFabio, T. Gori, and J. D. Parker Once Daily Therapy With Isosorbide-5-Mononitrate Causes Endothelial Dysfunction in Humans: Evidence of a Free-Radical-Mediated Mechanism J. Am. Coll. Cardiol., March 27, 2007; 49(12): 1289 - 1295. [Abstract] [Full Text] [PDF]

				J. V. Esplugues, M. Rocha, C. Nunez, I. Bosca, S. Ibiza, J. R. Herance, A. Ortega, J. M. Serrador, P. D'Ocon, and V. M. Victor Complex I Dysfunction and Tolerance to Nitroglycerin: An Approach Based on Mitochondrial-Targeted Antioxidants Circ. Res., November 10, 2006; 99(10): 1067 - 1075. [Abstract] [Full Text] [PDF]

				J. M. DiFabio, G. R. Thomas, L. Zucco, M. A. Kuliszewski, B. M. Bennett, M. J. Kutryk, and J. D. Parker Nitroglycerin Attenuates Human Endothelial Progenitor Cell Differentiation, Function, and Survival J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 117 - 123. [Abstract] [Full Text] [PDF]

				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]

				J. Abrams Chronic Stable Angina N. Engl. J. Med., June 16, 2005; 352(24): 2524 - 2533. [Full Text] [PDF]

				J. D. Horowitz Amelioration of nitrate tolerance: matching strategies with mechanisms J. Am. Coll. Cardiol., June 4, 2003; 41(11): 2001 - 2003. [Full Text] [PDF]