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(Circulation. 2001;104:2263.)
© 2001 American Heart Association, Inc.

Editorials

Tolerance to the Organic Nitrates

New Ideas, New Mechanisms, Continued Mystery

John D. Parker, MD FRCP(C); Tommaso Gori, MD

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

Correspondence to John D. Parker, MD, Division of Cardiology, Mount Sinai Hospital, Suite 1609, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5. E-mail jdp@inforamp.net

Key Words: Editorials • nitroglycerin • pharmacology • nitric oxide

Nitroglycerin (NTG) and other organic nitrates continue to be important drugs that are often used in cardiovascular medicine. All organic nitrates undergo denitrification, releasing nitric oxide (NO) through a biotransformation process that remains poorly understood to date. NO activates the enzyme soluble guanylyl cyclase in smooth muscle cells, causing increased levels of the second messenger cGMP. Finally, cGMP activates a cGMP-dependent protein kinase. This enzyme mediates vasorelaxation through inhibitory phosphorylation of different proteins involved in the regulation of intracellular Ca²⁺ levels.

See p 2338

All of the organic nitrates have potent short-term vascular, hemodynamic, and clinical effects. A critical limitation in their clinical application is the development of tolerance, whereby their initial effects are rapidly lost during sustained administration. Although there seems to be little doubt that NO, or some NO adjunct, mediates the pharmacodynamic effect of nitrates, the mechanism(s) underlying the development of tolerance remain an important and vexing problem for cardiovascular pharmacology.

Nitrate Tolerance: The State of the Art

The phenomenon of nitrate tolerance has been recognized for more than a century and has been intensely investigated for 3 decades. Despite these efforts, a unifying hypothesis concerning the mechanism of tolerance continues to be elusive. Initial investigations focused on abnormalities in biotransformation and denitrification of organic nitrates. Almost 30 years ago, Needleman and Johnson¹ proposed that tolerance might result from impaired nitrate metabolism caused by the reduced bioavailability of sulfhydryl groups. Although sulfhydryl depletion is no longer thought to play a causal role in tolerance,² abnormalities in nitrate biotransformation remain the subject of active investigation.³ . . . [Full Text of this Article]

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