Tolerance to the Organic Nitrates

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.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 Importantly, investigations in this area are severely limited by our poor understanding of the biotransformation pathway and by significant analytical problems in quantifying NO and/or NO adjunct production rates.Approximately 10 years ago, research in the field of nitrate tolerance shifted toward the description of systemic, …