Explaining the Phenomenon of Nitrate Tolerance

• Published in: Circulation research Vol. 97; no. 7; pp. 618 - 628
• Main Authors: Münzel, Thomas, Daiber, Andreas, Mülsch, Alexander
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 30.09.2005; Lippincott
• Subjects: Aldehyde Dehydrogenase - metabolism; Aldehyde Dehydrogenase, Mitochondrial; Animals; Biological and medical sciences; Biotransformation; Cyclic GMP-Dependent Protein Kinases - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 1; Drug Tolerance; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Fundamental and applied biological sciences. Psychology; Humans; Nitric Oxide - biosynthesis; Nitroglycerin - pharmacology; Nitroglycerin - therapeutic use; Oxidative Stress; Peroxynitrous Acid - metabolism; Phosphoric Diester Hydrolases - physiology; Reactive Oxygen Species; Signal Transduction; Superoxides - metabolism; Vasoconstriction - drug effects; Vasodilation - drug effects; Vasodilator Agents - pharmacology; Vertebrates: cardiovascular system; Oxidative stress; Vertebrata; Mammalia; Nitric oxide; Nitroglycerin; Organic nitrate; Tolerance; Endothelial dysfunction; Circulatory system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000184694.03262.6d

During the last century, nitroglycerin has been the most commonly used antiischemic and antianginal agent. Unfortunately, after continuous application, its therapeutic efficacy rapidly vanishes. Neurohormonal activation of vasoconstrictor signals and intravascular volume expansion constitute early counter-regulatory responses (pseudotolerance), whereas long-term treatment induces intrinsic vascular changes, eg, a loss of nitrovasodilator-responsiveness (vascular tolerance). This is caused by increased vascular superoxide production and a supersensitivity to vasoconstrictors secondary to a tonic activation of protein kinase C. NADPH oxidase(s) and uncoupled endothelial nitric oxide synthase have been proposed as superoxide sources. Superoxide and vascular NO rapidly form peroxynitrite, which aggravates tolerance by promoting NO synthase uncoupling and inhibition of soluble guanylyl cyclase and prostacyclin synthase. This oxidative stress concept may explain why radical scavengers and substances, which reduce oxidative stress indirectly, are able to relieve tolerance and endothelial dysfunction. Recent work has defined a new tolerance mechanism, ie, an inhibition of mitochondrial aldehyde dehydrogenase, the enzyme that accomplishes bioactivation of nitroglycerin, and has identified mitochondria as an additional source of reactive oxygen species. Nitroglycerin-induced reactive oxygen species inhibit the bioactivation of nitroglycerin by thiol oxidation of aldehyde dehydrogenase. Both mechanisms, increased oxidative stress and impaired bioactivation of nitroglycerin, can be joined to provide a new concept for nitroglycerin tolerance and cross-tolerance. The consequences of these processes for the nitroglycerin downstream targets soluble guanylyl cyclase, cGMP-dependent protein kinase, cGMP-degrading phosphodiesterases, and toxic side effects contributing to endothelial dysfunction, such as inhibition of prostacyclin synthase, are discussed in this review.