doi: 10.1161/CIRCRESAHA.108.184341
© 2008 American Heart Association, Inc.
Editorials |
Nitroglycerin-Mediated S-Nitrosylation of Proteins
A Field Comes Full Cycle
From the Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC.
Correspondence to Jonathan S. Stamler, MD, Department of Medicine, Box 2612, Duke University Medical Center, Durham, NC 27710. E-mail staml001@mc.duke.edu
See related article, pages 606–614
Key Words: nitroglycerin • tolerance • S-nitrosylation • guanylate cyclase
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
Nitroglycerin (glyceryl trinitrate) (GTN) has been an important part of the management of patients with angina or heart failure for over 135 years. GTN works through a combined action on the venous circulation and coronary vasculature to reduce preload and improve myocardial blood flow.1 Its attributes include a potent vasodilatory action on diseased coronary vessels as well as antiischemic effects elicited in the microcirculation.1,2 Dilation of conduit vessels by GTN is mediated in large part through nitric oxide (NO) binding to heme within, and activation of, soluble guanylate cyclase (sGC) in vascular smooth muscle, thereby leading to induction of the second messenger, cyclic GMP. The microvascular action of GTN involves additional effects on red blood cells (RBCs) to improve rheology and oxygen delivery.2 GTN is an exceptionally potent vasodilator compared to other organic nitrates (isosorbide di- or mononitrates) but loses efficacy over time. Tachyphylaxis to GTN is initially specific to GTN (mechanism-based tolerance), but is ultimately associated with diminished responsiveness to other nitro(so)vasodilators (cross-tolerance) and even other classes of drugs (as a result of fluid retention and perhaps cellular injury).1,3,4 Tolerance and cross-tolerance have generally been thought of in terms of an NO deficiency, resulting in attenuated sGC activity.5,6 Sayed et al had found recently that S-nitrosylation of sGC (the addition of an NO group to a cysteine thiol) by endothelium-derived NO inhibits sGC activity,7 and they now report that exposure to GTN can result in the S-nitrosylation and desensitization of sGC, thereby providing a mechanism for cross-tolerance.8
Related Article:
Circ. Res. 2008 103: 606-614.