Cited by 115Nitric Oxide and Endothelin EffectsReceptor Mechanisms and SignalingPhosphodiesterase function and regulation

Nitroglycerin-Induced S-nitrosylation and Desensitization of Soluble Guanylyl Cyclase Contribute to Nitrate Tolerance

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Sayed, Nazish, Kim, David D., Fioramonti, Xavier, Iwahashi, Toru, Durán, Walter N., Beuve, Annie·2008·Circulation Research

Abstract

Nitrates such as nitroglycerin (GTN) and nitric oxide donors such as S-nitrosothiols are clinically vasoactive through stimulation of soluble guanylyl cyclase (sGC), which produces the second messenger cGMP. Development of nitrate tolerance, after exposure to GTN for several hours, is a major drawback to a widely used cardiovascular therapy. We recently showed that exposure to nitric oxide and to S-nitrosothiols causes S-nitrosylation of sGC, which directly desensitizes sGC to stimulation by nitric oxide. We tested the hypothesis that desensitization of sGC by S-nitrosylation is a mechanism of nitrate tolerance. Our results established that vascular tolerance to nitrates can be recapitulated in vivo by S-nitrosylation through exposure to cell membrane-permeable S-nitrosothiols and that sGC is S-nitrosylated and desensitized in the tolerant, treated tissues. We next determined that (1) GTN treatment of primary aortic smooth muscle cells induces S-nitrosylation of sGC and its desensitization as a function of GTN concentration; (2) S-nitrosylation and desensitization are prevented by treatment with N-acetyl-cysteine, a precursor of glutathione, used clinically to prevent development of nitrate tolerance; and (3) S-nitrosylation and desensitization are reversed by cessation of GTN treatment. Finally, we demonstrated that in vivo development of nitrate tolerance and crosstolerance by 3-day chronic GTN treatment correlates with S-nitrosylation and desensitization of sGC in tolerant tissues. These results suggest that in vivo nitrate tolerance is mediated, in part, by desensitization of sGC through GTN-dependent S-nitrosylation.

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Authors
Sayed, N., Kim, D. D., Fioramonti, X., Iwahashi, T., Durán, W. N., & Beuve, A.
Affiliations
  • Rutgers New Jersey Medical School (US)
  • From the Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark.
Venue
Circulation Research
Published
2008-09-12
Volume
103
Issue
6
Pages
606-614
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
OpenAlex
W2170220747
Cited by
115
References
41
Citations by year
2025: 5 · 2024: 3 · 2023: 5 · 2022: 6 · 2021: 5 · 2020: 5 · 2019: 1 · 2018: 6 · 2017: 6 · 2016: 9 · 2015: 9 · 2014: 7 · 2013: 11 · 2012: 9
FWCI
6.32
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rutgers University Community Repository (Rutgers University) (submittedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL089771, HL-070634, R01HL070634, R21HL089771)
  • National Institute of General Medical Sciences (R01GM067640, GM067640)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
Keywords
nitrate tolerance, nitroglycerin, soluble guanylate cyclase, S-nitrosylation, receptor desensitization, S-nitrosothiols, nitric oxide signaling, cyclic GMP, aortic smooth muscle cells, N-acetylcysteine
MeSH terms
Soluble Guanylyl Cyclase, Animals, Arterioles, Cysteine, Drug Tolerance, Enzyme Activation, Nitroglycerin, Guanylate Cyclase, Cricetinae, Mouth Mucosa, Nitrates, Vasodilation, Receptors, Cytoplasmic and Nuclear, S-Nitrosothiols

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