Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Tetrahydrobiopterin Protects Soluble Guanylate Cyclase against Oxidative Inactivation

Kurt Schmidt, Andrea Neubauer, Bernd Kolesnik, Johannes-Peter Stasch, Ernst R. Werner, Antonius C. F. Gorren and Bernd Mayer
Molecular Pharmacology September 2012, 82 (3) 420-427; DOI: https://doi.org/10.1124/mol.112.079855
Kurt Schmidt
Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria (K.S., A.N., B.K., A.C.F.G., B.M.); Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria (E.R.W.); and Pharma Research Centre, Bayer HealthCare, Wuppertal Germany (J.-P.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrea Neubauer
Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria (K.S., A.N., B.K., A.C.F.G., B.M.); Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria (E.R.W.); and Pharma Research Centre, Bayer HealthCare, Wuppertal Germany (J.-P.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bernd Kolesnik
Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria (K.S., A.N., B.K., A.C.F.G., B.M.); Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria (E.R.W.); and Pharma Research Centre, Bayer HealthCare, Wuppertal Germany (J.-P.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Johannes-Peter Stasch
Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria (K.S., A.N., B.K., A.C.F.G., B.M.); Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria (E.R.W.); and Pharma Research Centre, Bayer HealthCare, Wuppertal Germany (J.-P.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ernst R. Werner
Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria (K.S., A.N., B.K., A.C.F.G., B.M.); Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria (E.R.W.); and Pharma Research Centre, Bayer HealthCare, Wuppertal Germany (J.-P.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Antonius C. F. Gorren
Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria (K.S., A.N., B.K., A.C.F.G., B.M.); Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria (E.R.W.); and Pharma Research Centre, Bayer HealthCare, Wuppertal Germany (J.-P.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bernd Mayer
Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria (K.S., A.N., B.K., A.C.F.G., B.M.); Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria (E.R.W.); and Pharma Research Centre, Bayer HealthCare, Wuppertal Germany (J.-P.S.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

Tetrahydrobiopterin (BH4) is a major endogenous vasoprotective agent that improves endothelial function by increasing nitric oxide (NO) synthesis and scavenging of superoxide and peroxynitrite. Therefore, administration of BH4 is considered a promising therapy for cardiovascular diseases associated with endothelial dysfunction and oxidative stress. Here we report on a novel function of BH4 that might contribute to the beneficial vascular effects of the pteridine. Treatment of cultured porcine aortic endothelial cells with nitroglycerin (GTN) or 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) resulted in heme oxidation of soluble guanylate cyclase (sGC), as evident from diminished NO-induced cGMP accumulation that was paralleled by increased cGMP response to a heme- and NO-independent activator of soluble guanylate cyclase [4-([(4-carboxybutyl)[2-(5-fluoro-2-([4′-(trifluoromethyl)biphenyl-4-yl]methoxy)phenyl)ethyl]amino]methyl)benzoic acid (BAY 60-2770)]. Whereas scavenging of superoxide and/or peroxynitrite with superoxide dismutase, tiron, Mn(III)tetrakis(4-benzoic acid)porphyrin, and urate had no protective effects, supplementation of the cells with BH4, either by application of BH4 directly or of its precursors dihydrobiopterin or sepiapterin, completely prevented the inhibition of NO-induced cGMP accumulation by GTN and ODQ. Tetrahydroneopterin had the same effect, and virtually identical results were obtained with RFL-6 fibroblasts, suggesting that our observation reflects a general feature of tetrahydropteridines that is unrelated to NO synthase function and not limited to endothelial cells. Protection of sGC against oxidative inactivation may contribute to the known beneficial effects of BH4 in cardiovascular disorders associated with oxidative stress.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was funded by the Austrian Science Fund [Grants P20669 and P21693] (to B.M.), [Grant P23135] (to A.C.F.G.), and [Grant P22289] (to E.R.W.)

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.079855.

  • ABBREVIATIONS:

    BH4
    (6R)-5,6,7,8-tetrahydro-l-biopterin
    DHFR
    dihydrofolate reductase
    eNOS
    endothelial nitric-oxide synthase
    NO
    nitric oxide
    NH4
    (6RS)-5,6,7,8-tetrahydro-d-neopterin
    BAY 60-2770
    4-([(4-carboxybutyl)[2-(5-fluoro-2-([4′-(trifluoromethyl)biphenyl-4-yl]methoxy)phenyl)ethyl]amino]methyl)benzoic acid
    DMSO
    dimethyl sulfoxide
    sGC
    soluble guanylate cyclase
    DEA/NO
    1,1-diethyl-2-hydroxy-2-nitroso-hydrazine
    GTN
    glycerol trinitrate (nitroglycerin)
    BH2
    7,8-dihydro-l-biopterin
    NH2
    7,8-diydro-d-neopterin
    ODQ
    1H-[1,2,4]-oxadiazolo[4,3-a]quinoxaline-1-one
    oxyHb
    oxyhemoglobin
    deoxyHb
    deoxyhemoglobin
    metHb
    methemoglobin
    MTX
    methotrexate
    SOD
    superoxide dismutase
    MnTBAP
    Mn(III)tetrakis(4-benzoic acid)porphyrin
    BAY 58-2667
    4-[((4-carboxybutyl){2-[(4-phenethylbenzyl)oxy]phenethyl]amino)methyl[benzoic]acid.

  • Received May 7, 2012.
  • Accepted May 30, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 82 (3)
Molecular Pharmacology
Vol. 82, Issue 3
1 Sep 2012
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Tetrahydrobiopterin Protects Soluble Guanylate Cyclase against Oxidative Inactivation
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Protection of Soluble Guanylate Cyclase by BH4

Kurt Schmidt, Andrea Neubauer, Bernd Kolesnik, Johannes-Peter Stasch, Ernst R. Werner, Antonius C. F. Gorren and Bernd Mayer
Molecular Pharmacology September 1, 2012, 82 (3) 420-427; DOI: https://doi.org/10.1124/mol.112.079855

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Protection of Soluble Guanylate Cyclase by BH4

Kurt Schmidt, Andrea Neubauer, Bernd Kolesnik, Johannes-Peter Stasch, Ernst R. Werner, Antonius C. F. Gorren and Bernd Mayer
Molecular Pharmacology September 1, 2012, 82 (3) 420-427; DOI: https://doi.org/10.1124/mol.112.079855
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Analgesic Effects and Mechanisms of Licochalcones
  • Induced Fit Ligand Binding to CYP3A4
  • Englerin A Inhibits T-Type Channels
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics