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
Journal of Pharmacology and Experimental Therapeutics
  • 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
Journal of Pharmacology and Experimental Therapeutics

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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleCARDIOVASCULAR

Inhibition of Phosphodiesterase 5 Selectively Reverses Nitrate Tolerance in the Venous Circulation

Jeffery D. MacPherson, Timothy D. Gillespie, Heather A. Dunkerley, Donald H. Maurice and Brian M. Bennett
Journal of Pharmacology and Experimental Therapeutics April 2006, 317 (1) 188-195; DOI: https://doi.org/10.1124/jpet.105.094763
Jeffery D. MacPherson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy D. Gillespie
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heather A. Dunkerley
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Donald H. Maurice
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brian M. Bennett
  • 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
Loading

Abstract

An important component of the antianginal efficacy of glyceryl trinitrate (GTN) is attributable to its selective venodilator effect, resulting in decreased cardiac preload and myocardial oxygen demand. Tolerance to nitrates occurs during chronic exposure, and the current study assessed whether this was due to increased phosphodiesterase (PDE) activity in the venous circulation. Tolerance was induced in rats by continuous exposure to 0.4 mg/h GTN for 48 h. Tension recordings of isolated femoral artery and vein indicated that tolerance was more pronounced in femoral vein. 4-[[3,4-(Methylenedioxy)benzyl]amino]-6-chloroquinazoline (MBCQ), a selective PDE5 inhibitor, significantly decreased the EC50 values for GTN-induced relaxation in both tolerant and nontolerant tissues, but with the greatest relative shift occurring in tolerant veins. MBCQ also increased the vasodilator potency of 1,1-diethyl-2-hydroxy-2-nitrosohydrazine (DEA/NO), a nitric oxide donor; however, cross-tolerance between DEA/NO and GTN was not observed. A significant increase in cGMP PDE activity was observed in tolerant femoral vein, whereas PDE activity was unchanged in femoral artery. Conscious rats treated with hexamethonium (30 mg/kg) to induce ganglionic blockade exhibited blunted central venous pressure (CVP) and mean arterial pressure (MAP) responses to bolus i.v. doses of GTN in GTN-tolerant animals. The cGMP PDE inhibitor zaprinast (1 mg/kg) selectively reversed the blunted CVP response to GTN in tolerant animals but had no effect on the CVP response to GTN in nontolerant animals or on the MAP response in either group. These results suggest that increased PDE5 activity in the venous circulation contributes to the altered hemodynamic response to GTN following chronic GTN exposure.

Footnotes

  • This work was supported by Grant T 5162 from the Heart and Stroke Foundation of Ontario.

  • doi:10.1124/jpet.105.094763.

  • ABBREVIATIONS: GTN, glyceryl trinitrate; sGC, soluble guanylyl cyclase; PDE, phosphodiesterase; PK, protein kinase; CVP, central venous pressure; MAP, mean arterial pressure; DEA/NO, 1,1-diethyl-2-hydroxy-2-nitrosohydrazine; MBCQ, 4-[[3,4-(methylenedioxy)benzyl]amino]-6-chloroquinazoline; Ca/CAM, calcium/calmodulin; ANOVA, analysis of variance.

    • Received August 31, 2005.
    • Accepted December 1, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET 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.
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
  • 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 Journal of Pharmacology and Experimental Therapeutics 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.
Inhibition of Phosphodiesterase 5 Selectively Reverses Nitrate Tolerance in the Venous Circulation
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleCARDIOVASCULAR

Inhibition of Phosphodiesterase 5 Selectively Reverses Nitrate Tolerance in the Venous Circulation

Jeffery D. MacPherson, Timothy D. Gillespie, Heather A. Dunkerley, Donald H. Maurice and Brian M. Bennett
Journal of Pharmacology and Experimental Therapeutics April 1, 2006, 317 (1) 188-195; DOI: https://doi.org/10.1124/jpet.105.094763

Citation Manager Formats

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

Share
Research ArticleCARDIOVASCULAR

Inhibition of Phosphodiesterase 5 Selectively Reverses Nitrate Tolerance in the Venous Circulation

Jeffery D. MacPherson, Timothy D. Gillespie, Heather A. Dunkerley, Donald H. Maurice and Brian M. Bennett
Journal of Pharmacology and Experimental Therapeutics April 1, 2006, 317 (1) 188-195; DOI: https://doi.org/10.1124/jpet.105.094763
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • 4-Chloro ring-substituted synthetic cathinones
  • 14-3-3 Influences Nav1.5 Response to Anti-Arrhythmic Drugs
  • Inhaled Treprostinil Palmitil in the Sugen/Hypoxia Rat Model
Show more Cardiovascular

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 JPET
  • 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
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

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