Skip Navigation

European Heart Journal 1989 10(Supplement F):127-133; doi:10.1093/eurheartj/10.suppl_F.127
Copyright © 1989 by the European Society of Cardiology.
This Article
Right arrow Full Text (PDF)
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Holtz, J.
Right arrow Articles by Bassenge, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Holtz, J.
Right arrow Articles by Bassenge, E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 1989 The European Society of Cardiology

Nitrate action on epicardial coronary arteries and tolerance: New aspects based on longterm glyceryl trinitrate infusions in dogs

J. Holtz, T. Münzel, D. J. Stewart and E. Bassenge

Institute of Applied Physiology, University of Freiburg F.R.G.

Address for correspondence: J. Holtz, Institute of Applied Physiology, University of Freiburg, Hermann-Herder-Strasse 7, D-7800 Freiburg, F.R.G.

Continuous application of organic nitrates in patients causes a well-documented attenuation of their antianginal efficacy. N-acetylcysteine (NAC) is assumed to reverse this nitrate tolerance by replenishing depleted intracellular sulphydryl groups, but data on NAC application in patients are controversial. Therefore, we studied the effect of NAC on epicardial artery vasomotion under nitrate tolerance, and we examined under these conditions the epicardial artery dilations induced by glyceryl trinitrate (GTN) and those mediated by the endothelium, since the activation of soluble guanylate cyclase is a common mechanism of these two reactions. Tolerance was induced in chronically instrumented dogs by long-term GTN infusion (1·5 µg kg–1 min–1i.v. for 5 to 6 days) and shifted the GTN dose response curve of epicardial arteries to 17- to 20-fold higher doses. However, there was no alteration of epicardial artery dilations induced by SIN-1, another activator of guanylate cyclase, or of endothelium-mediated dilations. Furthermore, NAC (100 mg kg–1i.v.) did not alter the dose-response relation of GTN under tolerance. In vitro, however, NAC potentiated the activation of purified soluble guanylate cyclase by GTN, while NAC without GTN was ineffective. In non-tolerant dogs, NAC slightly (1·5- to 2-fold) augmentated dilations induced by 0·5-1·5 µg kg–1 min–1 GTN, and a similar small augmentation of GTN dilations by NAC is observed in patients, regardless whether they are tolerant to nitrates or not. We conclude: (1) a step prior to the guanylate cyclase activation is responsible for GTN-specific tolerance of epicardial arteries in vivo. (2) NAC does not reverse GTN -specific tolerance. (3) A small, tolerance-independent augmentation of GTN action by NAC might result from extracellular interactions of GTN and NAC, inducing the formation of a guanylate cyclase stimulating metabolite.

Key Words: Antianginal efficacy • soluble guanylate cyclase • endothelium-mediated dilation • N-acetylcysteine • pseudo-tolerance


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.