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Cardiovascular Research Advance Access originally published online on April 28, 2008
Cardiovascular Research 2008 79(2):304-312; doi:10.1093/cvr/cvn107
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

Vascular tolerance to nitroglycerin in ascorbate deficiency

Gerald Wölkart, M. Verena Wenzl, Matteo Beretta, Heike Stessel, Kurt Schmidt and Bernd Mayer*

Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria

* Corresponding author. Tel: +43 316 380 5567; fax: +43 316 380 9890. E-mail address: mayer{at}uni-graz.at

Aims: Nitroglycerin (GTN) acts through release of a nitric oxide (NO)-related activator of soluble guanylate cyclase in vascular smooth muscle. Besides enzymatic GTN bioactivation catalysed by aldehyde dehydrogenase, non-enzymatic reaction of GTN with ascorbate also results in the formation of a bioactive product. Using an established guinea pig model of ascorbate deficiency, we investigated whether endogenous ascorbate contributes to GTN-induced vasodilation.

Methods and results: Guinea pigs were fed either standard or ascorbate-free diet for 2 or 4 weeks prior to measuring the GTN response of aortic rings and isolated hearts. The effects of ascorbate on GTN metabolism were studied with purified mitochondrial aldehyde dehydrogenase (ALDH2) and isolated mitochondria. Ascorbate deprivation led to severe scorbutic symptoms and loss of body weight, but had no (2 weeks) or only slight (4 weeks) effects on aortic relaxations to a direct NO donor. The EC50 of GTN was increased from 0.058 ± 0.018 to 0.46 ± 0.066 and 5.5 ± 0.9 µM after 2 and 4 weeks of ascorbate-free diet, respectively. Similarly, coronary vasodilation to GTN was severely impaired in ascorbate deficiency. The potency of GTN was reduced to a similar extent by ALDH inhibitors in control and ascorbate-deficient blood vessels. Up to 10 mM ascorbate had no effect on GTN metabolism catalysed by purified ALDH2 or liver mitochondria isolated from ascorbate-deficient guinea pigs.

Conclusion: Our results indicate that prolonged ascorbate deficiency causes tolerance to GTN without affecting NO/cyclic GMP-mediated vasorelaxation.

KEYWORDS Bioactivation; Cyclic GMP; Nitric oxide; Organic nitrate; Vitamin C

Time for primary review: 38 days


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Home page
 Cardiovasc ResHome page
A. Daiber and T. Gori
Vascular tolerance to nitroglycerin in ascorbate deficiency: results are in favour of an important role of oxidative stress in nitrate tolerance
Cardiovasc Res, September 1, 2008; 79(4): 722 - 723.
[Full Text] [PDF]

Home page
 Cardiovasc ResHome page
B. Mayer
Vascular tolerance to nitroglycerin in ascorbate deficiency: results are in favour of an important role of oxidative stress in nitrate tolerance: reply
Cardiovasc Res, September 1, 2008; 79(4): 724 - 724.
[Full Text] [PDF]


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