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Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 10, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp235
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. 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.

ASCORBIC ACID AND TETRAHYDROBIOPTERIN POTENTIATE THE EDHF PHENOMENON BY GENERATING HYDROGEN PEROXIDE

Ambroise Garry1, David H. Edwards1, Ian F. Fallis2, Robert L. Jenkins2 and Tudor M. Griffith1,*

1 Department of Diagnostic Radiology, Wales Heart Research Institute, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
2 School of Chemistry, Cardiff University, Main Building, Park Place Cardiff CF10 3AT, UK

* Correspondence: griffith{at}cardiff.ac.uk Tel 44-2920-744481 Fax 44-2920-743500

Aim: Our objective was to investigate whether pro-oxidant properties of ascorbic acid (AA) and tetrahydrobiopterin (BH4) modulate endothelium-dependent, electrotonically mediated arterial relaxation.

Methods and Results: In studies with rabbit iliac artery (RIA) rings, NO-independent, EDHF-type relaxations evoked by the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor cyclopiazonic acid and the G protein-coupled agonist acetylcholine (ACh) were enhanced by AA (1 mM) and BH4 (200 µM), which generated buffer concentrations of H2O2 in the range of 40-80 µM. Exogenous H2O2 potentiated CPA- and ACh-evoked relaxations with a threshold of 10-30 µM, and potentiation by AA and BH4 was abolished by catalase, which destroyed H2O2 generated by oxidation of these agents in the organ chamber. Adventitial application of H2O2 also enhanced EDHF-type dilator responses evoked by CPA and ACh in RIA segments perfused intraluminally with H2O2-free buffer, albeit with reduced efficacy. In RIA rings both control relaxations and their potentiation by H2O2 were overcome by blockade of gap junctions by connexin-mimetic peptides (YDKSFPISHVR and SRPTEK) targeted to the 1st and 2nd extracellular loops of the dominant vascular connexins expressed in the RIA. Superoxide dismutase attenuated the potentiation of EDHF-type relaxations by BH4, but not AA, consistent with findings demonstrating a differential role for superoxide anions in the generation of H2O2 by the two agents.

Conclusions: Pro-oxidant effects of AA and BH4 can enhance the EDHF phenomenon by generating H2O2, which has previously been shown to amplify electrotonic hyperpolarization-mediated relaxation by facilitating Ca2+ release from endothelial stores.

KEYWORDS connexin-mimetic peptides; gap junction; superoxide anion

Time for primary review: 23 Days


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