This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 28/10/1774    most recent ATVBAHA.108.172692v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Edwards, D. H. Articles by Griffith, T. M. Search for Related Content PubMed PubMed Citation Articles by Edwards, D. H. Articles by Griffith, T. M. Related Collections Related Article

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1774.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Hydrogen Peroxide Potentiates the EDHF Phenomenon by Promoting Endothelial Ca²⁺ Mobilization

David H. Edwards; Yiwen Li; Tudor M. Griffith

From the Wales Heart Research Institute, School of Medicine, Cardiff University, UK.

Correspondence to Tudor Griffith, Department of Diagnostic Radiology, Wales Heart Research Institute, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. E-mail griffith{at}cardiff.ac.uk

Objective— The purpose of this study was to test the hypothesis that H₂O₂ contributes to the EDHF phenomenon by mobilizing endothelial Ca²⁺ stores.

Methods and Results— Myograph studies with rabbit iliac arteries demonstrated that EDHF-type relaxations evoked by the SERCA inhibitor cyclopiazonic acid (CPA) required activation of K_Ca channels and were potentiated by exogenous H₂O₂ and the thiol oxidant thimerosal. Preincubation with a submaximal concentration of CPA unmasked an ability of exogenous H₂O₂ to stimulate an EDHF-type response that was sensitive to K_Ca channel blockade. Imaging of cytosolic and endoplasmic reticulum [Ca²⁺] in rabbit aortic valve endothelial cells with Fura-2 and Mag-fluo-4 demonstrated that H₂O₂ and thimerosal, which sensitizes the InsP₃ receptor, both enhanced CPA-evoked Ca²⁺ release from stores, and that the potentiating effect of H₂O₂ was suppressed by the cell-permeant thiol reductant glutathione monoethylester. CPA-evoked relaxations were attenuated by exogenous catalase and potentiated by the catalase inhibitor 3-aminotriazole, and were abolished by the connexin-mimetic peptide ⁴³Gap26, which interrupts intercellular communication via gap junctions constructed from connexin 43.

Conclusions— H₂O₂ can enhance EDHF-type relaxations by potentiating Ca²⁺ release from endothelial stores, probably via redox modification of the InsP₃ receptor, leading to the opening of hyperpolarizing endothelial K_Ca channels and an electrotonically-mediated relaxant response.

Pharmacological analysis of relaxation and imaging of intracellular Ca²⁺ mobilization has shown that H₂O₂ can contribute to electrotonically-mediated EDHF-type relaxations by promoting Ca²⁺ release from stores and secondary opening of K_Ca channels. The thiol oxidant thimerosal mimics this previously unrecognized endothelial action of H₂O₂, consistent with sensitization of the InsP₃ receptor.

Key Words: hydrogen peroxide • thimerosal • SERCA pump • EDHF

Related Article:

Endothelial H₂O₂: A Bad Guy Turning Good?

Wolfgang F. Graier and Markus Hecker
Arterioscler Thromb Vasc Biol 2008 28: 1691-1693. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				S. Fernandez-Rodriguez, D. H. Edwards, B. Newton, and T. M. Griffith Attenuated store-operated Ca2+ entry underpins the dual inhibition of nitric oxide and EDHF-type relaxations by iodinated contrast media Cardiovasc Res, December 1, 2009; 84(3): 470 - 478. [Abstract] [Full Text] [PDF]

				A. E. Loot, J. G. Schreiber, B. Fisslthaler, and I. Fleming Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase J. Exp. Med., November 23, 2009; (2009) jem.20090449v1. [Abstract] [Full Text] [PDF]

				A. Garry, D. H. Edwards, I. F. Fallis, R. L. Jenkins, and T. M. Griffith Ascorbic acid and tetrahydrobiopterin potentiate the EDHF phenomenon by generating hydrogen peroxide Cardiovasc Res, November 1, 2009; 84(2): 218 - 226. [Abstract] [Full Text] [PDF]

				J. M. Muller-Delp Ascorbic acid and tetrahydrobiopterin: looking beyond nitric oxide bioavailability Cardiovasc Res, November 1, 2009; 84(2): 178 - 179. [Full Text] [PDF]

				A. Brill, A. K. Chauhan, M. Canault, M. T. Walsh, W. Bergmeier, and D. D. Wagner Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion Cardiovasc Res, October 1, 2009; 84(1): 137 - 144. [Abstract] [Full Text] [PDF]

				S. W. Copp, L. F. Ferreira, K. F. Herspring, D. M. Hirai, B. S. Snyder, D. C. Poole, and T. I. Musch The effects of antioxidants on microvascular oxygenation and blood flow in skeletal muscle of young rats Exp Physiol, September 1, 2009; 94(9): 961 - 971. [Abstract] [Full Text] [PDF]

				L. S. A. Capettini, S. F. Cortes, M. A. Gomes, G. A. B. Silva, J. L. Pesquero, M. J. Lopes, M. M. Teixeira, and V. S. Lemos Neuronal nitric oxide synthase-derived hydrogen peroxide is a major endothelium-dependent relaxing factor Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2503 - H2511. [Abstract] [Full Text] [PDF]