on July 31, 2008
Published online before print July 31, 2008, doi: 10.1161/ATVBAHA.108.172692
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Submitted on January 2, 2008
Accepted on July 23, 2008
Hydrogen Peroxide Potentiates the EDHF Phenomenon by Promoting Endothelial Ca2+ Mobilization
David Edwards ;
From the Wales Heart Research Institute, School of Medicine, Cardiff University, UK.
* To whom correspondence should be addressed. 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 KCa 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 KCa 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 connexin43.
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 KCa channels and an electrotonically-mediated relaxant response.
Key words: hydrogen peroxide • thimerosal • SERCA pump • EDHF
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