Affiliation:
1. From the Wales Heart Research Institute, School of Medicine, Cardiff University, UK.
Abstract
Objective—
The purpose of this study was to test the hypothesis that H
2
O
2
contributes to the EDHF phenomenon by mobilizing endothelial Ca
2+
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 H
2
O
2
and the thiol oxidant thimerosal. Preincubation with a submaximal concentration of CPA unmasked an ability of exogenous H
2
O
2
to stimulate an EDHF-type response that was sensitive to K
Ca
channel blockade. Imaging of cytosolic and endoplasmic reticulum [Ca
2+
] in rabbit aortic valve endothelial cells with Fura-2 and Mag-fluo-4 demonstrated that H
2
O
2
and thimerosal, which sensitizes the InsP
3
receptor, both enhanced CPA-evoked Ca
2+
release from stores, and that the potentiating effect of H
2
O
2
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
43
Gap26, which interrupts intercellular communication via gap junctions constructed from connexin 43.
Conclusions—
H
2
O
2
can enhance EDHF-type relaxations by potentiating Ca
2+
release from endothelial stores, probably via redox modification of the InsP
3
receptor, leading to the opening of hyperpolarizing endothelial K
Ca
channels and an electrotonically-mediated relaxant response.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
57 articles.
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