title: Hydrogen peroxide potentiates the EDHF phenomenon by promoting endothelial Ca2+ mobilization.
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.
  
  
  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.
authors.affiliation: Wales Heart Research Institute, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Edwards
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Li
authors.forename: Tudor M
authors.initials: TM
authors.lastname: Griffith
mesh_terms: D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001685:Biological Factors / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017629:Gap Junctions / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006706:Homeostasis; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007083:Iliac Artery / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D009213:Myography; D016877:Oxidants / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013849:Thimerosal / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D004791:Enzyme Inhibitors; C514423:Gap 26 peptide; D007211:Indoles; D053496:Inositol 1,4,5-Trisphosphate Receptors; D016877:Oxidants; D010455:Peptides; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; C411671:TRAM 34; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D013849:Thimerosal; D001030:Apamin; C064719:iberiotoxin; C042431:S-ethyl glutathione; D006861:Hydrogen Peroxide; D002374:Catalase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D005978:Glutathione; D002118:Calcium; C000543:cyclopiazonic acid; D000640:Amitrole