title: Ascorbic acid and tetrahydrobiopterin potentiate the EDHF phenomenon by generating hydrogen peroxide.
abstract: OBJECTIVE
  Our objective was to investigate whether pro-oxidant properties of ascorbic acid (AA) and tetrahydrobiopterin (BH(4)) modulate endothelium-dependent, electrotonically mediated arterial relaxation.
  
  
  RESULTS
  In studies with rabbit iliac artery (RIA) rings, NO-independent, endothelium-derived hyperpolarizing factor (EDHF)-type relaxations evoked by the sarcoplasmic endoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid and the G protein-coupled agonist acetylcholine (ACh) were enhanced by AA (1 mM) and BH(4) (200 microM), which generated buffer concentrations of H(2)O(2) in the range of 40-80 microM. Exogenous H(2)O(2) potentiated cyclopiazonic acid (CPA)- and ACh-evoked relaxations with a threshold of 10-30 microM, and potentiation by AA and BH(4) was abolished by catalase, which destroyed H(2)O(2) generated by oxidation of these agents in the organ chamber. Adventitial application of H(2)O(2) also enhanced EDHF-type dilator responses evoked by CPA and ACh in RIA segments perfused intraluminally with H(2)O(2)-free buffer, albeit with reduced efficacy. In RIA rings, both control relaxations and their potentiation by H(2)O(2) were overcome by blockade of gap junctions by connexin-mimetic peptides (YDKSFPISHVR and SRPTEK) targeted to the first and second extracellular loops of the dominant vascular connexins expressed in the RIA. Superoxide dismutase attenuated the potentiation of EDHF-type relaxations by BH(4), but not AA, consistent with findings demonstrating a differential role for superoxide anions in the generation of H(2)O(2) by the two agents.
  
  
  CONCLUSIONS
  Pro-oxidant effects of AA and BH(4) can enhance the EDHF phenomenon by generating H(2)O(2), which has previously been shown to amplify electrotonic hyperpolarization-mediated relaxation by facilitating Ca(2+) release from endothelial stores.
authors: Department of Diagnostic Radiology, Wales Heart Research Institute, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors: Ambroise
authors: A
authors: Garry
authors: David H
authors: DH
authors: Edwards
authors: Ian F
authors: IF
authors: Fallis
authors: Robert L
authors: RL
authors: Jenkins
authors: Tudor M
authors: TM
authors: Griffith
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D001685:Biological Factors / Q000378:metabolism*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007083:Iliac Artery / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D016877:Oxidants / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D001685:Biological Factors; D017630:Connexins; D007211:Indoles; D016877:Oxidants; D010455:Peptides; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D013481:Superoxides; D001708:Biopterins; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C003402:sapropterin; D000109:Acetylcholine; D001205:Ascorbic Acid; D002118:Calcium; C000543:cyclopiazonic acid