Ascorbic acid and tetrahydrobiopterin potentiate the EDHF phenomenon by generating hydrogen peroxide

Garry, Ambroise, Edwards, David Hughes, Fallis, Ian Andrew ORCID: https://orcid.org/0000-0001-7361-0182, Jenkins, Robert Leyshon and Griffith, Tudor Morley 2009. Ascorbic acid and tetrahydrobiopterin potentiate the EDHF phenomenon by generating hydrogen peroxide. Cardiovascular Research 84 (2) , pp. 218-226. 10.1093/cvr/cvp235

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Abstract

Aims Our objective was to investigate whether pro-oxidant properties of ascorbic acid (AA) and tetrahydrobiopterin (BH4) modulate endothelium-dependent, electrotonically mediated arterial relaxation. Methods and results In studies with rabbit iliac artery (RIA) rings, NO-independent, endotheliumderived hyperpolarizing factor (EDHF)-type relaxations evoked by the sarcoplasmic endoplasmic reticulum Ca2þ-ATPase inhibitor cyclopiazonic acid and the G protein-coupled agonist acetylcholine (ACh) were enhanced by AA (1 mM) and BH4 (200 mM), which generated buffer concentrations of H2O2 in the range of 40–80 mM. Exogenous H2O2 potentiated cyclopiazonic acid (CPA)- and ACh-evoked relaxations with a threshold of 10–30 mM, and potentiation by AA and BH4 was abolished by catalase, which destroyed H2O2 generated by oxidation of these agents in the organ chamber. Adventitial application of H2O2 also enhanced EDHF-type dilator responses evoked by CPA and ACh in RIA segments perfused intraluminally with H2O2-free buffer, albeit with reduced efficacy. In RIA rings, both control relaxations and their potentiation by H2O2 were overcome by blockade of gap junctions by connexinmimetic 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 BH4, but not AA, consistent with findings demonstrating a differential role for superoxide anions in the generation of H2O2 by the two agents. Conclusion Pro-oxidant effects of AA and BH4 can enhance the EDHF phenomenon by generating H2O2, which has previously been shown to amplify electrotonic hyperpolarization-mediated relaxation by facilitating Ca2þ release from endothelial stores.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Chemistry Medicine
Subjects:	Q Science > QD Chemistry R Medicine > R Medicine (General)
Uncontrolled Keywords:	Connexin-mimetic peptides; Gap junction; Superoxide anion;
Publisher:	Elsevier
ISSN:	0008-6363
Last Modified:	05 Nov 2022 15:38
URI:	https://orca.cardiff.ac.uk/id/eprint/23688

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