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Attenuated store-operated Ca2+ entry underpins the dual inhibition of nitric oxide and EDHF-type relaxations by iodinated contrast media

Fernandez-Rodriguez, Sofia, Edwards, David Hughes, Newton, B. and Griffith, Tudor Morley 2009. Attenuated store-operated Ca2+ entry underpins the dual inhibition of nitric oxide and EDHF-type relaxations by iodinated contrast media. Cardiovascular Research 84 (3) , pp. 470-478. 10.1093/cvr/cvp239

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Aims Our objective was to investigate whether alterations in endothelial Ca2+ homeostasis contribute to the clinical toxicity of iodinated radiographic contrast media (IRCM) by modulating nitric oxide (NO) production and the endothelium-derived hyperpolarizing factor (EDHF) phenomenon. Methods and results The triiodinated monomer iohexol caused concentration-dependent reductions in store-operated Ca2+ entry (SOCE) in rabbit aortic valve endothelium incubated in Ca2+-free buffer with cyclopiazonic acid (CPA, 30 µM) to deplete endoplasmic reticulum Ca2+ stores. This action was mimicked by Gd3+ ions and 2-aminoethoxydiphenyl borate, two established inhibitors of SOCE, whereas Ca2+ entry was unaffected by the osmotic agent mannitol. Immunohistochemistry demonstrated that iohexol did not prevent CPA-evoked membrane clustering of Orai1, the key pore element of the store-operated Ca2+ channel (SOC) apparatus. In myograph studies with rabbit iliac artery rings, iohexol, and the hexaiodinated dimer iodixanol (both at 90 mg I/mL) attenuated NO-mediated and EDHF-type arterial relaxations evoked by CPA, but did not affect EDHF-type relaxations to acetylcholine, whose principal mode of action is to mobilize Ca2+ via inositol 1,4,5-trisphosphate (InsP3)-induced Ca2+ release. Iohexol also exerted inhibitory effects on NO-mediated relaxation and smooth muscle contraction that were not evident with iodixanol. Conclusions The data support the hypothesis that IRCM induce generalized endothelial dysfunction by inhibiting Ca2+ influx via SOCs rather than their assembly. The presence of organically bound iodine, rather than osmolar effects, may underpin this previously unrecognized phenomenon. In contrast, direct effects of IRCM on smooth muscle function may correlate with osmolarity rather than iodine concentration.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Nitric oxide; EDHF; Iodixanol; Iohexol; Orai1; 2-APB; Gadolinium
Publisher: Elsevier
ISSN: 0008-6363
Last Modified: 06 Feb 2022 10:35

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