Abstract
Our objective was to investigate whether alterations in endothelial Ca(2+) 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. The triiodinated monomer iohexol caused concentration-dependent reductions in store-operated Ca(2+) entry (SOCE) in rabbit aortic valve endothelium incubated in Ca(2+)-free buffer with cyclopiazonic acid (CPA, 30 microM) to deplete endoplasmic reticulum Ca(2+) stores. This action was mimicked by Gd(3+) ions and 2-aminoethoxydiphenyl borate, two established inhibitors of SOCE, whereas Ca(2+) 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 Ca(2+) 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 Ca(2+) via inositol 1,4,5-trisphosphate (InsP(3))-induced Ca(2+) release. Iohexol also exerted inhibitory effects on NO-mediated relaxation and smooth muscle contraction that were not evident with iodixanol. The data support the hypothesis that IRCM induce generalized endothelial dysfunction by inhibiting Ca(2+) 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.
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