title: Gadolinium released by the linear gadolinium-based contrast-agent Gd-DTPA decreases the activity of human epithelial Na+channels (ENaCs).
abstract: Gadolinium-based-contrast-agents (GBCAs) are used for magnetic-resonance-imaging and associated with renal and cardiovascular adverse reactions caused by released Gd3+ions. Gd3+is also a modulator of mechano-gated ion channels, including the epithelial Na+channel (ENaC) that is expressed in kidney epithelium and the vasculature. ENaC is important for salt-/water homeostasis and blood pressure regulation and a likely target of released Gd3+from GBCAs causing the above-mentioned adverse reactions. Therefore this study examined the effect of Gd3+and GBCAs on ENaC's activity.
  
  
  
  Human αβγENaC was expressed in Xenopus laevis oocytes and exposed to Gd3+, linear (Gd-DTPA, Magnevist) or cyclic (Dotarem) GBCAs. Transmembrane ion-currents (IM) were recorded by the two-electrode-voltage-clamp technique and Gd3+-release by Gd-DTPA was confirmed by inductively coupled plasma-mass spectrometry.
  
  
  
  Gd3+exerts biphasic effects on ENaC's activity: ≤0.3mmol/l decreased IMwhich was preventable by DEPC (modifies histidines). Strikingly Gd3+≥0.4mmol/l increased IMand this effect was prevented by cysteine-modifying MTSEA. Linear Gd-DTPA and Magnevist mimicked the effect of ≤0.3mmol/l Gd3+, whereas the chelator DTPA showed no effect. Gd3+and Gd-DTPA increased the IC50for amiloride, but did not affect ENaC's self-inhibition. Interestingly, cyclic Gd-DOTA (Dotarem) increased IMto a similar extent as its chelator DOTA, suggesting that the chelator rather than released Gd3+is responsible for this effect.
  
  
  
  These results confirm Gd3+-release from linear Gd-DTPA and indicate that the released Gd3+amount is sufficient to interfere with ENaC's activity to provide putative explanations for GBCA-related adverse effects.
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Justus-Liebig-University Giessen, Aulweg 130, 35392 Giessen, Germany.
authors.forename: Fenja
authors.initials: F
authors.lastname: Knoepp
authors.affiliation: Department of Physical and Analytical Chemistry, University of Oviedo, C/ Julián Clavería 8, 33006 Oviedo, Spain.
authors.forename: Joerg
authors.initials: J
authors.lastname: Bettmer
authors.affiliation: Department of Physiology, University of Otago, PO Box 913, Dunedin 9054, New Zealand. Electronic address: martin.fronius@otago.ac.nz.
authors.forename: Martin
authors.initials: M
authors.lastname: Fronius
mesh_terms: D000818:Animals; D001665:Binding Sites; D003287:Contrast Media / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D053503:Epithelial Sodium Channels / Q000187:drug effects*; D005682:Gadolinium / Q000009:adverse effects; D019786:Gadolinium DTPA / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D014982:Xenopus laevis
chemical_list: D003287:Contrast Media; D053503:Epithelial Sodium Channels; D005682:Gadolinium; D019786:Gadolinium DTPA
keywords: Epithelial Na(+) channel (ENaC); Gadolinium; Gadolinium-based contrast-agent; Gd-DTPA; Magnet resonance imaging