Abstract
Background: Gadolinium-based-contrast-agents (GBCA5) 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 GBCA5 on ENaC's activity.
Methods: Human alpha beta gamma ENaC was expressed in Xenopus laevis oocytes and exposed to Gd3+, linear (Gd-DTPA, Magnevist) or cyclic (Dotarem) GBCAs. Transmembrane ion-currents (I-M) were recorded by the two-electrode -voltage-clamp technique and Gd3+-release by Gd-DTPA was confirmed by inductively coupled plasma mass spectrometry.
Results: Gd3+ exerts biphasic effects on ENaC's activity: :<= 0.3 mmol/l decreased IM which was preventable by DEPC (modifies histidines). Strikingly Gd3+ >= 0.4 mmol/l increased I-M and this effect was prevented by cysteine-modifying MTSEA. Linear Gd-DTPA and Magnevist mimicked the effect of 550.3 mmol/l Gd3+, whereas the chelator DTPA showed no effect. Gd3+ and Gd-DTPA increased the IC50 for amiloride, but did not affect ENaC's self-inhibition. Interestingly, cyclic Gd-DOTA (Dotarem) increased IM to a similar extent as its chelator DOTA, suggesting that the chelator rather than released Gd3+ is responsible for this effect.
Conclusion: 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. (C) 2017 Elsevier B.V. All rights reserved.