Biochim Biophys Acta Biomembr 2017 May 01;18595:1040-1048. doi: 10.1016/j.bbamem.2017.02.019.

Gadolinium released by the linear gadolinium-based contrast-agent Gd-DTPA decreases the activity of human epithelial Na+ channels (ENaCs).

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BACKGROUND: 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. METHODS: 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. RESULTS: Gd3+ exerts biphasic effects on ENaC's activity: ≤0.3mmol/l decreased IM which was preventable by DEPC (modifies histidines). Strikingly Gd3+≥0.4mmol/l increased IM and 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 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.

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