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

Background: Gadolinium-based-contrast-agents (GBCAs) are used for magnetic-resonance-imaging and associated with renal and cardiovascular adverse reactions caused by released Gd ions. Gd 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 Gd from GBCAs causing the above-mentioned adverse reactions. Therefore this study examined the effect of Gd and GBCAs on ENaC's activity.

Methods: Human αβγENaC was expressed in Xenopus laevis oocytes and exposed to Gd, linear (Gd-DTPA, Magnevist) or cyclic (Dotarem) GBCAs. Transmembrane ion-currents (I) were recorded by the two-electrode-voltage-clamp technique and Gd-release by Gd-DTPA was confirmed by inductively coupled plasma-mass spectrometry.

Results: Gd exerts biphasic effects on ENaC's activity: ≤0.3mmol/l decreased I which was preventable by DEPC (modifies histidines). Strikingly Gd≥0.4mmol/l increased I and this effect was prevented by cysteine-modifying MTSEA. Linear Gd-DTPA and Magnevist mimicked the effect of ≤0.3mmol/l Gd, whereas the chelator DTPA showed no effect. Gd and Gd-DTPA increased the IC for amiloride, but did not affect ENaC's self-inhibition. Interestingly, cyclic Gd-DOTA (Dotarem) increased I to a similar extent as its chelator DOTA, suggesting that the chelator rather than released Gd is responsible for this effect.

Conclusion: These results confirm Gd-release from linear Gd-DTPA and indicate that the released Gd amount is sufficient to interfere with ENaC's activity to provide putative explanations for GBCA-related adverse effects.