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

Abstract

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: ≤ 0.3 mmol/l decreased IM which was preventable by DEPC (modifies histidines). Strikingly Gd3 + ≥ 0.4 mmol/l increased IM and this effect was prevented by cysteine-modifying MTSEA. Linear Gd-DTPA and Magnevist mimicked the effect of ≤ 0.3 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.