Abstract
Aim:
To compare the effects of two stereoisomeric forms of glycyrrhetinic acid on different components of Na+ current, HERG and Kv1.5 channel currents.
Methods:
Wild-type (WT) and long QT syndrome type 3 (LQT-3) mutant ΔKPQ Nav1.5 channels, as well as HERG and Kv1.5 channels were expressed in Xenopus oocytes. In addition, isolated human atrial myocytes were used. Two-microelectrode voltage-clamp technique was used to record the voltage-activated currents.
Results:
Superfusion of 18β-glycyrrhetinic acid (18β-GA, 1–100 μmol/L) blocked both the peak current (INa,P) and late current (INa,L) generated by WT and ΔKPQ Nav1.5 channels in a concentration-dependent manner, while 18α-glycyrrhetinic acid (18α-GA) at the same concentrations had no effects. 18β-GA preferentially blocked INa,L (IC50=37.2±14.4 μmol/L) to INa,P (IC50=100.4±11.2 μmol/L) generated by ΔKPQ Nav1.5 channels. In human atrial myocytes, 18β-GA (30 μmol/L) inhibited 47% of INa,P and 87% of INa,L induced by Anemonia sulcata toxin (ATX-II, 30 nmol/L). Superfusion of 18β-GA (100 μmol/L) had no effects on HERG and Kv1.5 channel currents.
Conclusion:
18β-GA preferentially blocked the late Na current without affecting HERG and Kv1.5 channels.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No 30971243, 81170164 to Dr Yi-mei DU, No 30872542 to Dr Jia-hong XIA) and the Open Foundation of Hubei Key Laboratory of Biological Targeted Therapy No 2010-79 to Dr Cheng-kun XIA.
We thank Drs Thomas ZIMMER (Friedrich Schiller University, Germany), Michael C SANGUINETTI (University of Utah, USA) and Maria L GARCIA (Merck & Co, Inc, USA) for generously providing the cDNA plasmid vector.
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Supplementary figure is available at the Acta Pharmacologica Sinica website.
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Supplementary information, Figure 1S
Effects of 18β-GA on the kinetics of INa,P of WT and ΔKPQ Nav1.5 channels. (PDF 162 kb)
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Du, Ym., Xia, Ck., Zhao, N. et al. 18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels. Acta Pharmacol Sin 33, 752–760 (2012). https://doi.org/10.1038/aps.2012.22
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DOI: https://doi.org/10.1038/aps.2012.22
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