Abstract
Flavonoids are naturally occurring food ingredients that have been associated with reduced cardiovascular mortality in epidemiological studies. In a previous study, we demonstrated for the first time that flavonoids are inhibitors of cardiac human ether-à-go-go-related gene (HERG) channels. Furthermore, we observed that grapefruit juice induced mild QTc prolongation in healthy subjects. HERG blockade by grapefruit flavonoid naringenin is most likely to be the mechanism underlying this effect. Therefore, the electrophysiological properties of HERG blockade by naringenin were analysed in detail. HERG potassium currents expressed in Xenopus oocytes were measured with a two-microelectrode voltage clamp. Naringenin blocked HERG potassium channels with an IC50 value of 102.6 μM in Xenopus oocytes. The onset of blockade was fast. The effect was completely reversible upon wash-out. Naringenin binding to HERG required aromatic residue F656 in the putative pore binding site. Channels were blocked in the open and inactivated states but not in the closed states. Naringenin did not affect HERG current activation. However, the half maximal inactivation voltage was shifted by 14.9 mV towards more negative potentials and current inactivation at negative potentials was accelerated. No frequency dependence of blockade was observed. Naringenin inhibits HERG channels with pharmacological characteristics similar to those of well-known HERG antagonists. From a clinical point of view, this effect could have both proarrhythmic and antiarrhythmic consequences. This may have important implications for phytotherapy and for dietary recommendations for cardiologic patients. Therefore, electrophysiological effects of flavonoids deserve further investigation.
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Acknowledgements
This paper was awarded the Rudolph-Fritz-Weiss-Prize 2004 by the German Society of Phytotherapy. The excellent assistance of Klara Gueth and Ramona Bloehs is gratefully acknowledged. This work was supported by grants from the Deutsche Forschungsgemeinschaft Ki 663/1-1 to Dr. Kiehn, KA 1714/1-1 to Dr. Karle, and TH 1120/1-1 to Dr. Thomas, from the Deutsche Stiftung für Herzforschung (project F/10/03) to Dr. Thomas, from the German Cardiac Society (Max Schaldach Research Scholarship) to Dr. Thomas and from the Karl and Veronica Carstens-Stiftung to E. Scholz.
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E. Scholz and E. Zitron contributed equally to this work
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Scholz, E.P., Zitron, E., Kiesecker, C. et al. Inhibition of cardiac HERG channels by grapefruit flavonoid naringenin: implications for the influence of dietary compounds on cardiac repolarisation. Naunyn Schmied Arch Pharmacol 371, 516–525 (2005). https://doi.org/10.1007/s00210-005-1069-z
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DOI: https://doi.org/10.1007/s00210-005-1069-z