Comparison of HERG channel blocking effects of various β-blockers – implication for clinical strategy
Article first published online: 30 JAN 2009
2006 British Pharmacological Society
British Journal of Pharmacology
Volume 147, Issue 6, pages 642–652, March 2006
How to Cite
Kawakami, K., Nagatomo, T., Abe, H., Kikuchi, K., Takemasa, H., Anson, B. D., Delisle, B. P., January, C. T. and Nakashima, Y. (2006), Comparison of HERG channel blocking effects of various β-blockers – implication for clinical strategy. British Journal of Pharmacology, 147: 642–652. doi: 10.1038/sj.bjp.0706508
- Issue published online: 30 JAN 2009
- Article first published online: 30 JAN 2009
- (Received August 26, 2005, Revised October 18, 2005, Accepted October 23, 2005)
- ion channels;
- K+ channel;
- membrane currents;
- long QT syndrome;
- heart failure;
- HEK293 cells
β-Blockers are widely used in the treatment of cardiovascular diseases. However, their effects on HERG channels at comparable conditions remain to be defined. We investigated the direct acute effects of β-blockers on HERG current and the molecular basis of drug binding to HERG channels with mutations of putative common binding site (Y652A and F656C).
β-Blockers were selected based on the receptor subtype. Wild-type, Y652A and F656C mutants of HERG channel were stably expressed in HEK293 cells, and the current was recorded by using whole-cell patch-clamp technique (23°C).
Carvedilol (nonselective), propranolol (nonselective) and ICI 118551 (β2-selective) inhibited HERG current in a concentration-dependent manner (IC50 0.51, 3.9 and 9.2 μM, respectively). The IC50 value for carvedilol was a clinically relevant concentration. High metoprolol (β1-selective) concentrations were required for blockade (IC50 145 μM), and atenolol (β1-selective) did not inhibit the HERG current.
Inhibition of HERG current by carvedilol, propranolol and ICI 118551 was partially but significantly attenuated in Y652A and F656C mutant channels. Affinities of metoprolol to Y652A and F656C mutant channels were not different compared with the wild-type.
HERG current block by all β-blockers was not frequency-dependent.
Drug affinities to HERG channels were different in β-blockers. Our results provide additional strategies for clinical usage of β-blockers. Atenolol and metoprolol may be preferable for patients with type 1 and 2 long QT syndrome. Carvedilol has a class III antiarrhythmic effect, which may provide the rationale for a favourable clinical outcome compared with other β-blockers as suggested in the recent COMET (Carvedilol Or Metoprolol European Trial) substudy.
British Journal of Pharmacology (2006) 147, 642–652. doi:10.1038/sj.bjp.0706508