Comparison of HERG channel blocking effects of various β ‐blockers – implication for clinical strategy

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 ( β 2 ‐selective) inhibited HERG current in a concentration‐dependent manner (IC 50 0.51, 3.9 and 9.2  μ M , respectively). The IC 50 value for carvedilol was a clinically relevant concentration. High metoprolol ( β 1 ‐selective) concentrations were required for blockade (IC 50 145  μ M ), and atenolol ( β 1 ‐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