title: Comparison of HERG channel blocking effects of various beta-blockers-- implication for clinical strategy.
abstract: beta-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 beta-blockers on HERG current and the molecular basis of drug binding to HERG channels with mutations of putative common binding site (Y652A and F656C). beta-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 degrees C). Carvedilol (nonselective), propranolol (nonselective) and ICI 118551 (beta(2)-selective) inhibited HERG current in a concentration-dependent manner (IC(50) 0.51, 3.9 and 9.2 microM, respectively). The IC(50) value for carvedilol was a clinically relevant concentration. High metoprolol (beta(1)-selective) concentrations were required for blockade (IC(50) 145 microM), and atenolol (beta(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 beta-blockers was not frequency-dependent. Drug affinities to HERG channels were different in beta-blockers. Our results provide additional strategies for clinical usage of beta-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 beta-blockers as suggested in the recent COMET (Carvedilol Or Metoprolol European Trial) substudy.
authors.affiliation: Second Department of Internal Medicine, University of Occupational and Environmental Health Japan, 1-1 Iseigaoka, Kitakyushu 807-8555, Japan.
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Kawakami
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Nagatomo
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Abe
authors.forename: Kan
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Takemasa
authors.forename: Blake D
authors.initials: BD
authors.lastname: Anson
authors.forename: Brian P
authors.initials: BP
authors.lastname: Delisle
authors.forename: Craig T
authors.initials: CT
authors.lastname: January
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Nakashima
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D002227:Carbazoles / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000150:complications / Q000188:drug therapy; D000077261:Carvedilol; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008133:Long QT Syndrome / Q000150:complications / Q000188:drug therapy; D008564:Membrane Potentials / Q000187:drug effects; D008790:Metoprolol / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D009154:Mutation; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011433:Propranolol / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D014162:Transfection
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D011412:Propanolamines; D000077261:Carvedilol; C026777:ICI 118551; D011433:Propranolol; D008790:Metoprolol