title: Differential effects of the β-adrenoceptor blockers carvedilol and metoprolol on SQT1- and SQT2-mutant channels.
abstract: BACKGROUND
  N588K-KCNH2 and V307L-KCNQ1 mutations lead to a gain-of-function of IKr and IKs thus causing short-QT syndromes (SQT1, SQT2). Combined pharmacotherapies using K(+) -channel-blockers and β-blockers are effective in SQTS. Since β-blockers can block IKr and IKs , we aimed at determining carvedilol's and metoprolol's electrophysiological effects on N588K-KCNH2 and V307L-KCNQ1 channels.
  
  
  METHODS
  Wild-type (WT)-KCNH2, WT-KCNQ1 and mutant N588K-KCNH2 and V307L-KCNQ1 channels were expressed in CHO-K1 or HEK-293T cells and IKs and IKr were recorded at baseline and during β-blocker exposure.
  
  
  RESULTS
  Carvedilol (10 μM) reduced IKs tail in WT- and V307L-KCNQ1 by 36.5 ± 5% and 18.6 ± 9% (P < 0.05). IC50 values were 16.3 μM (WT) and 46.1 μM (V307L), indicating a 2.8-fold decrease in carvedilol's IKs -blocking potency in V307L-KCNQ1. Carvedilol's (1 μM) inhibition of the IKr tail was attenuated in N588K-KCNH2 (4.5 ± 3% vs 50.3 ± 4%, WT, P < 0.001) with IC50 values of 2.8 μM (WT) and 25.4 μM (N588K). Carvedilol's IKr end-pulse inhibition, however, was increased in N588K-KCNH2 (10 μM, 60.7 ± 6% vs 36.5 ± 5%, WT, P < 0.01). Metoprolol (100 μM) reduced IKr end-pulse by 0.23 ± 3% (WT) and 74.1 ± 7% (N588K, P < 0.05), IKr tail by 32.9 ± 10% (WT) and 68.8 ± 7% (N588K, P < 0.05), and reduced IKs end-pulse by 18.3 ± 5% (WT) and 57.1 ± 11% (V307L, P < 0.05) and IKs tail by 3.3 ± 1% (WT) and 45.1 ± 13 % (V307L, P < 0.05), indicating an increased sensitivity to metoprolol in SQT mutated channels.
  
  
  CONCLUSIONS
  N588K-KCNH2 and V307L-KCNQ1 mutations decrease carvedilol's inhibition of the IKs or IKr tail but increase carvedilol's IKr end-pulse inhibition and metoprolol's inhibition of tail and end-pulse currents. These different effects on SQT1 and SQT2 mutated channels should be considered when using β-blocker therapy in SQTS patients.
authors.affiliation: Heart Center Freiburg University, Department of Cardiology and Angiology I, Freiburg, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Bodi
authors.forename: Gerlind
authors.initials: G
authors.lastname: Franke
authors.forename: Naga Deepa
authors.initials: ND
authors.lastname: Pantulu
authors.forename: Kezhong
authors.initials: K
authors.lastname: Wu
authors.forename: Stefanie
authors.initials: S
authors.lastname: Perez-Feliz
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Manfred
authors.initials: M
authors.lastname: Zehender
authors.forename: Axel
authors.initials: A
authors.lastname: zur Hausen
authors.forename: Michael
authors.initials: M
authors.lastname: Brunner
authors.forename: Katja E
authors.initials: KE
authors.lastname: Odening
mesh_terms: D000200:Action Potentials; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006329:Heart Conduction System / Q000002:abnormalities* / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008790:Metoprolol / Q000494:pharmacology*; D009154:Mutation; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D026902:Potassium Channel Blockers; D011412:Propanolamines; D000077261:Carvedilol; D008790:Metoprolol; D011188:Potassium
keywords: beta-adrenergic blocker; carvedilol; metoprolol; potassium current; short-QT syndrome