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Differential Effects of the β-Adrenoceptor Blockers Carvedilol and Metoprolol on SQT1- and SQT2-Mutant Channels

Authors


  • This research was supported by the German Research Foundation (DFG; BR 2107/4-1) to Dr. M. Brunner and Dr. K. E. Odening and by the “Margarete von Wrangell Habilitation Program” by the Ministry of Sciences, Research, and Arts in Baden Württemberg and the European Social Fund to Dr. K. E. Odening.

  • No disclosures.

Address for correspondence: Katja E. Odening, M.D., Heart Center Freiburg University, Department of Cardiology and Angiology I, Hugstetter Str. 55, 79106 Freiburg, Germany. Fax: 49-761-270-70450; E-mail: katja.odening@uniklinik-freiburg.de

β-Blocker Effects on SQTS-Mutant K+ Channels

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.

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