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The 5‐HT 2 antagonist ketanserin is an open channel blocker of human cardiac ether‐à‐go‐go ‐related gene (hERG) potassium channels
Author(s) -
Tang Q,
Li ZQ,
Li W,
Guo J,
Sun HY,
Zhang XH,
Lau CP,
Tse HF,
Zhang S,
Li GR
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.261
Subject(s) - herg , ketanserin , potassium channel , pharmacology , cardiac action potential , chemistry , qt interval , potassium channel blocker , long qt syndrome , biophysics , medicine , electrophysiology , repolarization , 5 ht receptor , biology , biochemistry , receptor , serotonin
Background and purpose: Ketanserin, a selective 5‐HT receptor antagonist, prolongs the QT interval of ECG in patients. The purpose of the present study was to determine whether ketanserin would block human cardiac ether‐à‐go‐go ‐related gene (hERG) potassium channels. Experimental approach: Whole‐cell patch voltage‐clamp technique was used to record membrane currents in HEK 293 cells expressing wild type or mutant hERG channel genes. Key results: Ketanserin blocked hERG current ( I hERG ) in a concentration‐dependent manner (IC 50 =0.11 μ M ). The drug showed an open channel blocking property, the block increasing significantly at depolarizing voltages between +10 to +60 mV. Voltage‐dependence for inactivation of hERG channels was negatively shifted by 0.3 μ M ketanserin. A 2.8 fold attenuation of inhibition by elevation of external K + concentration (from 5.0 to 20 m M ) was observed, whereas the inactivation‐deficient mutants S620T and S631A had the IC 50 s of 0.84±0.2 and 1.7±0.4 μ M (7.6 and 15.4 fold attenuation of block). In addition, the hERG mutants in pore helix and S6 also significantly reduced the channel block (2–59 fold) by ketanserin. Conclusions and implications: These results suggest that ketanserin binds to and blocks the open hERG channels in the pore helix and the S6 domain; channel inactivation is also involved in the blockade of hERG channels. Blockade of hERG channels most likely contributes to the prolongation of QT intervals in ECG observed clinically at therapeutic concentrations of ketanserin. British Journal of Pharmacology (2008) 155 , 365–373; doi: 10.1038/bjp.2008.261 ; published online 23 June 2008