Skip Navigation

Cardiovascular Research 2003 57(3):651-659; doi:10.1016/S0008-6363(02)00774-5
© 2003 by European Society of Cardiology
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Ishii, K.
Right arrow Articles by Endoh, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ishii, K.
Right arrow Articles by Endoh, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2003, European Society of Cardiology

Dissociation of E-4031 from the HERG channel caused by mutations of an amino acid results in greater block at high stimulation frequency

Kuniaki Ishii*, Mirei Nagai, Masahiro Takahashi and Masao Endoh

Department of Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan

* Corresponding author. Tel.: +81-23-628-5234; fax: +81-23-628-5235. kuishii{at}med.id.yamagata-u.ac.jp

Objective: We have reported identification of the amino acid whose mutation reduces effects of quinidine on the HERG channel. Although the residue (isoleucine at 647) is not in the recently reported methanesulfonanilide binding site, a single concentration of E-4031 (10 µM) was less effective to I647 mutant channels than wild type HERG channel. We designed the present experiment to further investigate influence of mutations at 647 on the effects of methanesulfonanilides. Methods and results: HERG channels were expressed in Xenopus oocytes and their currents were measured by a two-microelectrode voltage clamp method. Of the two mutations initially studied (I647A and I647F), the I647F had a greater influence and differentially affected the effects of dofetilide and E-4031. The IC50 for dofetilide of the two mutant channels (I647A and I647F) was increased only 2-fold, but the IC50 for E-4031 was increased 6-fold (I647A) and 14-fold (I647F). Aromatic residues other than phenylalanine were then substituted for I647, and found to reduce the effects of E-4031. Whereas E-4031 dissociated from the mutant channels during rested state, dofetilide little dissociated. The mutant channels that showed recovery from E-4031 block were inhibited greater at 1 Hz than at 0.1 Hz. Conclusions: The present results indicate that dissociation of a drug from the HERG channel results in greater block at high frequency. Although the mechanism by which the mutations cause the dissociation of E-4031 is uncertain, it is noteworthy that one methanesulfonanilide dissociates from the channel more easily than another.

KEYWORDS Antiarrhythmic agents; Arrhythmia (mechanisms); K-channel; Long QT syndrome


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.