HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 586/12/2961    most recent jphysiol.2007.150367v2 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kurokawa, J. Articles by Furukawa, T. Search for Related Content PubMed PubMed Citation Articles by Kurokawa, J. Articles by Furukawa, T. Related Collections Cardiovascular Related Article

¹ Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan
² Department of Pharmacology, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan
³ Department of Biochemistry, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan

Female gender is a risk factor for drug-induced arrhythmias associated with QT prolongation, which results mostly from blockade of the human ether-a-go-go-related gene (hERG) channel. Some clinical evidence suggests that oestrogen is a determinant of the gender-differences in drug-induced QT prolongation and baseline QT_C intervals. Although the chronic effects of oestrogen have been studied, it remains unclear whether the gender differences are due entirely to transcriptional regulations through oestrogen receptors. We therefore investigated acute effects of the most bioactive oestrogen, 17β-oestradiol (E2) at its physiological concentrations on cardiac repolarization and drug-sensitivity of the hERG (I_Kr) channel in Langendorff-perfused guinea pig hearts, patch-clamped guinea pig cardiomyocytes and culture cells over-expressing hERG. We found that physiological concentrations of E2 partially suppressed I_Kr in a receptor-independent manner. E2-induced modification of voltage-dependence causes partial suppression of hERG currents. Mutagenesis studies showed that a common drug-binding residue at the inner pore cavity was critical for the effects of E2 on the hERG channel. Furthermore, E2 enhanced both hERG suppression and QT_C prolongation by its blocker, E4031. The lack of effects of testosterone at its physiological concentrations on both of hERG currents and E4031-sensitivity of the hERG channel implicates the critical role of aromatic centroid present in E2 but not in testosterone. Our data indicate that E2 acutely affects the hERG channel gating and the E4031-induced QT_C prolongation, and may provide a novel mechanism for the higher susceptibility to drug-induced arrhythmia in women.

(Received 20 December 2007; accepted after revision 23 April 2008; first published online 25 April 2008)
Corresponding author J. Kurokawa: Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan. Email: junkokuro.bip{at}mri.tmd.ac.jp

Related Article

Male and female equality: still far from goal

Liliana Sintra Grilo and Hugues Abriel
J. Physiol. 2008 586: 2825-2826. [Full Text] [PDF]

This article has been cited by other articles:

				L. S. Grilo and H. Abriel Male and female equality: still far from goal J. Physiol., June 15, 2008; 586(12): 2825 - 2826. [Full Text] [PDF]