Format

Send to

Choose Destination
Br J Pharmacol. 1999 May;127(1):243-51.

Inhibition of HERG channels stably expressed in a mammalian cell line by the antianginal agent perhexiline maleate.

Author information

1
Department of Clinical Pharmacology, University of New South Wales, Victor Chang Cardiac Research Institute, St Vincent's Hospital, Darlinghurst, Australia. b.walker@garvan.unsw.edu.au

Abstract

Perhexiline has been used as an anti-anginal agent for over 25 years, and is known to cause QT prolongation and torsades de pointes. We hypothesized that the cellular basis for these effects was blockade of I(Kr). A stable transfection of HERG into a CHO-K1 cell line produced a delayed rectifier, potassium channel with similar properties to those reported for transient expression in Xenopus oocytes. Perhexiline caused voltage- and frequency-dependent block of HERG (IC50 7.8 microM). The rate of inactivation was increased and there was a 10 mV hyperpolarizing shift in the voltage-dependence of steady-state inactivation, suggestive of binding to the inactivated state. In conclusion, perhexiline potently inhibits transfected HERG channels and this is the probable mechanism for QT prolongation and torsades de pointes. Channel blockade shows greatest affinity for the inactivated state.

PMID:
10369479
PMCID:
PMC1565989
DOI:
10.1038/sj.bjp.0702502
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center