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First published online on May 9, 2003.
 Copyright © 2003 by The Physiological Society
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Received March 27, 2003
Accepted after revision May 1, 2003

Inhibition of HERG K+ current and prolongation of the guinea-pig ventricular action potential by 4-aminopyridine

J.M. Ridley1, J.T. Milnes1, Y.H. Zhang1, H.J. Witchel1, and J. C. Hancox1*

1 Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK

* To whom correspondence should be addressed. E-mail: jules.hancox{at}bristol.ac.uk.

4-Aminopyridine (4-AP) has been used extensively to study transient outward K+ current (ITO,1) in cardiac cells and tissues. We report here inhibition by 4-AP of HERG (the human ether-à-go-go-related gene) K+ channels expressed in a mammalian cell line, at concentrations relevant to those used to study ITO,1. Under voltage clamp, whole cell HERG current (IHERG) tails following commands to +30 mV were blocked with an IC50 of 4.4 ± 0.5 mM. Development of block was contingent upon HERG channel gating, with a preference for activated over inactivated channels. Treatment with 5 mM 4-AP inhibited peak IHERG during an applied action potential clamp waveform by ~59 %. It also significantly prolonged action potentials and inhibited resurgent IK tails from guinea-pig isolated ventricular myocytes, which lack an ITO,1. We conclude that by blocking the {alpha}-subunit of the IKr channel, millimolar concentrations of 4-AP can modulate ventricular repolarisation independently of any action on ITO,1.




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