Inhibition of HERG K+ Current and Prolongation of the Guinea-Pig Ventricular Action Potential by 4-Aminopyridine |
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Authors: | J. M. Ridley J. T. Milnes Y. H. Zhang H. J. Witchel J. C. Hancox |
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Affiliation: | Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK |
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Abstract: | 4-Aminopyridine (4-AP) has been used extensively to study transient outward K+ current ( I TO,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 I TO,1. Under voltage clamp, whole cell HERG current ( I HERG) tails following commands to +30 mV were blocked with an IC50 of 4.4 ± 0.5 m m . Development of block was contingent upon HERG channel gating, with a preference for activated over inactivated channels. Treatment with 5 m m 4-AP inhibited peak I HERG during an applied action potential clamp waveform by ∼59 %. It also significantly prolonged action potentials and inhibited resurgent I K tails from guinea-pig isolated ventricular myocytes, which lack an I TO,1. We conclude that by blocking the α-subunit of the I Kr channel, millimolar concentrations of 4-AP can modulate ventricular repolarisation independently of any action on I TO,1. |
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