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

J. M. Ridley, J. T. Milnes, Y. H. Zhang, H. J. Witchel and J. C. Hancox

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 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 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 -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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