Inhibition of HERG K+ Current and Prolongation of the Guinea‐Pig Ventricular Action Potential by 4‐Aminopyridine

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Abstract
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 α‐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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