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

4-Aminopyridine (4-AP) has been used extensively to study transient outward K+ current (I-TO,I-1) in cardiac cells and tissues. We report here inhibition by 4-AP of HERG (the human ether-a-go-go-related gene) K+ channels expressed in a mammalian cell line, at concentrations relevant to those used to study I-TO,I-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 similar to59%. It also significantly prolonged action potentials and inhibited resurgent I-K tails from guinea-pig isolated ventricular myocytes, which lack an I-TO,I-1. We conclude that by blocking the alpha-subunit of the I-Kr channel, millimolar concentrations of 4-AP can modulate ventricular repolarisation independently of any action on I-TO,I-1.